The Drosophila hnRNP F/H homolog glorund uses two distinct RNA-binding modes to diversify target recognition

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

Tamayo, Joel V.; Teramoto, Takamasa; Chatterjee, Seema

The Drosophila hnRNP F/H homolog, Glorund (Glo), regulates nanos mRNA translation by interacting with a structured UA-rich motif in the nanos 3' untranslated region. Glo regulates additional RNAs, however, and mammalian homologs bind G-tract sequences to regulate alternative splicing, suggesting that Glo also recognizes G-tract RNA. To gain insight into how Glo recognizes both structured UA-rich and G-tract RNAs, we used mutational analysis guided by crystal structures of Glo’s RNA-binding domains and identified two discrete RNA-binding surfaces that allow Glo to recognize both RNA motifs. By engineering Glo variants that favor a single RNA-binding mode, we show that a subsetmore » of Glo’s functions in vivo is mediated solely by the G-tract binding mode, whereas regulation of nanos requires both recognition modes. Lastly, our findings suggest a molecular mechanism for the evolution of dual RNA motif recognition in Glo that may be applied to understanding the functional diversity of other RNA-binding proteins.« less

Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action

EPA Science Inventory

Knowledge of possible toxic mechanisms/modes of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, such as reducing uncertainties related to extrapolation across species, endpoints and chemical structure. However,...

Reflections on a study tour to explore history taking and physical assessment education.

PubMed

Rushforth, Helen

2008-01-01

In 2005 a study tour, funded by a Florence Nightingale Foundation Travel Scholarship, was undertaken by the author to gain insight into the teaching of 'History Taking and Physical Assessment' (HTPA) across different countries of the UK and beyond. The study tour was inspired by recent developments in health professional practice, which increasingly require nurses and other health care professionals to undertake the skills of history taking, inspection, palpation, percussion and auscultation. The study tour visit included 16 Universities across the UK, Eire, Canada and the United States. Insights were gained into similarities and differences in the content and structure of HTPA courses across the centres visited, with valuable observations in respect of mental health assessment and optimal session ordering. Insights into modes of delivery reinforced perceptions regarding the value of theory, demonstration and small group supervised practice, and highlighted interesting issues for debate in respect of course text options, videotaped demonstrations, electronic learning support programmes and use of mannequins. Consideration of assessment issues focused in particular on the value and design of Objective Structured Clinical Examination (OSCE) as a core mode of assessment. Wider insights gained in relation to HTPA included suggestions of the need for its cautious use in preregistration education. There is also debate regarding the teaching of HTPA within advanced practitioner preparation. Throughout the report, current and planned changes to local practice inspired by the study tour and underpinning literature are identified, alongside several recommendations for further research.

New insights on boundary plasma turbulence and the Quasi-Coherent Mode in Alcator C-Mod using a Mirror Langmuir Probe

NASA Astrophysics Data System (ADS)

Labombard, Brian

2013-10-01

A ``Mirror Langmuir Probe'' (MLP) diagnostic has been used to interrogate edge plasma profiles and turbulence in Alcator C-Mod with unprecedented detail, yielding fundamental insights on the Quasi-Coherent Mode (QCM) - a mode that regulates plasma density and impurities in EDA H-modes without ELMs. The MLP employs a fast-switching, self-adapting bias scheme, recording density, electron temperature and plasma potential simultaneously at high bandwidth (~1 MHz) on each of four separate electrodes on a scanning probe. Temporal dynamics are followed in detail; wavenumber-frequency spectra and phase relationships are readily deduced. Poloidal field fluctuations are recorded separately with a two-coil, scanning probe. Results from ohmic L-mode and H-mode plasmas are reported, including key observations of the QCM: The QCM lives in a region of positive radial electric field, with a mode width (~3 mm) that spans open and closed field line regions. Remarkably large amplitude (~30%), sinusoidal bursts in density, electron temperature and plasma potential fluctuations are observed that are in phase; potential lags density by at most 10 degrees. Propagation velocity of the mode corresponds to the sum of local E × B and electron diamagnetic drift velocities - quantities that are deduced directly from time-averaged profiles. Poloidal magnetic field fluctuations project to parallel current densities of ~5 amps/cm2 in the mode layer, with significant parallel electromagnetic induction. Electron force balance is examined, unambiguously identifying the mode type. It is found that fluctuations in parallel electron pressure gradient are roughly balanced by the sum of electrostatic and electromotive forces. Thus the primary mode structure of the QCM is that of a drift-Alfven wave. Work supported by US DoE award DE-FC02-99ER54512.

Direct writing of tunable multi-wavelength polymer lasers on a flexible substrate.

PubMed

Zhai, Tianrui; Wang, Yonglu; Chen, Li; Zhang, Xinping

2015-08-07

Tunable multi-wavelength polymer lasers based on two-dimensional distributed feedback structures are fabricated on a transparent flexible substrate using interference ablation. A scalene triangular lattice structure was designed to support stable tri-wavelength lasing emission and was achieved through multiple exposure processes. Three wavelengths were controlled by three periods of the compound cavity. Mode competition among different cavity modes was observed by changing the pump fluence. Both a redshift and blueshift of the laser wavelength could be achieved by bending the soft substrate. These results not only provide insight into the physical mechanisms behind co-cavity polymer lasers but also introduce new laser sources and laser designs for white light lasers.

Mode decomposition and Lagrangian structures of the flow dynamics in orbitally shaken bioreactors

NASA Astrophysics Data System (ADS)

Weheliye, Weheliye Hashi; Cagney, Neil; Rodriguez, Gregorio; Micheletti, Martina; Ducci, Andrea

2018-03-01

In this study, two mode decomposition techniques were applied and compared to assess the flow dynamics in an orbital shaken bioreactor (OSB) of cylindrical geometry and flat bottom: proper orthogonal decomposition and dynamic mode decomposition. Particle Image Velocimetry (PIV) experiments were carried out for different operating conditions including fluid height, h, and shaker rotational speed, N. A detailed flow analysis is provided for conditions when the fluid and vessel motions are in-phase (Fr = 0.23) and out-of-phase (Fr = 0.47). PIV measurements in vertical and horizontal planes were combined to reconstruct low order models of the full 3D flow and to determine its Finite-Time Lyapunov Exponent (FTLE) within OSBs. The combined results from the mode decomposition and the FTLE fields provide a useful insight into the flow dynamics and Lagrangian coherent structures in OSBs and offer a valuable tool to optimise bioprocess design in terms of mixing and cell suspension.

A Locally Modal B-Spline Based Full-Vector Finite-Element Method with PML for Nonlinear and Lossy Plasmonic Waveguide

NASA Astrophysics Data System (ADS)

Karimi, Hossein; Nikmehr, Saeid; Khodapanah, Ehsan

2016-09-01

In this paper, we develop a B-spline finite-element method (FEM) based on a locally modal wave propagation with anisotropic perfectly matched layers (PMLs), for the first time, to simulate nonlinear and lossy plasmonic waveguides. Conventional approaches like beam propagation method, inherently omit the wave spectrum and do not provide physical insight into nonlinear modes especially in the plasmonic applications, where nonlinear modes are constructed by linear modes with very close propagation constant quantities. Our locally modal B-spline finite element method (LMBS-FEM) does not suffer from the weakness of the conventional approaches. To validate our method, first, propagation of wave for various kinds of linear, nonlinear, lossless and lossy materials of metal-insulator plasmonic structures are simulated using LMBS-FEM in MATLAB and the comparisons are made with FEM-BPM module of COMSOL Multiphysics simulator and B-spline finite-element finite-difference wide angle beam propagation method (BSFEFD-WABPM). The comparisons show that not only our developed numerical approach is computationally more accurate and efficient than conventional approaches but also it provides physical insight into the nonlinear nature of the propagation modes.

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations.

PubMed

De Simone, Giuseppina; Langella, Emma; Esposito, Davide; Supuran, Claudiu T; Monti, Simona Maria; Winum, Jean-Yves; Alterio, Vincenzo

2017-12-01

Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure of hCA II in complex with a sulphamate inhibitor incorporating a nitroimidazole moiety. The comparison with the structure of hCA II in complex with its sulphamide analogue revealed that the two inhibitors adopt a completely different binding mode within the hCA II active site. Starting from these results, we performed a theoretical study on sulphamate and sulphamide derivatives, demonstrating that electrostatic interactions with residues within the enzyme active site play a key role in determining their binding conformation. These findings open new perspectives in the design of effective CAIs using the sulphamate and sulphamide zinc binding groups as lead compounds.

Low frequency mechanical modes of viruses with atomic detail

NASA Astrophysics Data System (ADS)

Dykeman, Eric; Sankey, Otto

2008-03-01

The low frequency mechanical modes of viruses can provide important insights into the large global motions that a virus may exhibit. Recently it has been proposed that these large global motions may be excited using impulsive stimulated Raman scattering producing permanent damage to the virus. In order to understand the coupling of external probes to the capsid, vibrational modes with atomic detail are essential. The standard approach to find the atomic modes of a molecule with N atoms requires the formation and diagonlization of a 3Nx3N matrix. As viruses have 10^5 or more atoms, the standard approach is difficult. Using ideas from electronic structure theory, we have developed a method to construct the mechanical modes of large molecules such as viruses with atomic detail. Application to viruses such as the cowpea chlorotic mottle virus, satellite tobacco necrosis virus, and M13 bacteriophage show a fairly complicated picture of the mechanical modes.

Liquid crystal mediated active nano-plasmonic based on the formation of hybrid plasmonic-photonic modes

NASA Astrophysics Data System (ADS)

Mehrzad, Hossein; Mohajerani, Ezeddin

2018-02-01

The present study aims to demonstrate how active hybrid nano-plasmonic modes become excited due to the coupling of localized plasmonic resonance and Fabry-Perot (FP) optical modes. The proposed structure includes an integration of a micro-cavity filled with liquid crystals with high anisotropy and a layer of gold nanoislands (NIs). The optical absorption of NI is controllably discretized to the narrow-width modes, called "hybrid modes (HM)," due to the interplay between FP and plasmonic modes. HM could demonstrate a strongly intensified and diminished absorption, compared to the absorption of the bare gold layer. Based on the active plasmonic experiments, the HM boosted the figure of merit related to activation capability up to 40 times and subsequently experienced impressive spectral shifts, leading to very wavelength-selective changes. The theoretical simulation of the HM is provided to suggest relevant insights into the experimental results.

Distributed collaborative probabilistic design of multi-failure structure with fluid-structure interaction using fuzzy neural network of regression

NASA Astrophysics Data System (ADS)

Song, Lu-Kai; Wen, Jie; Fei, Cheng-Wei; Bai, Guang-Chen

2018-05-01

To improve the computing efficiency and precision of probabilistic design for multi-failure structure, a distributed collaborative probabilistic design method-based fuzzy neural network of regression (FR) (called as DCFRM) is proposed with the integration of distributed collaborative response surface method and fuzzy neural network regression model. The mathematical model of DCFRM is established and the probabilistic design idea with DCFRM is introduced. The probabilistic analysis of turbine blisk involving multi-failure modes (deformation failure, stress failure and strain failure) was investigated by considering fluid-structure interaction with the proposed method. The distribution characteristics, reliability degree, and sensitivity degree of each failure mode and overall failure mode on turbine blisk are obtained, which provides a useful reference for improving the performance and reliability of aeroengine. Through the comparison of methods shows that the DCFRM reshapes the probability of probabilistic analysis for multi-failure structure and improves the computing efficiency while keeping acceptable computational precision. Moreover, the proposed method offers a useful insight for reliability-based design optimization of multi-failure structure and thereby also enriches the theory and method of mechanical reliability design.

Structural Insights into Bacillus thuringiensis Cry, Cyt and Parasporin Toxins

PubMed Central

Xu, Chengchen; Wang, Bi-Cheng; Yu, Ziniu; Sun, Ming

2014-01-01

Since the first X-ray structure of Cry3Aa was revealed in 1991, numerous structures of B. thuringiensis toxins have been determined and published. In recent years, functional studies on the mode of action and resistance mechanism have been proposed, which notably promoted the developments of biological insecticides and insect-resistant transgenic crops. With the exploration of known pore-forming toxins (PFTs) structures, similarities between PFTs and B. thuringiensis toxins have provided great insights into receptor binding interactions and conformational changes from water-soluble to membrane pore-forming state of B. thuringiensis toxins. This review mainly focuses on the latest discoveries of the toxin working mechanism, with the emphasis on structural related progress. Based on the structural features, B. thuringiensis Cry, Cyt and parasporin toxins could be divided into three categories: three-domain type α-PFTs, Cyt toxin type β-PFTs and aerolysin type β-PFTs. Structures from each group are elucidated and discussed in relation to the latest data, respectively. PMID:25229189

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

PubMed

Da, Chenxiao; Telang, Nakul; Barelli, Peter; Jia, Xin; Gupton, John T; Mooberry, Susan L; Kellogg, Glen E

2012-01-12

3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.

Insights into the Mutation-Induced HHH Syndrome from Modeling Human Mitochondrial Ornithine Transporter-1

PubMed Central

Wang, Jing-Fang; Chou, Kuo-Chen

2012-01-01

Human mitochondrial ornithine transporter-1 is reported in coupling with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, which is a rare autosomal recessive disorder. For in-depth understanding of the molecular mechanism of the disease, it is crucially important to acquire the 3D structure of human mitochondrial ornithine transporter-1. Since no such structure is available in the current protein structure database, we have developed it via computational approaches based on the recent NMR structure of human mitochondrial uncoupling protein (Berardi MJ, Chou JJ, et al. Nature 2011, 476:109–113). Subsequently, we docked the ligand L-ornithine into the computational structure to search for the favorable binding mode. It was observed that the binding interaction for the most favorable binding mode is featured by six remarkable hydrogen bonds between the receptor and ligand, and that the most favorable binding mode shared the same ligand-binding site with most of the homologous mitochondrial carriers from different organisms, implying that the ligand-binding sites are quite conservative in the mitochondrial carriers family although their sequences similarity is very low with 20% or so. Moreover, according to our structural analysis, the relationship between the disease-causing mutations of human mitochondrial ornithine transporter-1 and the HHH syndrome can be classified into the following three categories: (i) the mutation occurs in the pseudo-repeat regions so as to change the region of the protein closer to the mitochondrial matrix; (ii) the mutation is directly affecting the substrate binding pocket so as to reduce the substrate binding affinity; (iii) the mutation is located in the structural region closer to the intermembrane space that can significantly break the salt bridge networks of the protein. These findings may provide useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and developing effective drugs against the disease. PMID:22292090

Sampling considerations for modal analysis with damping

NASA Astrophysics Data System (ADS)

Park, Jae Young; Wakin, Michael B.; Gilbert, Anna C.

2015-03-01

Structural health monitoring (SHM) systems are critical for monitoring aging infrastructure (such as buildings or bridges) in a cost-effective manner. Wireless sensor networks that sample vibration data over time are particularly appealing for SHM applications due to their flexibility and low cost. However, in order to extend the battery life of wireless sensor nodes, it is essential to minimize the amount of vibration data these sensors must collect and transmit. In recent work, we have studied the performance of the Singular Value Decomposition (SVD) applied to the collection of data and provided new finite sample analysis characterizing conditions under which this simple technique{also known as the Proper Orthogonal Decomposition (POD){can correctly estimate the mode shapes of the structure. Specifically, we provided theoretical guarantees on the number and duration of samples required in order to estimate a structure's mode shapes to a desired level of accuracy. In that previous work, however, we considered simplified Multiple-Degree-Of-Freedom (MDOF) systems with no damping. In this paper we consider MDOF systems with proportional damping and show that, with sufficiently light damping, the POD can continue to provide accurate estimates of a structure's mode shapes. We support our discussion with new analytical insight and experimental demonstrations. In particular, we study the tradeoffs between the level of damping, the sampling rate and duration, and the accuracy to which the structure's mode shapes can be estimated.

Tensile failure criteria for fiber composite materials

NASA Technical Reports Server (NTRS)

Rosen, B. W.; Zweben, C. H.

1972-01-01

The analysis provides insight into the failure mechanics of these materials and defines criteria which serve as tools for preliminary design material selection and for material reliability assessment. The model incorporates both dispersed and propagation type failures and includes the influence of material heterogeneity. The important effects of localized matrix damage and post-failure matrix shear stress transfer are included in the treatment. The model is used to evaluate the influence of key parameters on the failure of several commonly used fiber-matrix systems. Analyses of three possible failure modes were developed. These modes are the fiber break propagation mode, the cumulative group fracture mode, and the weakest link mode. Application of the new model to composite material systems has indicated several results which require attention in the development of reliable structural composites. Prominent among these are the size effect and the influence of fiber strength variability.

A Society without a "State"? Political Organization, Social Conflict, and Welfare Provision in the United States.

ERIC Educational Resources Information Center

Skocpol, Theda

The programmatic structure and modes of implementation of U.S. social provisions must be understood in order to gain insight into social programs in the United States. National standards have not been established for public benefits and "social security" has remained firmly separated, both institutionally and symbolically, from…

Structure, mechanics, and binding mode heterogeneity of LEDGF/p75-DNA nucleoprotein complexes revealed by scanning force microscopy

NASA Astrophysics Data System (ADS)

Vanderlinden, Willem; Lipfert, Jan; Demeulemeester, Jonas; Debyser, Zeger; de Feyter, Steven

2014-04-01

LEDGF/p75 is a transcriptional coactivator implicated in the pathogenesis of AIDS and leukemia. In these contexts, LEDGF/p75 acts as a cofactor by tethering protein cargo to transcriptionally active regions in the human genome. Our study - based on scanning force microscopy (SFM) imaging - is the first to provide structural information on the interaction of LEDGF/p75 with DNA. Two novel approaches that allow obtaining insights into the DNA conformation inside nucleoprotein complexes revealed (1) that LEDGF/p75 can bind at least in three different binding modes, (2) how DNA topology and protein dimerization affect these binding modes, and (3) geometrical and mechanical aspects of the nucleoprotein complexes. These structural and mechanical details will help us to better understand the cellular mechanisms of LEDGF/p75 as a transcriptional coactivator and as a cofactor in disease.LEDGF/p75 is a transcriptional coactivator implicated in the pathogenesis of AIDS and leukemia. In these contexts, LEDGF/p75 acts as a cofactor by tethering protein cargo to transcriptionally active regions in the human genome. Our study - based on scanning force microscopy (SFM) imaging - is the first to provide structural information on the interaction of LEDGF/p75 with DNA. Two novel approaches that allow obtaining insights into the DNA conformation inside nucleoprotein complexes revealed (1) that LEDGF/p75 can bind at least in three different binding modes, (2) how DNA topology and protein dimerization affect these binding modes, and (3) geometrical and mechanical aspects of the nucleoprotein complexes. These structural and mechanical details will help us to better understand the cellular mechanisms of LEDGF/p75 as a transcriptional coactivator and as a cofactor in disease. Electronic supplementary information (ESI) available: SFM topographs of phage lambda DNA in situ, in the absence and presence of LEDGF/p75; model-independent tests for DNA chain equilibration in 2D; SFM topographs of plasmid DNA substrates I-IV in the absence of LEDGF/p75; proof-of-principle of bend angle determination on supercoiled plasmid DNA-EcoRV binding to cognate and non-cognate sites in pBR322 plasmid DNA. See DOI: 10.1039/c4nr00022f

Insights into Fanconi Anaemia from the structure of human FANCE

PubMed Central

Nookala, Ravi K.; Hussain, Shobbir; Pellegrini, Luca

2007-01-01

Fanconi Anaemia (FA) is a cancer predisposition disorder characterized by spontaneous chromosome breakage and high cellular sensitivity to genotoxic agents. In response to DNA damage, a multi-subunit assembly of FA proteins, the FA core complex, monoubiquitinates the downstream FANCD2 protein. The FANCE protein plays an essential role in the FA process of DNA repair as the FANCD2-binding component of the FA core complex. Here we report a crystallographic and biological study of human FANCE. The first structure of a FA protein reveals the presence of a repeated helical motif that provides a template for the structural rationalization of other proteins defective in Fanconi Anaemia. The portion of FANCE defined by our crystallographic analysis is sufficient for interaction with FANCD2, yielding structural information into the mode of FANCD2 recruitment to the FA core complex. Disease-associated mutations disrupt the FANCE–FANCD2 interaction, providing structural insight into the molecular mechanisms of FA pathogenesis. PMID:17308347

Factorial Structure and Preliminary Validation of the Schema Mode Inventory for Eating Disorders (SMI-ED)

PubMed Central

Simpson, Susan G.; Pietrabissa, Giada; Rossi, Alessandro; Seychell, Tahnee; Manzoni, Gian Mauro; Munro, Calum; Nesci, Julian B.; Castelnuovo, Gianluca

2018-01-01

Objective: The aim of this study was to examine the psychometric properties and factorial structure of the Schema Mode Inventory for Eating Disorders (SMI-ED) in a disordered eating population. Method: 573 participants with disordered eating patterns as measured by the Eating Disorder Examination Questionnaire (EDE-Q) completed the 190-item adapted version of the Schema Mode Inventory (SMI). The new SMI-ED was developed by clinicians/researchers specializing in the treatment of eating disorders, through combining items from the original SMI with a set of additional questions specifically representative of the eating disorder population. Psychometric testing included Confirmatory Factor Analysis (CFA) and internal consistency (Cronbach's α). Multivariate Analyses of Covariance (MANCOVA) was also run to test statistical differences between the EDE-Q subscales on the SMI-ED modes, while controlling for possible confounding variables. Results: Factorial analysis confirmed an acceptable 16-related-factors solution for the SMI-ED, thus providing preliminary evidence for the adequate validity of the new measure based on internal structure. Concurrent validity was also established through moderate to high correlations on the modes most relevant to eating disorders with EDE-Q subscales. This study represents the first step in creating a psychometrically sound instrument for measuring schema modes in eating disorders, and provides greater insight into the relevant schema modes within this population. Conclusion: This research represents an important preliminary step toward understanding and labeling the schema mode model for this clinical group. Findings from the psychometric evaluation of SMI-ED suggest that this is a useful tool which may further assist in the measurement and conceptualization of schema modes in this population. PMID:29740379

Factorial Structure and Preliminary Validation of the Schema Mode Inventory for Eating Disorders (SMI-ED).

PubMed

Simpson, Susan G; Pietrabissa, Giada; Rossi, Alessandro; Seychell, Tahnee; Manzoni, Gian Mauro; Munro, Calum; Nesci, Julian B; Castelnuovo, Gianluca

2018-01-01

Objective: The aim of this study was to examine the psychometric properties and factorial structure of the Schema Mode Inventory for Eating Disorders (SMI-ED) in a disordered eating population. Method: 573 participants with disordered eating patterns as measured by the Eating Disorder Examination Questionnaire (EDE-Q) completed the 190-item adapted version of the Schema Mode Inventory (SMI). The new SMI-ED was developed by clinicians/researchers specializing in the treatment of eating disorders, through combining items from the original SMI with a set of additional questions specifically representative of the eating disorder population. Psychometric testing included Confirmatory Factor Analysis (CFA) and internal consistency (Cronbach's α). Multivariate Analyses of Covariance (MANCOVA) was also run to test statistical differences between the EDE-Q subscales on the SMI-ED modes, while controlling for possible confounding variables. Results: Factorial analysis confirmed an acceptable 16-related-factors solution for the SMI-ED, thus providing preliminary evidence for the adequate validity of the new measure based on internal structure. Concurrent validity was also established through moderate to high correlations on the modes most relevant to eating disorders with EDE-Q subscales. This study represents the first step in creating a psychometrically sound instrument for measuring schema modes in eating disorders, and provides greater insight into the relevant schema modes within this population. Conclusion: This research represents an important preliminary step toward understanding and labeling the schema mode model for this clinical group. Findings from the psychometric evaluation of SMI-ED suggest that this is a useful tool which may further assist in the measurement and conceptualization of schema modes in this population.

Insight into cofactor recognition in arylamine N-acetyltransferase enzymes: structure of Mesorhizobium loti arylamine N-acetyltransferase in complex with coenzyme A.

PubMed

Xu, Ximing; Li de la Sierra-Gallay, Inés; Kubiak, Xavier; Duval, Romain; Chaffotte, Alain F; Dupret, Jean Marie; Haouz, Ahmed; Rodrigues-Lima, Fernando

2015-02-01

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes that catalyze the acetyl-CoA-dependent acetylation of arylamines. To better understand the mode of binding of the cofactor by this family of enzymes, the structure of Mesorhizobium loti NAT1 [(RHILO)NAT1] was determined in complex with CoA. The F42W mutant of (RHILO)NAT1 was used as it is well expressed in Escherichia coli and displays enzymatic properties similar to those of the wild type. The apo and holo structures of (RHILO)NAT1 F42W were solved at 1.8 and 2 Å resolution, respectively. As observed in the Mycobacterium marinum NAT1-CoA complex, in (RHILO)NAT1 CoA binding induces slight structural rearrangements that are mostly confined to certain residues of its `P-loop'. Importantly, it was found that the mode of binding of CoA is highly similar to that of M. marinum NAT1 but different from the modes reported for Bacillus anthracis NAT1 and Homo sapiens NAT2. Therefore, in contrast to previous data, this study shows that different orthologous NATs can bind their cofactors in a similar way, suggesting that the mode of binding CoA in this family of enzymes is less diverse than previously thought. Moreover, it supports the notion that the presence of the `mammalian/eukaryotic insertion loop' in certain NAT enzymes impacts the mode of binding CoA by imposing structural constraints.

Transformation-optics description of plasmonic nanostructures containing blunt edges/corners: from symmetric to asymmetric edge rounding.

PubMed

Luo, Yu; Lei, Dang Yuan; Maier, Stefan A; Pendry, John B

2012-07-24

The sharpness of corners/edges can have a large effect on the optical responses of metallic nanostructures. Here we deploy the theory of transformation optics to analytically investigate a variety of blunt plasmonic structures, including overlapping nanowire dimers and crescent-shaped nanocylinders. These systems are shown to support several discrete optical modes, whose energy and line width can be controlled by tuning the nanoparticle geometry. In particular, the necessary conditions are highlighted respectively for the broadband light absorption effect and the invisibility dips that appear in the radiative spectrum. More detailed discussions are provided especially with respect to the structures with asymmetric edge rounding. These structures can support additional subradiant modes, whose interference with the neighboring dipolar modes results in a rapid change of the scattering cross-section, similar to the phenomenon observed in plasmonic Fano resonances. Finite element numerical calculations are also performed to validate the analytical predictions. The physical insights into blunt nanostructures presented in this work may be of great interest for the design of broadband light-harvesting devices, invisible and noninvasive biosensors, and slowing-light devices.

On the "Demystification" of Insight: A Critique of Neuroimaging Studies of Insight

ERIC Educational Resources Information Center

Weisberg, Robert W.

2013-01-01

Psychologists studying problem solving have, for over 100 years, been interested in the question of whether there are two different modes of solving problems. One mode--problem solving based on analysis--depends on application of past experience to the problem at hand and proceeds incrementally toward solution. The second mode--problem solving…

Structural insights into the unique inhibitory mechanism of the silkworm protease inhibitor serpin18

PubMed Central

Guo, Peng-Chao; Dong, Zhaoming; Zhao, Ping; Zhang, Yan; He, Huawei; Tan, Xiang; Zhang, Weiwei; Xia, Qingyou

2015-01-01

Serpins generally serve as inhibitors that utilize a mobile reactive center loop (RCL) as bait to trap protease targets. Here, we present the crystal structure of serpin18 from Bombyx mori at 1.65 Å resolution, which has a very short and stable RCL. Activity analysis showed that the inhibitory target of serpin18 is a cysteine protease rather than a serine protease. Notably, this inhibitiory reaction results from the formation of an intermediate complex, which then follows for the digestion of protease and inhibitor into small fragments. This activity differs from previously reported modes of inhibition for serpins. Our findings have thus provided novel structural insights into the unique inhibitory mechanism of serpin18. Furthermore, one physiological target of serpin18, fibroinase, was identified, which enables us to better define the potential role for serpin18 in regulating fibroinase activity during B. mori development. PMID:26148664

Noise transmission from a curved panel into a cylindrical enclosure: analysis of structural acoustic coupling.

PubMed

Henry, J K; Clark, R L

2001-04-01

Much of the research on sound transmission through the aircraft fuselage into the interior of aircraft has considered coupling of the entire cylinder to the acoustic modes of the enclosure. Yet, much of the work on structural acoustic control of sound radiation has focused on reducing sound radiation from individual panels into an acoustic space. Research by the authors seeks to bridge this gap by considering the transmission of sound from individual panels on the fuselage to the interior of the aircraft. As part of this research, an analytical model of a curved panel, with attached piezoelectric actuators, subjected to a static pressure load was previously developed. In the present work, the analytical model is extended to consider the coupling of a curved panel to the interior acoustics of a rigid-walled cylinder. Insight gained from an accurate analytical model of the dynamics of the noise transmission from the curved panels of the fuselage into the cylindrical enclosure of an aircraft is essential to the development of feedback control systems for the control of stochastic inputs, such as turbulent boundary layer excitation. The criteria for maximal structural acoustic coupling between the modes of the curved panel and the modes of the cylindrical enclosure are studied. For panels with aspect ratios typical of those found in aircraft, results indicate that predominately axial structural modes couple most efficiently to the acoustic modes of the enclosure. The effects of the position of the curved panel on the cylinder are also studied. Structural acoustic coupling is found to not be significantly affected by varying panel position. The impact of the findings of this study on structural acoustic control design is discussed.

Microsatellite loci in two epiphytic lichens with contrasting dispersal modes: Nephroma laevigatum and N. parile (Nephromataceae).

PubMed

Belinchón, Rocío; Ellis, Christopher J; Yahr, Rebecca

2014-11-01

Microsatellite markers were characterized for two epiphytic cyanolichens, Nephroma laevigatum and N. parile (Nephromataceae), and will be used to investigate population structure and estimate gene flow among populations of these two closely related species with contrasting dispersal modes. • Twelve and 14 microsatellite loci were characterized for N. laevigatum and N. parile, respectively. Allele number in N. laevigatum ranged from three to 13 per locus, while in N. parile there were from two to six alleles per locus. As expected, the sexually reproducing N. laevigatum had higher genetic diversity than the predominantly asexual N. parile. • This new set of markers is suitable for studying population structure and providing insights into gene flow among populations and for understanding processes of diversification. Compared between the species, they will facilitate an understanding of the influence of contrasting reproductive strategies on population and community structure.

Structural insight into TPX2-stimulated microtubule assembly

PubMed Central

2017-01-01

During mitosis and meiosis, microtubule (MT) assembly is locally upregulated by the chromatin-dependent Ran-GTP pathway. One of its key targets is the MT-associated spindle assembly factor TPX2. The molecular mechanism of how TPX2 stimulates MT assembly remains unknown because structural information about the interaction of TPX2 with MTs is lacking. Here, we determine the cryo-electron microscopy structure of a central region of TPX2 bound to the MT surface. TPX2 uses two flexibly linked elements (’ridge’ and ‘wedge’) in a novel interaction mode to simultaneously bind across longitudinal and lateral tubulin interfaces. These MT-interacting elements overlap with the binding site of importins on TPX2. Fluorescence microscopy-based in vitro reconstitution assays reveal that this interaction mode is critical for MT binding and facilitates MT nucleation. Together, our results suggest a molecular mechanism of how the Ran-GTP gradient can regulate TPX2-dependent MT formation. PMID:29120325

Antifungal plant defensins: increased insight in their mode of action as a basis for their use to combat fungal infections.

PubMed

Cools, Tanne L; Struyfs, Caroline; Cammue, Bruno Pa; Thevissen, Karin

2017-04-01

Plant defensins are small, cationic peptides with a highly conserved 3D structure. They have been studied extensively in the past decades. Various biological activities have been attributed to plant defensins, such as anti-insect and antimicrobial activities, but they are also known to affect ion channels and display antitumor activity. This review focuses on the structure, biological activity and antifungal mode of action of some well-characterized plant defensins, with particular attention to their fungal membrane target(s), their induced cell death mechanisms as well as their antibiofilm activity. As plant defensins are, in general, not toxic to human cells, show in vivo efficacy and have low frequencies of resistance occurrence, they are of particular interest in the fight against fungal infections.

Deep insights into the mode of ATP-binding mechanism in Zebrafish cyclin-dependent protein kinase-like 1 (zCDKL1): A molecular dynamics approach.

PubMed

Rout, Ajaya Kumar; Dehury, Budheswar; Maharana, Jitendra; Nayak, Chirasmita; Baisvar, Vishwamitra Singh; Behera, Bijay Kumar; Das, Basanta Kumar

2018-05-01

In eukaryotes, the serine/threonine kinases (STKs) belonging to cyclin-dependent protein kinases (CDKs) play significant role in control of cell division and curb transcription in response to several extra and intra-cellular signals indispensable for enzymatic activity. The zebrafish cyclin-dependent protein kinase-like 1 protein (zCDKL1) shares a high degree of sequence and structural similarity with mammalian orthologs and express in brain, ovary, testis, and low levels in other tissues. Regardless of its importance in the developmental process, the structure, function and mode of ATP recognition have not been investigated yet due to lack of experimental data. Henceforth, to gain atomistic insights in to the structural dynamics and mode of ATP binding, a series of computational techniques involving theoretical modeling, docking, molecular dynamics (MD) simulations and MM/PBSA binding free energies were employed. The modeled bi-lobed zCDKL1 shares a high degree of secondary structure topology with human orthologs where ATP prefers to lie in the central cavity of the bi-lobed catalytic domain enclosed by strong hydrogen bonding, electrostatic and hydrophobic contacts. Long range MD simulation portrayed that catalytic domain of zCDKL1 to be highly rigid in nature as compared to the complex (zCDKL1-ATP) form. Comparative analysis with its orthologs revealed that conserved amino acids i.e., Ile10, Gly11, Glu12, Val18, Arg31, Phe80, Glu 130, Cys143 and Asp144 were crucial for ATP binding mechanism, which needs further investigation for legitimacy. MM/PBSA method revealed that van der Waals, electrostatic and polar solvation energy mostly contributes towards negative free energy. The implications of ATP binding mechanism inferred through these structural bioinformatics approaches will help in understanding the catalytic mechanisms of important STKs in eukaryotic system. Copyright © 2018. Published by Elsevier Inc.

Stronger default mode network connectivity is associated with poorer clinical insight in youth at ultra high-risk for psychotic disorders.

PubMed

Clark, Sarah V; Mittal, Vijay A; Bernard, Jessica A; Ahmadi, Aral; King, Tricia Z; Turner, Jessica A

2018-03-01

Impaired clinical insight (CI) is a common symptom of psychotic disorders and a promising treatment target. However, to date, our understanding of how variability in CI is tied to underlying brain dysfunction in the clinical high-risk period is limited. Developing a stronger conception of this link will be a vital first step for efforts to determine if CI can serve as a useful prognostic indicator. The current study investigated whether variability in CI is related to major brain networks in adolescents and young adults at ultra high-risk (UHR) of developing psychosis. Thirty-five UHR youth were administered structured clinical interviews as well as an assessment for CI and underwent resting-state magnetic resonance imaging scans. Functional connectivity was calculated in the default mode network (DMN) and fronto-parietal network (FPN), two major networks that are dysfunctional in psychosis and are hypothesized to affect insight. Greater DMN connectivity between the posterior cingulate/precuneus and ventromedial prefrontal cortex (DMN) was related to poorer CI (R 2 =0.399). There were no significant relationships between insight and the FPN. This is the first study to relate a major brain network to clinical insight before the onset of psychosis. Findings are consistent with evidence if a hyperconnected DMN in schizophrenia and UHR, and similar to a previous study of insight and connectivity in schizophrenia. Results suggest that a strongly connected DMN may be related to poor self-awareness of subthreshold psychotic symptoms in UHR adolescents and young adults. Copyright © 2017 Elsevier B.V. All rights reserved.

Risk management of key issues of FPSO

NASA Astrophysics Data System (ADS)

Sun, Liping; Sun, Hai

2012-12-01

Risk analysis of key systems have become a growing topic late of because of the development of offshore structures. Equipment failures of offloading system and fire accidents were analyzed based on the floating production, storage and offloading (FPSO) features. Fault tree analysis (FTA), and failure modes and effects analysis (FMEA) methods were examined based on information already researched on modules of relex reliability studio (RRS). Equipment failures were also analyzed qualitatively by establishing a fault tree and Boolean structure function based on the shortage of failure cases, statistical data, and risk control measures examined. Failure modes of fire accident were classified according to the different areas of fire occurrences during the FMEA process, using risk priority number (RPN) methods to evaluate their severity rank. The qualitative analysis of FTA gave the basic insight of forming the failure modes of FPSO offloading, and the fire FMEA gave the priorities and suggested processes. The research has practical importance for the security analysis problems of FPSO.

Homotropic Cooperativity from the Activation Pathway of the Allosteric Ligand-Responsive Regulatory Protein TRAP†

PubMed Central

Kleckner, Ian R.; McElroy, Craig A.; Kuzmic, Petr; Gollnick, Paul; Foster, Mark P.

2014-01-01

The trp RNA-binding Attenuation Protein (TRAP) assembles into an 11-fold symmetric ring that regulates transcription and translation of trp-mRNA in bacilli via heterotropic allosteric activation by the amino acid tryptophan (Trp). Whereas nuclear magnetic resonance studies have revealed that Trp-induced activation coincides with both μs-ms rigidification and local structural changes in TRAP, the pathway of binding of the 11 Trp ligands to the TRAP ring remains unclear. Moreover, because each of eleven bound Trp molecules is completely surrounded by protein, its release requires flexibility of Trp-bound (holo) TRAP. Here, we used stopped-flow fluorescence to study the kinetics of Trp binding by Bacillus stearothermophilus TRAP over a range of temperatures and we observed well-separated kinetic steps. These data were analyzed using non-linear least-squares fitting of several two- and three-step models. We found that a model with two binding steps best describes the data, although the structural equivalence of the binding sites in TRAP implies a fundamental change in the time-dependent structure of the TRAP rings upon Trp binding. Application of the two binding step model reveals that Trp binding is much slower than the diffusion limit, suggesting a gating mechanism that depends on the dynamics of apo TRAP. These data also reveal that Trp dissociation from the second binding mode is much slower than after the first Trp binding mode, revealing insight into the mechanism for positive homotropic allostery, or cooperativity. Temperature dependent analyses reveal that both binding modes imbue increases in bondedness and order toward a more compressed active state. These results provide insight into mechanisms of cooperative TRAP activation, and underscore the importance of protein dynamics for ligand binding, ligand release, protein activation, and allostery. PMID:24224873

Ultralow-frequency collective compression mode and strong interlayer coupling in multilayer black phosphorus

DOE PAGES

Dong, Shan; Zhang, Anmin; Liu, Kai; ...

2016-02-26

The recent renaissance of black phosphorus (BP) as a two-dimensional (2D) layered material has generated tremendous interest, but its unique structural characters underlying many of its outstanding properties still need elucidation. Here we report Raman measurements that reveal an ultralow-frequency collective compression mode (CCM) in BP, which is unprecedented among similar 2D layered materials. This novel CCM indicates an unusually strong interlayer coupling, and this result is quantitatively supported by a phonon frequency analysis and first-principles calculations. Moreover, the CCM and another branch of low-frequency Raman modes shift sensitively with changing number of layers, allowing an accurate determination of themore » thickness up to tens of atomic layers, which is considerably higher than previously achieved by using high-frequency Raman modes. Lastly, these findings offer fundamental insights and practical tools for further exploration of BP as a highly promising new 2D semiconductor.« less

Stellar Rotation: New Insight from CoRoT

NASA Astrophysics Data System (ADS)

Catala, C.; Goupil, M. J.; Michel, E.; Baglin, A.; de Medeiros, J. Renan; Gondoin, Ph.

2009-02-01

We present an overview of the new insight provided by the CoRoT satellite on stellar rotation. Thanks to its ultra-high precision, high duty cycle, long photometric monitoring of thousands of stars, CoRoT gives us a powerful tool to study stellar rotational modulation, and therefore to measure stellar rotational periods and to study active structures at the surface of stars. This paper presents preliminary results concerning this type of study. CoRoT will also provide us with an insight of internal stellar rotation via the measurement and exploitation of rotational splittings of oscillation modes. This approach to stellar rotation with CoRoT will require a careful analysis of the oscillation power spectra, which is in progress, but prospects for such measurements are presented.

Texaphyrins: Tumor Localizing Redox Active Expanded Porphyrins

PubMed Central

Arambula, Jonathan F.; Preihs, Christian; Borthwick, Derric; Magda, Darren; Sessler, Jonathan L.

2011-01-01

Texaphyrins, a class of tumor selective expanded porphyrins capable of coordinating large metals, have been found to act as redox mediators within biological systems. This review summarizes studies involving their experimentaluse in cancer chemotherapy. Mechanistic insights involving their presumed mode of action are also described, as well as certain structure activity relationships. Finally, newer texaphyrin-based applications associated with targeted drug delivery are presented. PMID:21355841

RiboSketch: Versatile Visualization of Multi-stranded RNA and DNA Secondary Structure.

PubMed

Lu, Jacob S; Bindewald, Eckart; Kasprzak, Wojciech; Shapiro, Bruce A

2018-06-15

Creating clear, visually pleasing 2D depictions of RNA and DNA strands and their interactions is important to facilitate and communicate insights related to nucleic acid structure. Here we present RiboSketch, a secondary structure image production application that enables the visualization of multistranded structures via layout algorithms, comprehensive editing capabilities, and a multitude of simulation modes. These interactive features allow RiboSketch to create publication quality diagrams for structures with a wide range of composition, size, and complexity. The program may be run in any web browser without the need for installation, or as a standalone Java application. https://binkley2.ncifcrf.gov/users/bindewae/ribosketch_web.

Inhibitor-binding mode of homobelactosin C to proteasomes: New insights into class I MHC ligand generation

PubMed Central

Groll, Michael; Larionov, Oleg V.; Huber, Robert; de Meijere, Armin

2006-01-01

Most class I MHC ligands are generated from the vast majority of cellular proteins by proteolysis within the ubiquitin–proteasome pathway and are presented on the cell surface by MHC class I molecules. Here, we present the crystallographic analysis of yeast 20S proteasome in complex with the inhibitor homobelactosin C. The structure reveals a unique inhibitor-binding mode and provides information about the composition of proteasomal primed substrate-binding sites. IFN-γ inducible substitution of proteasomal constitutive subunits by immunosubunits modulates characteristics of generated peptides, thus producing fragments with higher preference for binding to MHC class I molecules. The structural data for the proteasome:homobelactosin C complex provide an explanation for involvement of immunosubunits in antigen generation and open perspectives for rational design of ligands, inhibiting exclusively constitutive proteasomes or immunoproteasomes. PMID:16537370

SEISMIC DIAGNOSTICS OF RED GIANTS: FIRST COMPARISON WITH STELLAR MODELS

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

Montalban, J.; Miglio, A.; Noels, A.

2010-10-01

The clear detection with CoRoT and KEPLER of radial and non-radial solar-like oscillations in many red giants paves the way for seismic inferences on the structure of such stars. We present an overview of the properties of the adiabatic frequencies and frequency separations of radial and non-radial oscillation modes for an extended grid of models. We highlight how their detection allows a deeper insight into the internal structure and evolutionary state of red giants. In particular, we find that the properties of dipole modes constitute a promising seismic diagnostic tool of the evolutionary state of red giant stars. We comparemore » our theoretical predictions with the first 34 days of KEPLER data and predict the frequency diagram expected for red giants in the CoRoT exofield in the galactic center direction.« less

Simulations of resonant Raman response in bundles of semiconductor carbon nanotubes

NASA Astrophysics Data System (ADS)

Roslyak, Oleksiy; Doorn, Stephen; Haroz, Erik; Duque, Juan; Crochet, Jared; Telg, Hagen; Hight Walker, Angela; Simpson, Jeffrey; Piryatinski, Andrei

This work is motivated by experimental study of resonant Raman response associated with E22 exciton state coupled to G+-mode vibrational mode in bundles of (6,5) semiconductor carbon nanotubes. In order to provide an insight into experimental data, we model Raman excitation spectra using our modified discrete dipole approximation (DDA) method. The calculations account for the exciton states polarized along and across the nanotube axis that are characterized by a small energy splitting. Strong polarization of the nanotubes forming the bundle results in the exciton state mixing whose spectroscopic signatures such as peaks positions, line widths, and depolarization ratio are calculated and compared to the experiment. Furthermore, the effects of the energy and structural disorder, as well as structural defects within the bundle are also examined and compared with the experimental data.

An air-coupled actuator array for active modal control of timpani

NASA Astrophysics Data System (ADS)

Rollow, Douglas; Sparrow, Victor W.; Swanson, David C.

2005-09-01

The timbral characteristics of kettledrums can be described by a modal formulation of the vibration of a thin, air-loaded membrane. Modification of the modal time history can be brought about with the use of a control system which has independent influence on each structural mode. By replacing the usual kettle with a shallow chamber and a planar array of piston sources, a modal controller is created when driving the sources in appropriate linear combinations. A theoretical formulation of active control of structural vibration by means of fluid-coupled actuators is expressed, and a Boundary Element simulation provides insight to the coupled modes, independence of control, and constraints due to the geometry of the chamber. Advantages and limitations of this type of control source to general problems in actively controlled musical instruments are explored.

Modeling Coherent Structures in Canopy Flows

NASA Astrophysics Data System (ADS)

Luhar, Mitul

2017-11-01

It is well known that flows over vegetation canopies are characterized by the presence of energetic coherent structures. Since the mean profile over dense canopies exhibits an inflection point, the emergence of such structures is often attributed to a Kelvin-Helmholtz instability. However, though stability analyses provide useful mechanistic insights into canopy flows, they are limited in their ability to generate predictions for spectra and coherent structure. The present effort seeks to address this limitation by extending the resolvent formulation (McKeon and Sharma, 2010, J. Fluid Mech.) to canopy flows. Under the resolvent formulation, the turbulent velocity field is expressed as a superposition of propagating modes, identified via a gain-based (singular value) decomposition of the Navier-Stokes equations. A key advantage of this approach is that it reconciles multiple mechanisms that lead to high amplification in turbulent flows, including modal instability, transient growth, and critical-layer phenomena. Further, individual high-gain modes can be combined to generate more complete models for coherent structure and velocity spectra. Preliminary resolvent-based model predictions for canopy flows agree well with existing experiments and simulations.

Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor.

PubMed

Yang, Zhenlin; Han, Shuo; Keller, Max; Kaiser, Anette; Bender, Brian J; Bosse, Mathias; Burkert, Kerstin; Kögler, Lisa M; Wifling, David; Bernhardt, Guenther; Plank, Nicole; Littmann, Timo; Schmidt, Peter; Yi, Cuiying; Li, Beibei; Ye, Sheng; Zhang, Rongguang; Xu, Bo; Larhammar, Dan; Stevens, Raymond C; Huster, Daniel; Meiler, Jens; Zhao, Qiang; Beck-Sickinger, Annette G; Buschauer, Armin; Wu, Beili

2018-04-01

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology 1,2 . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y 1 , Y 2 , Y 4 and Y 5 receptors, with different affinity and selectivity 3 . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y 1 receptor (Y 1 R) 4 . A number of peptides and small-molecule compounds have been characterized as Y 1 R antagonists and have shown clinical potential in the treatment of obesity 4 , tumour 1 and bone loss 5 . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability 6 . Here we report crystal structures of the human Y 1 R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y 1 R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y 1 R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y 1 R can enable structure-based drug discovery that targets NPY receptors.

Shallow structure of the InSight 2018 landing site in Elysium Planitia, Mars, from ambient vibration Rayleigh wave ellipticity: A modeling study

NASA Astrophysics Data System (ADS)

Knapmeyer-Endrun, B.; Golombek, M.; Ohrnberger, M. M.

2016-12-01

The SEIS (Seismic Experiment for Interior Structure) instrument onboard NASA's InSight mission, scheduled to land in November 2018, will be the first seismometer directly deployed on the surface of Mars. From studies on both the Earth and the Moon, it is well known that site amplification in low-velocity sediments, e.g. regolith, on top of more competent rocks has a strong influence on seismic signals, but can also be used to constrain the subsurface structure. Based on orbital data, lab measurements and terrestrial analogues, we construct a model of the shallow sub-surface at the landing site in western Elysium Planitia and simulate the ambient vibration wavefield. We show how Rayleigh wave ellipticity can be extracted from these data and inverted for shallow structure. Using reasonable variations in regolith properties, we do not expect any influence of site resonances on teleseismic quakes recorded by InSight, but recordings of local events will likely be affected. We find that higher mode ellipticity information might be extracted from the data, significantly reducing uncertainties in the inversion. Though the data are most sensitive to properties of the upper-most layer and show a strong trade-off between layer depth and velocity, it is possible to estimate the velocity and thickness of the sub-regolith layer and distinguish between different models by using reasonable constraints on regolith properties. Model parameters are best constrained if either higher mode data can be used or additional constraints on regolith properties, e.g. from analysis of hammer strokes of the HP3 heat flow probe or orbital mapping of regolith thickness from the onset diameter of rocky ejecta craters, are available. In addition, Rayleigh wave ellipticity can differentiate between models with a constant regolith velocity and models with increasing velocity with depth. We also discuss the influence of lander and leveling system mechanical noise on the identification of site resonances.

Effect of Zn2+ binding and enzyme active site on the transition state for RNA 2′-O-transphosphorylation interpreted through kinetic isotope effects

PubMed Central

Chen, Haoyuan; Piccirilli, Joseph A.; Harris, Michael E.; York, Darrin M.

2016-01-01

Divalent metal ions, due to their ability to stabilize high concentrations of negative charge, are important for RNA folding and catalysis. Detailed models derived from the structures and kinetics of enzymes and from computational simulations have been developed. However, in most cases the specific catalytic modes involving metal ions and their mechanistic roles and effects on transition state structures remains controversial. Valuable information about the nature of the transition state is provided by measurement of kinetic isotope effects (KIEs). However, KIEs reflect changes in all bond vibrational modes that differ between the ground state and transition state. QM calculations are therefore essential for developing structural models of the transition state and evaluating mechanistic alternatives. Herein, we present computational models for Zn2+ binding to RNA 2′O-transphosphorylation reaction models that aid in the interpretation of KIE experiments. Different Zn2+ binding modes produce distinct KIE signatures, and one binding mode involving two zinc ions is in close agreement with KIEs measured for non-enzymatic catalysis by Zn2+ aquo ions alone. Interestingly, the KIE signatures in this specific model are also very close to those in RNase A catalysis. These results allow a quantitative connection to be made between experimental KIE measurements and transition state structure and bonding, and provide insight into RNA 2′O-transphosphorylation reactions catalyzed by metal ions and enzymes. PMID:25812974

Resolvent analysis of suboptimal control for turbulent skin friction drag reduction

NASA Astrophysics Data System (ADS)

Nakashima, Satoshi; Fukagata, Koji; Luhar, Mitul

2017-11-01

We study the drag reduction mechanisms of suboptimal control (Lee et al. 1998) via the resolvent formulation developed by McKeon and Sharma (2010). Under this formulation, the nonlinear term in the Navier-Stokes equations is regarded as a forcing which acts upon the linear dynamics to output a velocity response across Fourier space. This analysis enables targeted analyses of the effects of the control on modes resembling dynamically important coherent structures such as the near-wall (NW) cycle. Suboptimal control generates blowing and suction at the wall that is proportional to the streamwise (Case ST) or spanwise (Case SP) wall shear-stress, with the magnitude of blowing and suction being a design parameter. Both Case ST and SP can suppress resolvent modes resembling the NW cycle. However, for Case ST, the analysis reveals that the control leads to substantial increase in amplification for structures that are long in the spanwise direction. High actuation of such energetic spanwise structures was confirmed by conducting limited direct numerical simulations. In addition to the study of modes resembling the NW cycle, we will discuss modes of varying propagating speed and wavelength to provide insight into the effects of suboptimal control across spectral space. This work was supported through Grant-in-Aid for Scientific Research (C) (No. 25420129) by Japan Society for the Promotion of Science (JSPS).

Microsatellite loci in two epiphytic lichens with contrasting dispersal modes: Nephroma laevigatum and N. parile (Nephromataceae)1

PubMed Central

Belinchón, Rocío; Ellis, Christopher J.; Yahr, Rebecca

2014-01-01

• Premise of the study: Microsatellite markers were characterized for two epiphytic cyanolichens, Nephroma laevigatum and N. parile (Nephromataceae), and will be used to investigate population structure and estimate gene flow among populations of these two closely related species with contrasting dispersal modes. • Methods and Results: Twelve and 14 microsatellite loci were characterized for N. laevigatum and N. parile, respectively. Allele number in N. laevigatum ranged from three to 13 per locus, while in N. parile there were from two to six alleles per locus. As expected, the sexually reproducing N. laevigatum had higher genetic diversity than the predominantly asexual N. parile. • Conclusions: This new set of markers is suitable for studying population structure and providing insights into gene flow among populations and for understanding processes of diversification. Compared between the species, they will facilitate an understanding of the influence of contrasting reproductive strategies on population and community structure. PMID:25383271

Machine Detection of Enhanced Electromechanical Energy Conversion in PbZr 0.2Ti 0.8O 3 Thin Films

DOE PAGES

Agar, Joshua C.; Cao, Ye; Naul, Brett; ...

2018-05-28

Many energy conversion, sensing, and microelectronic applications based on ferroic materials are determined by the domain structure evolution under applied stimuli. New hyperspectral, multidimensional spectroscopic techniques now probe dynamic responses at relevant length and time scales to provide an understanding of how these nanoscale domain structures impact macroscopic properties. Such approaches, however, remain limited in use because of the difficulties that exist in extracting and visualizing scientific insights from these complex datasets. Using multidimensional band-excitation scanning probe spectroscopy and adapting tools from both computer vision and machine learning, an automated workflow is developed to featurize, detect, and classify signatures ofmore » ferroelectric/ferroelastic switching processes in complex ferroelectric domain structures. This approach enables the identification and nanoscale visualization of varied modes of response and a pathway to statistically meaningful quantification of the differences between those modes. Lastly, among other things, the importance of domain geometry is spatially visualized for enhancing nanoscale electromechanical energy conversion.« less

Machine Detection of Enhanced Electromechanical Energy Conversion in PbZr 0.2Ti 0.8O 3 Thin Films

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

Agar, Joshua C.; Cao, Ye; Naul, Brett

Many energy conversion, sensing, and microelectronic applications based on ferroic materials are determined by the domain structure evolution under applied stimuli. New hyperspectral, multidimensional spectroscopic techniques now probe dynamic responses at relevant length and time scales to provide an understanding of how these nanoscale domain structures impact macroscopic properties. Such approaches, however, remain limited in use because of the difficulties that exist in extracting and visualizing scientific insights from these complex datasets. Using multidimensional band-excitation scanning probe spectroscopy and adapting tools from both computer vision and machine learning, an automated workflow is developed to featurize, detect, and classify signatures ofmore » ferroelectric/ferroelastic switching processes in complex ferroelectric domain structures. This approach enables the identification and nanoscale visualization of varied modes of response and a pathway to statistically meaningful quantification of the differences between those modes. Lastly, among other things, the importance of domain geometry is spatially visualized for enhancing nanoscale electromechanical energy conversion.« less

Regulation of chromatin structure in the cardiovascular system.

PubMed

Rosa-Garrido, Manuel; Karbassi, Elaheh; Monte, Emma; Vondriska, Thomas M

2013-01-01

It has been appreciated for some time that cardiovascular disease involves large-scale transcriptional changes in various cell types. What has become increasingly clear only in the past few years, however, is the role of chromatin remodeling in cardiovascular phenotypes in normal physiology, as well as in development and disease. This review summarizes the state of the chromatin field in terms of distinct mechanisms to regulate chromatin structure in vivo, identifying when these modes of regulation have been demonstrated in cardiovascular tissues. We describe areas in which a better understanding of chromatin structure is leading to new insights into the fundamental biology of cardiovascular disease. 

Theoretical aspects of tidal and planetary wave propagation at thermospheric heights

NASA Technical Reports Server (NTRS)

Volland, H.; Mayr, H. G.

1977-01-01

A simple semiquantitative model is presented which allows analytic solutions of tidal and planetary wave propagation at thermospheric heights. This model is based on perturbation approximation and mode separation. The effects of viscosity and heat conduction are parameterized by Rayleigh friction and Newtonian cooling. Because of this simplicity, one gains a clear physical insight into basic features of atmospheric wave propagation. In particular, we discuss the meridional structures of pressure and horizontal wind (the solutions of Laplace's equation) and their modification due to dissipative effects at thermospheric heights. Furthermore, we solve the equations governing the height structure of the wave modes and arrive at a very simple asymptotic solution valid in the upper part of the thermosphere. That 'system transfer function' of the thermosphere allows one to estimate immediately the reaction of the thermospheric wave mode parameters such as pressure, temperature, and winds to an external heat source of arbitrary temporal and spatial distribution. Finally, the diffusion effects of the minor constituents due to the global wind circulation are discussed, and some results of numerical calculations are presented.

The Evolution of a Long-Lived Mesoscale Convective System Observed by GLM

NASA Astrophysics Data System (ADS)

Peterson, M. J.; Rudlosky, S. D.; Antunes, L.

2017-12-01

Continuous Geostationary Lightning Mapper (GLM) observations are used to document total lightning activity over the life cycle of a long-lived Mesoscale Convective System (MCS). MCS's may be few in number, but they are important for the Global Electric Circuit (GEC) because they sustain high lightning flash rates and quasi steady state conduction currents (Wilson currents) over longer time periods than ordinary isolated convection. The optical characteristics of the flashes produced by MCS's change over time, providing additional insights into the precipitation structure, convective mode, and evolution of the storm system. These insights are particularly useful in areas void of radar observations. Intercalibrated passive microwave radiometer data from the Global Precipitation Measurement (GPM) constellation also are used to estimate changes in Wilson current generation as the system evolves. These results highlight the role of MCS's in the GEC, and showcase how optical flash descriptors relate to thunderstorm organization, maturity, and structure.

A structural insight into the P1S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

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

Węglarz-Tomczak, Ewelina; Berlicki, Łukasz; Pawełczak, Małgorzata

N0 -substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki ¼ 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-more » diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.« less

Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.

PubMed

Istyastono, Enade P; Nijmeijer, Saskia; Lim, Herman D; van de Stolpe, Andrea; Roumen, Luc; Kooistra, Albert J; Vischer, Henry F; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

2011-12-08

The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

PubMed Central

Eyal, Zohar; Matzov, Donna; Krupkin, Miri; Wekselman, Itai; Paukner, Susanne; Zimmerman, Ella; Rozenberg, Haim; Bashan, Anat; Yonath, Ada

2015-01-01

The emergence of bacterial multidrug resistance to antibiotics threatens to cause regression to the preantibiotic era. Here we present the crystal structure of the large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with the known antibiotics linezolid and telithromycin, as well as with a new, highly potent pleuromutilin derivative, BC-3205. These crystal structures shed light on specific structural motifs of the S. aureus ribosome and the binding modes of the aforementioned antibiotics. Moreover, by analyzing the ribosome structure and comparing it with those of nonpathogenic bacterial models, we identified some unique internal and peripheral structural motifs that may be potential candidates for improving known antibiotics and for use in the design of selective antibiotic drugs against S. aureus. PMID:26464510

Effect of Zn2+ binding and enzyme active site on the transition state for RNA 2'-O-transphosphorylation interpreted through kinetic isotope effects.

PubMed

Chen, Haoyuan; Piccirilli, Joseph A; Harris, Michael E; York, Darrin M

2015-11-01

Divalent metal ions, due to their ability to stabilize high concentrations of negative charge, are important for RNA folding and catalysis. Detailed models derived from the structures and kinetics of enzymes and from computational simulations have been developed. However, in most cases the specific catalytic modes involving metal ions and their mechanistic roles and effects on transition state structures remain controversial. Valuable information about the nature of the transition state is provided by measurement of kinetic isotope effects (KIEs). However, KIEs reflect changes in all bond vibrational modes that differ between the ground state and transition state. QM calculations are therefore essential for developing structural models of the transition state and evaluating mechanistic alternatives. Herein, we present computational models for Zn2+ binding to RNA 2'O-transphosphorylation reaction models that aid in the interpretation of KIE experiments. Different Zn2+ binding modes produce distinct KIE signatures, and one binding mode involving two zinc ions is in close agreement with KIEs measured for non-enzymatic catalysis by Zn2+ aquo ions alone. Interestingly, the KIE signatures in this specific model are also very close to those in RNase A catalysis. These results allow a quantitative connection to be made between experimental KIE measurements and transition state structure and bonding, and provide insight into RNA 2'O-ransphosphorylation reactions catalyzed by metal ions and enzymes. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. Copyright © 2015. Published by Elsevier B.V.

Dynamic Behavior of Spicules Inferred from Perpendicular Velocity Components

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

Sharma, Rahul; Verth, Gary; Erdélyi, Robertus

2017-05-10

Understanding the dynamic behavior of spicules, e.g., in terms of magnetohydrodynamic (MHD) wave mode(s), is key to unveiling their role in energy and mass transfer from the photosphere to corona. The transverse, torsional, and field-aligned motions of spicules have previously been observed in imaging spectroscopy and analyzed separately for embedded wave-mode identification. Similarities in the Doppler signatures of spicular structures for both kink and torsional Alfvén wave modes have led to the misinterpretation of the dominant wave mode in these structures and is a subject of debate. Here, we aim to combine line- of-sight (LOS) and plane-of-sky (POS) velocity componentsmore » using the high spatial/temporal resolution H α imaging-spectroscopy data from the CRisp Imaging SpectroPolarimeter based at the Swedish Solar Telescope to achieve better insight into the underlying nature of these motions as a whole. The resultant three-dimensional velocity vectors and the other derived quantities (e.g., magnetic pressure perturbations) are used to identify the MHD wave mode(s) responsible for the observed spicule motion. We find a number of independent examples where the bulk transverse motion of the spicule is dominant either in the POS or along the LOS. It is shown that the counterstreaming action of the displaced external plasma due to spicular bulk transverse motion has a similar Doppler profile to that of the m = 0 torsional Alfvén wave when this motion is predominantly perpendicular to the LOS. Furthermore, the inferred magnetic pressure perturbations support the kink wave interpretation of observed spicular bulk transverse motion rather than any purely incompressible MHD wave mode, e.g., the m = 0 torsional Alfvén wave.« less

Unveiling the molecular mechanism of brassinosteroids: Insights from structure-based molecular modeling studies.

PubMed

Lei, Beilei; Liu, Jiyuan; Yao, Xiaojun

2015-12-01

Brassinosteroid (BR) phytohormones play indispensable roles in plant growth and development. Brassinolide (BL) and 24-epibrassinolide (24-epiBL) are the most active ones among the BRs reported thus far. Unfortunately, the extremely low natural content and intricate synthesis process limit their popularization in agricultural production. Earlier reports to discover alternative compounds have resulted in molecules with nearly same scaffold structure and without diversity in chemical space. In the present study, receptors structure based BRs regulation mechanism was analyzed. First, we examined the detailed binding interactions and their dynamic stability between BL and its receptor BRI1 and co-receptor BAK1. Then, the binding modes and binding free energies for 24-epiBL and a series of representative BRs binding with BRI1 and BRI1-BAK1 were carried out by molecular docking, energy minimization and MM-PBSA free energy calculation. The obtained binding structures and energetic results provided vital insights into the structural factors affecting the activity from both receptors and BRs aspects. Subsequently, the obtained knowledge will serve as valuable guidance to build pharmacophore models for rational screening of new scaffold alternative BRs. Copyright © 2015 Elsevier Inc. All rights reserved.

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities Are Predicted for C-2 Analogues in the Colchicine Site

PubMed Central

2011-01-01

3,5-Dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogues were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structure–activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design. PMID:22611477

Insights into the structural/conformational requirements of cytotoxic oxadiazoles as potential chemotherapeutic target binding agents

NASA Astrophysics Data System (ADS)

Alikhani, Radin; Razzaghi-Asl, Nima; Ramazani, Ali; Hosseinzadeh, Zahra

2018-07-01

A few novel previously synthesized 2,5-disubstituted 1,3,4-oxadiazoles with cytotoxic activity (1-17) were subjected to combined docking/quantum mechanical studies against chemotherapeutic targets. Selected macromolecular targets were those that were previously known to be inhibited by 1,3,4-oxadiazoles. Within this work, favorable binding modes/affinities of the oxadiazoles toward validated cancer targets were elucidated. Some oxadiazole structures exhibited ΔGbs comparable to or stronger than crystallographic ligands that were previously demonstrated to inhibit such targets. On the basis of obtained results, a general structure activity/binding relationship (SAR/SBR) was developed and a few 2,5-disubstituted 1,3,4-oxadiazole structures were proposed and virtually validated as potential cytotoxic candidates. To get more insight into structure binding relationship of candidate molecules within best correlated targets, docked conformation of the best in silico in vitro correlated oxadiazole structure was analyzed in terms of intermolecular binding energy components by functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). We believe that such modeling studies may be complementary to our previous results on the synthesis and cytotoxicity assessment of novel 1,3,4-oxadiazole derivatives through extending the scope of privileged structures toward designing new potential anti-tumor compounds.

Complexation of NpO2+ with (2-Hydroxyethyl)ethylenediaminetriacetic Acid (HEDTA) in Aqueous Solutions: Thermodynamic Studies and Structural Analysis

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

Li, Xingliang; Zhang, Zhicheng; Martin, Leigh R

Complexation of Np(V) with N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) was studied in aqueous solution (I = 1.0 mol L -1 NaClO 4, t = 25 °C) by spectrophotometry, microcalorimetry and Extended X-ray absorption fine structure (EXAFS) spectroscopy. Equilibrium constants for the formation of three complexes, NpO 2L 2-, NpO 2(HL) -, and (NpO 2)2(OH)2L26 -, were determined to be (6.91 ± 0.06), (4.28 ± 0.03) and -(4.93 ± 0.03), respectively. The enthalpies of complexation were determined to be -(8.0 ± 2.0) kJ mol -1 for NpO 2L 2 - and -(2.2 ± 2.0) kJ mol-1 for NpO 2(HL) -. Thermodynamic data ofmore » the complexation of Np(V) with HEDTA were compared to those of Np(V) with other aminopolycarboxylic acids, gaining insight into the possible coordination modes of the complexes. The EXAFS studies provided further structural information on those modes. In both NpO 2L 2 - and NpO 2(HL) - complexes, HEDTA coordinates to Np(V) in a tridentate mode through two oxygens of two carboxylic groups and one nitrogen of the amine group. In the (NpO 2) 2(OH) 2L 2 6- complex, two Np(V) atoms are bridged by two hydroxides and each HEDTA maintains the tridentate coordination mode.« less

Complexation of NpO2+ with (2-Hydroxyethyl)ethylenediaminetriacetic Acid (HEDTA) in Aqueous Solutions: Thermodynamic Studies and Structural Analysis

DOE PAGES

Li, Xingliang; Zhang, Zhicheng; Martin, Leigh R; ...

2016-12-02

Complexation of Np(V) with N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) was studied in aqueous solution (I = 1.0 mol L -1 NaClO 4, t = 25 °C) by spectrophotometry, microcalorimetry and Extended X-ray absorption fine structure (EXAFS) spectroscopy. Equilibrium constants for the formation of three complexes, NpO 2L 2-, NpO 2(HL) -, and (NpO 2)2(OH)2L26 -, were determined to be (6.91 ± 0.06), (4.28 ± 0.03) and -(4.93 ± 0.03), respectively. The enthalpies of complexation were determined to be -(8.0 ± 2.0) kJ mol -1 for NpO 2L 2 - and -(2.2 ± 2.0) kJ mol-1 for NpO 2(HL) -. Thermodynamic data ofmore » the complexation of Np(V) with HEDTA were compared to those of Np(V) with other aminopolycarboxylic acids, gaining insight into the possible coordination modes of the complexes. The EXAFS studies provided further structural information on those modes. In both NpO 2L 2 - and NpO 2(HL) - complexes, HEDTA coordinates to Np(V) in a tridentate mode through two oxygens of two carboxylic groups and one nitrogen of the amine group. In the (NpO 2) 2(OH) 2L 2 6- complex, two Np(V) atoms are bridged by two hydroxides and each HEDTA maintains the tridentate coordination mode.« less

Investigating light curve modulation via kernel smoothing. II. New additional modes in single-mode OGLE classical Cepheids

NASA Astrophysics Data System (ADS)

Süveges, Maria; Anderson, Richard I.

2018-04-01

Detailed knowledge of the variability of classical Cepheids, in particular their modulations and mode composition, provides crucial insight into stellar structure and pulsation. However, tiny modulations of the dominant radial-mode pulsation were recently found to be very frequent, possibly ubiquitous in Cepheids, which makes secondary modes difficult to detect and analyse, since these modulations can easily mask the potentially weak secondary modes. The aim of this study is to re-investigate the secondary mode content in the sample of OGLE-III and -IV single-mode classical Cepheids using kernel regression with adaptive kernel width for pre-whitening, instead of using a constant-parameter model. This leads to a more precise removal of the modulated dominant pulsation, and enables a more complete survey of secondary modes with frequencies outside a narrow range around the primary. Our analysis reveals that significant secondary modes occur more frequently among first overtone Cepheids than previously thought. The mode composition appears significantly different in the Large and Small Magellanic Clouds, suggesting a possible dependence on chemical composition. In addition to the formerly identified non-radial mode at P2 ≈ 0.6…0.65P1 (0.62-mode), and a cluster of modes with near-primary frequency, we find two more candidate non-radial modes. One is a numerous group of secondary modes with P2 ≈ 1.25P1, which may represent the fundamental of the 0.62-mode, supposed to be the first harmonic of an l ∈ {7, 8, 9} non-radial mode. The other new mode is at P2 ≈ 1.46P1, possibly analogous to a similar, rare mode recently discovered among first overtone RR Lyrae stars.

Photonic crystals, light manipulation, and imaging in complex nematic structures

NASA Astrophysics Data System (ADS)

Ravnik, Miha; Å timulak, Mitja; Mur, Urban; Čančula, Miha; Čopar, Simon; Žumer, Slobodan

2016-03-01

Three selected approaches for manipulation of light by complex nematic colloidal and non-colloidal structures are presented using different own custom developed theoretical and modelling approaches. Photonic crystals bands of distorted cholesteric liquid crystal helix and of nematic colloidal opals are presented, also revealing distinct photonic modes and density of states. Light propagation along half-integer nematic disclinations is shown with changes in the light polarization of various winding numbers. As third, simulated light transmission polarization micrographs of nematic torons are shown, offering a new insight into the complex structure characterization. Finally, this work is a contribution towards using complex soft matter in optics and photonics for advanced light manipulation.

Integrating protein structural dynamics and evolutionary analysis with Bio3D.

PubMed

Skjærven, Lars; Yao, Xin-Qiu; Scarabelli, Guido; Grant, Barry J

2014-12-10

Popular bioinformatics approaches for studying protein functional dynamics include comparisons of crystallographic structures, molecular dynamics simulations and normal mode analysis. However, determining how observed displacements and predicted motions from these traditionally separate analyses relate to each other, as well as to the evolution of sequence, structure and function within large protein families, remains a considerable challenge. This is in part due to the general lack of tools that integrate information of molecular structure, dynamics and evolution. Here, we describe the integration of new methodologies for evolutionary sequence, structure and simulation analysis into the Bio3D package. This major update includes unique high-throughput normal mode analysis for examining and contrasting the dynamics of related proteins with non-identical sequences and structures, as well as new methods for quantifying dynamical couplings and their residue-wise dissection from correlation network analysis. These new methodologies are integrated with major biomolecular databases as well as established methods for evolutionary sequence and comparative structural analysis. New functionality for directly comparing results derived from normal modes, molecular dynamics and principal component analysis of heterogeneous experimental structure distributions is also included. We demonstrate these integrated capabilities with example applications to dihydrofolate reductase and heterotrimeric G-protein families along with a discussion of the mechanistic insight provided in each case. The integration of structural dynamics and evolutionary analysis in Bio3D enables researchers to go beyond a prediction of single protein dynamics to investigate dynamical features across large protein families. The Bio3D package is distributed with full source code and extensive documentation as a platform independent R package under a GPL2 license from http://thegrantlab.org/bio3d/ .

Insight into the molecular composition of laboratory organic residues produced from interstellar/pre-cometary ice analogues using very high resolution mass spectrometry

NASA Astrophysics Data System (ADS)

Danger, G.; Fresneau, A.; Abou Mrad, N.; de Marcellus, P.; Orthous-Daunay, F.-R.; Duvernay, F.; Vuitton, V.; Le Sergeant d'Hendecourt, L.; Thissen, R.; Chiavassa, T.

2016-09-01

Experimental simulations in the laboratory may provide important information about the chemical evolution occurring in various astrophysical objects such as extraterrestrial ices. Interstellar or (pre)cometary ice analogues made of H2O, CH3OH, and NH3 at 77 K, when subjected to an energetic process (VUV photons, electrons or ions) and then warmed-up to room temperature, lead, in the laboratory, to the formation of an organic residue. In this paper we expand our previous analysis of the residues in order to obtain a better insight into their molecular content. Data analyses show that three different chemical groups are present in the residue in the negative electrospray ionization (ESI) mode: CHN, CHO and CHNOsbnd whereas only two groups are detected in the positive ESI mode: CHN and CHNO. In both cases, the CHNO group is the most abundant. The application of specific data treatment shows that residue mainly contains aliphatic linear molecules or cyclic structures connected to unsaturated chemical functions such as esters, carboxylic acids, amides or aldehydes. In lower abundances, some molecules do present aromatic structures. The comparison of our residue with organic compounds detected in the Murchison meteorite gives an interesting match, which suggests that laboratory simulation of interstellar ice chemistry is relevant to understand astrophysical organic matter evolution.

Superhard BC(3) in cubic diamond structure.

PubMed

Zhang, Miao; Liu, Hanyu; Li, Quan; Gao, Bo; Wang, Yanchao; Li, Hongdong; Chen, Changfeng; Ma, Yanming

2015-01-09

We solve the crystal structure of recently synthesized cubic BC(3) using an unbiased swarm structure search, which identifies a highly symmetric BC(3) phase in the cubic diamond structure (d-BC(3)) that contains a distinct B-B bonding network along the body diagonals of a large 64-atom unit cell. Simulated x-ray diffraction and Raman peaks of d-BC(3) are in excellent agreement with experimental data. Calculated stress-strain relations of d-BC(3) demonstrate its intrinsic superhard nature and reveal intriguing sequential bond-breaking modes that produce superior ductility and extended elasticity, which are unique among superhard solids. The present results establish the first boron carbide in the cubic diamond structure with remarkable properties, and these new findings also provide insights for exploring other covalent solids with complex bonding configurations.

Characterizing Chemical Similarity with Vibrational Spectroscopy: New Insights into the Substituent Effects in Monosubstituted Benzenes.

PubMed

Tao, Yunwen; Zou, Wenli; Cremer, Dieter; Kraka, Elfi

2017-10-26

A novel approach is presented to assess chemical similarity based the local vibrational mode analysis developed by Konkoli and Cremer. The local mode frequency shifts are introduced as similarity descriptors that are sensitive to any electronic structure change. In this work, 59 different monosubstituted benzenes are compared. For a subset of 43 compounds, for which experimental data was available, the ortho-/para- and meta-directing effect in electrophilic aromatic substitution reactions could be correctly reproduced, proving the robustness of the new similarity index. For the remaining 16 compounds, the directing effect was predicted. The new approach is broadly applicable to all compounds for which either experimental or calculated vibrational frequency information is available.

Fracture modes under uniaxial compression in hydroxyapatite scaffolds fabricated by robocasting.

PubMed

Miranda, Pedro; Pajares, Antonia; Saiz, Eduardo; Tomsia, Antoni P; Guiberteau, Fernando

2007-12-01

The fracture modes of hydroxyapatite (HA) scaffolds fabricated by direct-write assembly (robocasting) are analyzed in this work. Concentrated HA inks with suitable viscoelastic properties were developed to enable the fabrication of prototype structures consisting of a 3-D square mesh of interpenetrating rods. The fracture behavior of these model scaffolds under compressive stresses is determined from in situ uniaxial tests performed in two different directions: perpendicular to the rods and along one of the rod directions. The results are analyzed in terms of the stress field calculated by finite element modeling (FEM). This analysis provides valuable insight into the mechanical behavior of scaffolds for bone tissue engineering applications fabricated by robocasting. Copyright 2007 Wiley Periodicals, Inc.

A computational analysis of the binding mode of closantel as inhibitor of the Onchocerca volvulus chitinase: insights on macrofilaricidal drug design

NASA Astrophysics Data System (ADS)

Segura-Cabrera, Aldo; Bocanegra-García, Virgilio; Lizarazo-Ortega, Cristian; Guo, Xianwu; Correa-Basurto, José; Rodríguez-Pérez, Mario A.

2011-12-01

Onchocerciasis is a leading cause of blindness with at least 37 million people infected and more than 120 million people at risk of contracting the disease; most (99%) of this population, threatened by infection, live in Africa. The drug of choice for mass treatment is the microfilaricidal Mectizan® (ivermectin); it does not kill the adult stages of the parasite at the standard dose which is a single annual dose aimed at disease control. However, multiple treatments a year with ivermectin have effects on adult worms. The discovery of new therapeutic targets and drugs directed towards the killing of the adult parasites are thus urgently needed. The chitinase of filarial nematodes is a new drug target due to its essential function in the metabolism and molting of the parasite. Closantel is a potent and specific inhibitor of chitinase of Onchocerca volvulus (OvCHT1) and other filarial chitinases. However, the binding mode and specificity of closantel towards OvCHT1 remain unknown. In the absence of a crystallographic structure of OvCHT1, we developed a homology model of OvCHT1 using the currently available X-ray structures of human chitinases as templates. Energy minimization and molecular dynamics (MD) simulation of the model led to a high quality of 3D structure of OvCHIT1. A flexible docking study using closantel as the ligand on the binding site of OvCHIT1 and human chitinases was performed and demonstrated the differences in the closantel binding mode between OvCHIT1 and human chitinase. Furthermore, molecular dynamics simulations and free-energy calculation were employed to determine and compare the detailed binding mode of closantel with OvCHT1 and the structure of human chitinase. This comparative study allowed identification of structural features and properties responsible for differences in the computationally predicted closantel binding modes. The homology model and the closantel binding mode reported herein might help guide the rational development of novel drugs against the adult parasite of O. volvulus and such findings could be extrapolated to other filarial neglected diseases.

Using Entropy Maximization to Understand the Determinants of Structural Dynamics beyond Native Contact Topology

PubMed Central

Lezon, Timothy R.; Bahar, Ivet

2010-01-01

Comparison of elastic network model predictions with experimental data has provided important insights on the dominant role of the network of inter-residue contacts in defining the global dynamics of proteins. Most of these studies have focused on interpreting the mean-square fluctuations of residues, or deriving the most collective, or softest, modes of motions that are known to be insensitive to structural and energetic details. However, with increasing structural data, we are in a position to perform a more critical assessment of the structure-dynamics relations in proteins, and gain a deeper understanding of the major determinants of not only the mean-square fluctuations and lowest frequency modes, but the covariance or the cross-correlations between residue fluctuations and the shapes of higher modes. A systematic study of a large set of NMR-determined proteins is analyzed using a novel method based on entropy maximization to demonstrate that the next level of refinement in the elastic network model description of proteins ought to take into consideration properties such as contact order (or sequential separation between contacting residues) and the secondary structure types of the interacting residues, whereas the types of amino acids do not play a critical role. Most importantly, an optimal description of observed cross-correlations requires the inclusion of destabilizing, as opposed to exclusively stabilizing, interactions, stipulating the functional significance of local frustration in imparting native-like dynamics. This study provides us with a deeper understanding of the structural basis of experimentally observed behavior, and opens the way to the development of more accurate models for exploring protein dynamics. PMID:20585542

Using entropy maximization to understand the determinants of structural dynamics beyond native contact topology.

PubMed

Lezon, Timothy R; Bahar, Ivet

2010-06-17

Comparison of elastic network model predictions with experimental data has provided important insights on the dominant role of the network of inter-residue contacts in defining the global dynamics of proteins. Most of these studies have focused on interpreting the mean-square fluctuations of residues, or deriving the most collective, or softest, modes of motions that are known to be insensitive to structural and energetic details. However, with increasing structural data, we are in a position to perform a more critical assessment of the structure-dynamics relations in proteins, and gain a deeper understanding of the major determinants of not only the mean-square fluctuations and lowest frequency modes, but the covariance or the cross-correlations between residue fluctuations and the shapes of higher modes. A systematic study of a large set of NMR-determined proteins is analyzed using a novel method based on entropy maximization to demonstrate that the next level of refinement in the elastic network model description of proteins ought to take into consideration properties such as contact order (or sequential separation between contacting residues) and the secondary structure types of the interacting residues, whereas the types of amino acids do not play a critical role. Most importantly, an optimal description of observed cross-correlations requires the inclusion of destabilizing, as opposed to exclusively stabilizing, interactions, stipulating the functional significance of local frustration in imparting native-like dynamics. This study provides us with a deeper understanding of the structural basis of experimentally observed behavior, and opens the way to the development of more accurate models for exploring protein dynamics.

On-chip hybrid photonic-plasmonic light concentrator for nanofocusing in an integrated silicon photonics platform.

PubMed

Luo, Ye; Chamanzar, Maysamreza; Apuzzo, Aniello; Salas-Montiel, Rafael; Nguyen, Kim Ngoc; Blaize, Sylvain; Adibi, Ali

2015-02-11

The enhancement and confinement of electromagnetic radiation to nanometer scale have improved the performances and decreased the dimensions of optical sources and detectors for several applications including spectroscopy, medical applications, and quantum information. Realization of on-chip nanofocusing devices compatible with silicon photonics platform adds a key functionality and provides opportunities for sensing, trapping, on-chip signal processing, and communications. Here, we discuss the design, fabrication, and experimental demonstration of light nanofocusing in a hybrid plasmonic-photonic nanotaper structure. We discuss the physical mechanisms behind the operation of this device, the coupling mechanisms, and how to engineer the energy transfer from a propagating guided mode to a trapped plasmonic mode at the apex of the plasmonic nanotaper with minimal radiation loss. Optical near-field measurements and Fourier modal analysis carried out using a near-field scanning optical microscope (NSOM) show a tight nanofocusing of light in this structure to an extremely small spot of 0.00563(λ/(2n(rmax)))(3) confined in 3D and an exquisite power input conversion of 92%. Our experiments also verify the mode selectivity of the device (low transmission of a TM-like input mode and high transmission of a TE-like input mode). A large field concentration factor (FCF) of about 4.9 is estimated from our NSOM measurement with a radius of curvature of about 20 nm at the apex of the nanotaper. The agreement between our theory and experimental results reveals helpful insights about the operation mechanism of the device, the interplay of the modes, and the gradual power transfer to the nanotaper apex.

Fundamental (f) oscillations in a magnetically coupled solar interior-atmosphere system - An analytical approach

NASA Astrophysics Data System (ADS)

Pintér, Balázs; Erdélyi, R.

2018-01-01

Solar fundamental (f) acoustic mode oscillations are investigated analytically in a magnetohydrodynamic (MHD) model. The model consists of three layers in planar geometry, representing the solar interior, the magnetic atmosphere, and a transitional layer sandwiched between them. Since we focus on the fundamental mode here, we assume the plasma is incompressible. A horizontal, canopy-like, magnetic field is introduced to the atmosphere, in which degenerated slow MHD waves can exist. The global (f-mode) oscillations can couple to local atmospheric Alfvén waves, resulting, e.g., in a frequency shift of the oscillations. The dispersion relation of the global oscillation mode is derived, and is solved analytically for the thin-transitional layer approximation and for the weak-field approximation. Analytical formulae are also provided for the frequency shifts due to the presence of a thin transitional layer and a weak atmospheric magnetic field. The analytical results generally indicate that, compared to the fundamental value (ω =√{ gk }), the mode frequency is reduced by the presence of an atmosphere by a few per cent. A thin transitional layer reduces the eigen-frequencies further by about an additional hundred microhertz. Finally, a weak atmospheric magnetic field can slightly, by a few percent, increase the frequency of the eigen-mode. Stronger magnetic fields, however, can increase the f-mode frequency by even up to ten per cent, which cannot be seen in observed data. The presence of a magnetic atmosphere in the three-layer model also introduces non-permitted propagation windows in the frequency spectrum; here, f-mode oscillations cannot exist with certain values of the harmonic degree. The eigen-frequencies can be sensitive to the background physical parameters, such as an atmospheric density scale-height or the rate of the plasma density drop at the photosphere. Such information, if ever observed with high-resolution instrumentation and inverted, could help to gain further insight into solar magnetic structures by means of solar magneto-seismology, and could provide further insight into the role of magnetism in solar oscillations.

Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor

PubMed Central

Saleh, Noureldin; Kleinau, Gunnar; Heyder, Nicolas; Clark, Timothy; Hildebrand, Peter W.; Scheerer, Patrick

2018-01-01

The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems.

Detection of Propagating Fast Sausage Waves through Detailed Analysis of a Zebra-pattern Fine Structure in a Solar Radio Burst

NASA Astrophysics Data System (ADS)

Kaneda, K.; Misawa, H.; Iwai, K.; Masuda, S.; Tsuchiya, F.; Katoh, Y.; Obara, T.

2018-03-01

Various magnetohydrodynamic (MHD) waves have recently been detected in the solar corona and investigated intensively in the context of coronal heating and coronal seismology. In this Letter, we report the first detection of short-period propagating fast sausage mode waves in a metric radio spectral fine structure observed with the Assembly of Metric-band Aperture Telescope and Real-time Analysis System. Analysis of Zebra patterns (ZPs) in a type-IV burst revealed a quasi-periodic modulation in the frequency separation between the adjacent stripes of the ZPs (Δf ). The observed quasi-periodic modulation had a period of 1–2 s and exhibited a characteristic negative frequency drift with a rate of 3–8 MHz s‑1. Based on the double plasma resonance model, the most accepted generation model of ZPs, the observed quasi-periodic modulation of the ZP can be interpreted in terms of fast sausage mode waves propagating upward at phase speeds of 3000–8000 km s‑1. These results provide us with new insights for probing the fine structure of coronal loops.

Uncertainty quantification in operational modal analysis with stochastic subspace identification: Validation and applications

NASA Astrophysics Data System (ADS)

Reynders, Edwin; Maes, Kristof; Lombaert, Geert; De Roeck, Guido

2016-01-01

Identified modal characteristics are often used as a basis for the calibration and validation of dynamic structural models, for structural control, for structural health monitoring, etc. It is therefore important to know their accuracy. In this article, a method for estimating the (co)variance of modal characteristics that are identified with the stochastic subspace identification method is validated for two civil engineering structures. The first structure is a damaged prestressed concrete bridge for which acceleration and dynamic strain data were measured in 36 different setups. The second structure is a mid-rise building for which acceleration data were measured in 10 different setups. There is a good quantitative agreement between the predicted levels of uncertainty and the observed variability of the eigenfrequencies and damping ratios between the different setups. The method can therefore be used with confidence for quantifying the uncertainty of the identified modal characteristics, also when some or all of them are estimated from a single batch of vibration data. Furthermore, the method is seen to yield valuable insight in the variability of the estimation accuracy from mode to mode and from setup to setup: the more informative a setup is regarding an estimated modal characteristic, the smaller is the estimated variance.

Self-Assembly and Nanostructures in Organogels Based on a Bolaform Cholesteryl Imide Compound with Conjugated Aromatic Spacer

PubMed Central

Jiao, Ti-Feng; Gao, Feng-Qing; Shen, Xi-Hai; Zhang, Qing-Rui; Zhang, Xian-Fu; Zhou, Jing-Xin; Gao, Fa-Ming

2013-01-01

The self-assembly of small functional molecules into supramolecular structures is a powerful approach toward the development of new nanoscale materials and devices. As a class of self-assembled materials, low weight molecular organic gelators, organized in special nanoarchitectures through specific non-covalent interactions, has become one of the hot topics in soft matter research due to their scientific values and many potential applications. Here, a bolaform cholesteryl imide compound with conjugated aromatic spacer was designed and synthesized. The gelation behaviors in 23 solvents were investigated as efficient low-molecular-mass organic gelator. The experimental results indicated that the morphologies and assembly modes of as-formed organogels can be regulated by changing the kinds of organic solvents. Scanning electron microscopy and atomic force microscopy observations revealed that the gelator molecule self-assemble into different aggregates, from wrinkle and belt to fiber with the change of solvents. Spectral studies indicated that there existed different H-bond formations between imide groups and assembly modes. Finally, some rational assembly modes in organogels were proposed and discussed. The present work may give some insight to the design and character of new organogelators and soft materials with special structures. PMID:28788428

Global Motions of the Nuclear Pore Complex: Insights from Elastic Network Models

PubMed Central

Lezon, Timothy R.; Sali, Andrej; Bahar, Ivet

2009-01-01

The nuclear pore complex (NPC) is the gate to the nucleus. Recent determination of the configuration of proteins in the yeast NPC at ∼5 nm resolution permits us to study the NPC global dynamics using coarse-grained structural models. We investigate these large-scale motions by using an extended elastic network model (ENM) formalism applied to several coarse-grained representations of the NPC. Two types of collective motions (global modes) are predicted by the ENMs to be intrinsically favored by the NPC architecture: global bending and extension/contraction from circular to elliptical shapes. These motions are shown to be robust against tested variations in the representation of the NPC, and are largely captured by a simple model of a toroid with axially varying mass density. We demonstrate that spoke multiplicity significantly affects the accessible number of symmetric low-energy modes of motion; the NPC-like toroidal structures composed of 8 spokes have access to highly cooperative symmetric motions that are inaccessible to toroids composed of 7 or 9 spokes. The analysis reveals modes of motion that may facilitate macromolecular transport through the NPC, consistent with previous experimental observations. PMID:19730674

Global motions of the nuclear pore complex: insights from elastic network models.

PubMed

Lezon, Timothy R; Sali, Andrej; Bahar, Ivet

2009-09-01

The nuclear pore complex (NPC) is the gate to the nucleus. Recent determination of the configuration of proteins in the yeast NPC at approximately 5 nm resolution permits us to study the NPC global dynamics using coarse-grained structural models. We investigate these large-scale motions by using an extended elastic network model (ENM) formalism applied to several coarse-grained representations of the NPC. Two types of collective motions (global modes) are predicted by the ENMs to be intrinsically favored by the NPC architecture: global bending and extension/contraction from circular to elliptical shapes. These motions are shown to be robust against tested variations in the representation of the NPC, and are largely captured by a simple model of a toroid with axially varying mass density. We demonstrate that spoke multiplicity significantly affects the accessible number of symmetric low-energy modes of motion; the NPC-like toroidal structures composed of 8 spokes have access to highly cooperative symmetric motions that are inaccessible to toroids composed of 7 or 9 spokes. The analysis reveals modes of motion that may facilitate macromolecular transport through the NPC, consistent with previous experimental observations.

Biochemical and Structural Characterization of the Human TL1A Ectodomain†¶

PubMed Central

Zhan, Chenyang; Yan, Qingrong; Patskovsky, Yury; Li, Zhenhong; Toro, Rafael; Meyer, Amanda; Cheng, Huiyong; Brenowitz, Michael; Nathenson, Stanley G; Almo, Steven C

2009-01-01

TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 Å, which reveals a jelly-roll fold typical of the TNF superfamily. This structural information, in combination with complementary mutagenesis and biochemical characterization, provides insights into the binding interface and the specificity of the interactions between TL1A and the DcR3 and DR3 receptors. These studies suggest that the mode of interaction between TL1A and DcR3 differs from other characterized TNF ligand/receptor complexes. In addition, we have generated functional TL1A mutants with altered disulfide bonding capability that exhibit enhanced solution properties, which will facilitate the production of materials for future cell-based and whole animal studies. In summary, these studies provide insights into the structure and function of TL1A and provide the basis for the rational manipulation of its interactions with cognate receptors. PMID:19522538

Biochemical and Structural Characterization of the Human TL1A Ectodomain

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

Zhan, C.; Yan, Q; Patskovsky, Y

TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 {angstrom}, which reveals a jelly-roll fold typical of the TNF superfamily. This structural information, in combination with complementary mutagenesis and biochemical characterization, provides insights into the binding interface and the specificity of the interactions between TL1A and the DcR3 and DR3 receptors. These studies suggest that the mode of interaction between TL1A and DcR3more » differs from other characterized TNF ligand/receptor complexes. In addition, we have generated functional TL1A mutants with altered disulfide bonding capability that exhibit enhanced solution properties, which will facilitate the production of materials for future cell-based and whole animal studies. In summary, these studies provide insights into the structure and function of TL1A and provide the basis for the rational manipulation of its interactions with cognate receptors.« less

Structural Insights Into DNA Repair by RNase T—An Exonuclease Processing 3′ End of Structured DNA in Repair Pathways

PubMed Central

Hsiao, Yu-Yuan; Fang, Woei-Horng; Lee, Chia-Chia; Chen, Yi-Ping; Yuan, Hanna S.

2014-01-01

DNA repair mechanisms are essential for preservation of genome integrity. However, it is not clear how DNA are selected and processed at broken ends by exonucleases during repair pathways. Here we show that the DnaQ-like exonuclease RNase T is critical for Escherichia coli resistance to various DNA-damaging agents and UV radiation. RNase T specifically trims the 3′ end of structured DNA, including bulge, bubble, and Y-structured DNA, and it can work with Endonuclease V to restore the deaminated base in an inosine-containing heteroduplex DNA. Crystal structure analyses further reveal how RNase T recognizes the bulge DNA by inserting a phenylalanine into the bulge, and as a result the 3′ end of blunt-end bulge DNA can be digested by RNase T. In contrast, the homodimeric RNase T interacts with the Y-structured DNA by a different binding mode via a single protomer so that the 3′ overhang of the Y-structured DNA can be trimmed closely to the duplex region. Our data suggest that RNase T likely processes bulge and bubble DNA in the Endonuclease V–dependent DNA repair, whereas it processes Y-structured DNA in UV-induced and various other DNA repair pathways. This study thus provides mechanistic insights for RNase T and thousands of DnaQ-like exonucleases in DNA 3′-end processing. PMID:24594808

Detailed Analysis of the Binding Mode of Vanilloids to Transient Receptor Potential Vanilloid Type I (TRPV1) by a Mutational and Computational Study

PubMed Central

Mori, Yoshikazu; Ogawa, Kazuo; Warabi, Eiji; Yamamoto, Masahiro; Hirokawa, Takatsugu

2016-01-01

Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel and a multimodal sensor protein. Since the precise structure of TRPV1 was obtained by electron cryo-microscopy, the binding mode of representative agonists such as capsaicin and resiniferatoxin (RTX) has been extensively characterized; however, detailed information on the binding mode of other vanilloids remains lacking. In this study, mutational analysis of human TRPV1 was performed, and four agonists (capsaicin, RTX, [6]-shogaol and [6]-gingerol) were used to identify amino acid residues involved in ligand binding and/or modulation of proton sensitivity. The detailed binding mode of each ligand was then simulated by computational analysis. As a result, three amino acids (L518, F591 and L670) were newly identified as being involved in ligand binding and/or modulation of proton sensitivity. In addition, in silico docking simulation and a subsequent mutational study suggested that [6]-gingerol might bind to and activate TRPV1 in a unique manner. These results provide novel insights into the binding mode of various vanilloids to the channel and will be helpful in developing a TRPV1 modulator. PMID:27606946

Assembly and analysis of eukaryotic Argonaute–RNA complexes in microRNA-target recognition

PubMed Central

Gan, Hin Hark; Gunsalus, Kristin C.

2015-01-01

Experimental studies have uncovered a variety of microRNA (miRNA)–target duplex structures that include perfect, imperfect and seedless duplexes. However, non-canonical binding modes from imperfect/seedless duplexes are not well predicted by computational approaches, which rely primarily on sequence and secondary structural features, nor have their tertiary structures been characterized because solved structures to date are limited to near perfect, straight duplexes in Argonautes (Agos). Here, we use structural modeling to examine the role of Ago dynamics in assembling viable eukaryotic miRNA-induced silencing complexes (miRISCs). We show that combinations of low-frequency, global modes of motion of Ago domains are required to accommodate RNA duplexes in model human and C. elegans Ago structures. Models of viable miRISCs imply that Ago adopts variable conformations at distinct target sites that generate distorted, imperfect miRNA-target duplexes. Ago's ability to accommodate a duplex is dependent on the region where structural distortions occur: distortions in solvent-exposed seed and 3′-end regions are less likely to produce steric clashes than those in the central duplex region. Energetic analyses of assembled miRISCs indicate that target recognition is also driven by favorable Ago-duplex interactions. Such structural insights into Ago loading and target recognition mechanisms may provide a more accurate assessment of miRNA function. PMID:26432829

The unifying role of dissipative action in the dynamic failure of solids

DOE PAGES

Grady, Dennis

2015-05-19

Dissipative action, the product of dissipation energy and transport time, is fundamental to the dynamic failure of solids. Invariance of the dissipative action underlies the fourth-power nature of structured shock waves observed in selected solid metals and compounds. Dynamic failure through shock compaction, tensile spall and adiabatic shear are also governed by a constancy of the dissipative action. This commonality underlying the various modes of dynamic failure is described and leads to deeper insights into failure of solids in the intense shock wave event. These insights are in turn leading to a better understanding of the shock deformation processes underlyingmore » the fourth-power law. Experimental result and material models encompassing the dynamic failure of solids are explored for the purpose of demonstrating commonalities leading to invariance of the dissipation action. As a result, calculations are extended to aluminum and uranium metals with the intent of predicting micro-scale energetics and spatial scales in the structured shock wave.« less

Fermionic entanglement that survives a black hole

NASA Astrophysics Data System (ADS)

Martín-Martínez, Eduardo; León, Juan

2009-10-01

We introduce an arbitrary number of accessible modes when analyzing bipartite entanglement degradation due to Unruh effect between two partners Alice and Rob. Under the single mode approximation (SMA) a fermion field only had a few accessible levels due to Pauli exclusion principle conversely to bosonic fields which had an infinite number of excitable levels. This was argued to justify entanglement survival in the fermionic case in the SMA infinite acceleration limit. Here we relax SMA. Hence, an infinite number of modes are excited as the observer Rob accelerates, even for a fermion field. We will prove that, despite this analogy with the bosonic case, entanglement loss is limited. We will show that this comes from fermionic statistics through the characteristic structure it imposes on the infinite dimensional density matrix for Rob. Surprisingly, the surviving entanglement is independent of the specific maximally entangled state chosen, the kind of fermionic field analyzed, and the number of accessible modes considered. We shall discuss whether this surviving entanglement goes beyond the purely statistical correlations, giving insight concerning the black hole information paradox.

The effect of visual arrangement on visuospatial short-term memory: Insights from children with 22q11.2 deletion syndrome.

PubMed

Attout, Lucie; Noël, Marie-Pascale; Rousselle, Laurence

2018-04-11

Recent models of visuospatial (VSSP) short-term memory postulate the existence of two dissociable mechanisms depending on whether VSSP information is presented simultaneously or sequentially. However, they do not specify to what extent VSSP short-term memory is under the influence of general VSSP processing. This issue was examined in people with 22q11.2 deletion syndrome, a genetic condition involving a VSSP deficit. The configuration of VSSP information was manipulated (structured vs. unstructured) to explore the impact of arrangement on VSSP short-term memory. Two presentation modes were used to see whether the VSSP arrangement has the same impact on simultaneous and sequential short-term memory. Compared to children matched on chronological age, children with 22q11.2 deletion syndrome showed impaired performance only for structured arrangement, regardless of the presentation mode, suggesting an influence of VSSP processing on VSSP short-term memory abilities. A revised cognitive architecture for a model of VSSP short-term memory is proposed.

Negative Gaussian curvature induces significant suppression of thermal conduction in carbon crystals.

PubMed

Zhang, Zhongwei; Chen, Jie; Li, Baowen

2017-09-28

From the mathematic category of surface Gaussian curvature, carbon allotropes can be classified into three types: zero curvature, positive curvature, and negative curvature. By performing Green-Kubo equilibrium molecular dynamics simulations, we found that surface curvature has a significant impact on the phonon vibration and thermal conductivity (κ) of carbon crystals. When curving from zero curvature to negative or positive curvature structures, κ is reduced by several orders of magnitude. Interestingly, we found that κ of negatively curved carbon crystals exhibits a monotonic dependence on curvature. Through phonon mode analysis, we show that curvature induces remarkable phonon softening in phonon dispersion, which results in the reduction of phonon group velocity and flattening of phonon band structure. Furthermore, the curvature was found to induce phonon mode hybridization, leading to the suppression of phonon relaxation time. Our study provides physical insight into thermal transport in curvature materials, and will be valuable in the modulation of phonon activity through surface curvature.

Molecular simulations enlighten the binding mode of quercetin to lipoxygenase-3.

PubMed

Fiorucci, Sébastien; Golebiowski, Jérôme; Cabrol-Bass, Daniel; Antonczak, Serge

2008-11-01

Inhibition of lipoxygenases (LOXs) by flavonoid compounds is now well documented, but the description of the associated mechanism remains controversial due to a lack of information at the molecular level. For instance, X-ray determination of quercetin/LOX-3 system has led to a structure where the enzyme was cocrystallized with a degradation product of the substrate, which rendered the interpretation of the reported interactions between this flavonoid compound and the enzyme difficult. Molecular modeling simulations can in principle allow obtaining precious insights that could fill this lack of structural information. Thus, in this study, we have investigated various binding modes of quercetin to LOX-3 enzyme in order to understand the first step of the inhibition process, that is the association of the two entities. Molecular dynamics simulations and free energy calculations suggest that quercetin binds the metal center via its 3-hydroxychromone function. Moreover, enzyme/substrate interactions within the cavity impose steric hindrances to quercetin that may activate a direct dioxygen addition on the substrate. (c) 2008 Wiley-Liss, Inc.

Density of photon states in dye-doped chiral nematic liquid crystal cells in the presence of losses and gain.

PubMed

Mavrogordatos, Th K; Morris, S M; Castles, F; Hands, P J W; Ford, A D; Coles, H J; Wilkinson, T D

2012-07-01

We calculate the density of photon states (DOS) of the normal modes in dye-doped chiral nematic liquid crystal (LC) cells in the presence of various loss mechanisms. Losses and gain are incorporated into the transmission characteristics through the introduction of a small imaginary part in the dielectric constant perpendicular and along the director, for which we assume no frequency dispersion. Theoretical results are presented on the DOS in the region of the photonic band gap for a range of values of the loss coefficient and different values of the optical anisotropy. The obtained values of the DOS at the photonic band gap edges predict a reversal of the dominant modes in the structure. Our results are found to be in good agreement with the experimentally obtained excitation thresholds in chiral nematic LC lasers. The behavior of the DOS is also discussed for amplifying LC cells providing additional insight to the lasing mechanism of these structures.

Superhard BC 3 in cubic diamond structure

DOE PAGES

Zhang, Miao; Liu, Hanyu; Li, Quan; ...

2015-01-06

We solve the crystal structure of recently synthesized cubic BC 3 using an unbiased swarm structure search, which identifies a highly symmetric BC 3 phase in the cubic diamond structure (d–BC3) that contains a distinct B-B bonding network along the body diagonals of a large 64-atom unit cell. Simulated x-ray diffraction and Raman peaks of d–BC 3 are in excellent agreement with experimental data. Calculated stress-strain relations of d–BC 3 demonstrate its intrinsic superhard nature and reveal intriguing sequential bond-breaking modes that produce superior ductility and extended elasticity, which are unique among superhard solids. Here, the present results establish themore » first boron carbide in the cubic diamond structure with remarkable properties, and these new findings also provide insights for exploring other covalent solids with complex bonding configurations.« less

Structural insights into SAM domain‐mediated tankyrase oligomerization

PubMed Central

DaRosa, Paul A.; Ovchinnikov, Sergey

2016-01-01

Abstract Tankyrase 1 (TNKS1; a.k.a. ARTD5) and tankyrase 2 (TNKS2; a.k.a ARTD6) are highly homologous poly(ADP‐ribose) polymerases (PARPs) that function in a wide variety of cellular processes including Wnt signaling, Src signaling, Akt signaling, Glut4 vesicle translocation, telomere length regulation, and centriole and spindle pole maturation. Tankyrase proteins include a sterile alpha motif (SAM) domain that undergoes oligomerization in vitro and in vivo. However, the SAM domains of TNKS1 and TNKS2 have not been structurally characterized and the mode of oligomerization is not yet defined. Here we model the SAM domain‐mediated oligomerization of tankyrase. The structural model, supported by mutagenesis and NMR analysis, demonstrates a helical, homotypic head‐to‐tail polymer that facilitates TNKS self‐association. Furthermore, we show that TNKS1 and TNKS2 can form (TNKS1 SAM‐TNKS2 SAM) hetero‐oligomeric structures mediated by their SAM domains. Though wild‐type tankyrase proteins have very low solubility, model‐based mutations of the SAM oligomerization interface residues allowed us to obtain soluble TNKS proteins. These structural insights will be invaluable for the functional and biophysical characterization of TNKS1/2, including the role of TNKS oligomerization in protein poly(ADP‐ribosyl)ation (PARylation) and PARylation‐dependent ubiquitylation. PMID:27328430

Structural insights into SAM domain-mediated tankyrase oligomerization.

PubMed

DaRosa, Paul A; Ovchinnikov, Sergey; Xu, Wenqing; Klevit, Rachel E

2016-09-01

Tankyrase 1 (TNKS1; a.k.a. ARTD5) and tankyrase 2 (TNKS2; a.k.a ARTD6) are highly homologous poly(ADP-ribose) polymerases (PARPs) that function in a wide variety of cellular processes including Wnt signaling, Src signaling, Akt signaling, Glut4 vesicle translocation, telomere length regulation, and centriole and spindle pole maturation. Tankyrase proteins include a sterile alpha motif (SAM) domain that undergoes oligomerization in vitro and in vivo. However, the SAM domains of TNKS1 and TNKS2 have not been structurally characterized and the mode of oligomerization is not yet defined. Here we model the SAM domain-mediated oligomerization of tankyrase. The structural model, supported by mutagenesis and NMR analysis, demonstrates a helical, homotypic head-to-tail polymer that facilitates TNKS self-association. Furthermore, we show that TNKS1 and TNKS2 can form (TNKS1 SAM-TNKS2 SAM) hetero-oligomeric structures mediated by their SAM domains. Though wild-type tankyrase proteins have very low solubility, model-based mutations of the SAM oligomerization interface residues allowed us to obtain soluble TNKS proteins. These structural insights will be invaluable for the functional and biophysical characterization of TNKS1/2, including the role of TNKS oligomerization in protein poly(ADP-ribosyl)ation (PARylation) and PARylation-dependent ubiquitylation. © 2016 The Protein Society.

Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2

NASA Astrophysics Data System (ADS)

Kalinić, Marko; Zloh, Mire; Erić, Slavica

2014-11-01

Enhancer of Zeste Homolog 2 (EZH2) is a SET domain protein lysine methyltransferase (PKMT) which has recently emerged as a chemically tractable and therapeutically promising epigenetic target, evidenced by the discovery and characterization of potent and highly selective EZH2 inhibitors. However, no experimental structures of the inhibitors co-crystallized to EZH2 have been resolved, and the structural basis for their activity and selectivity remains unknown. Considering the need to minimize cross-reactivity between prospective PKMT inhibitors, much can be learned from understanding the molecular basis for selective inhibition of EZH2. Thus, to elucidate the binding of small-molecule inhibitors to EZH2, we have developed a model of its fully-formed cofactor binding site and used it to carry out molecular dynamics simulations of protein-ligand complexes, followed by molecular mechanics/generalized born surface area calculations. The obtained results are in good agreement with biochemical inhibition data and reflect the structure-activity relationships of known ligands. Our findings suggest that the variable and flexible post-SET domain plays an important role in inhibitor binding, allowing possibly distinct binding modes of inhibitors with only small variations in their structure. Insights from this study present a good basis for design of novel and optimization of existing compounds targeting the cofactor binding site of EZH2.

Anatomy of filamentary threshold switching in amorphous niobium oxide.

PubMed

Li, Shuai; Liu, Xinjun; Nandi, Sanjoy Kumar; Elliman, Robert Glen

2018-06-25

The threshold switching behaviour of Pt/NbOx/TiN devices is investigated as a function device area and NbOx film thickness and shown to reveal important insight into the structure of the self-assembled switching region. The devices exhibit combined selector-memory (1S1R) behavior after an initial voltage-controlled forming process, but exhibit symmetric threshold switching when the RESET and SET currents are kept below a critical value. In this mode, the threshold and hold voltages are independent of the device area and film thickness but the threshold current (power), while independent of device area, decreases with increasing film thickness. These results are shown to be consistent with a structure in which the threshold switching volume is confined, both laterally and vertically, to the region between the residual memory filament and the TiN electrode, and where the memory filament has a core-shell structure comprising a metallic core and a semiconducting shell. The veracity of this structure is demonstrated by comparing experimental results with the predictions of a simple circuit model, and more detailed finite element simulations. These results provide further insight into the structure and operation of NbOx threshold switching devices that have application in emerging memory and neuromorphic computing fields. © 2018 IOP Publishing Ltd.

An assessment of spacecraft target mode selection methods

NASA Astrophysics Data System (ADS)

Mercer, J. F.; Aglietti, G. S.; Remedia, M.; Kiley, A.

2017-11-01

Coupled Loads Analyses (CLAs), using finite element models (FEMs) of the spacecraft and launch vehicle to simulate critical flight events, are performed in order to determine the dynamic loadings that will be experienced by spacecraft during launch. A validation process is carried out on the spacecraft FEM beforehand to ensure that the dynamics of the analytical model sufficiently represent the behavior of the physical hardware. One aspect of concern is the containment of the FEM correlation and update effort to focus on the vibration modes which are most likely to be excited under test and CLA conditions. This study therefore provides new insight into the prioritization of spacecraft FEM modes for correlation to base-shake vibration test data. The work involved example application to large, unique, scientific spacecraft, with modern FEMs comprising over a million degrees of freedom. This comprehensive investigation explores: the modes inherently important to the spacecraft structures, irrespective of excitation; the particular 'critical modes' which produce peak responses to CLA level excitation; an assessment of several traditional target mode selection methods in terms of ability to predict these 'critical modes'; and an indication of the level of correlation these FEM modes achieve compared to corresponding test data. Findings indicate that, although the traditional methods of target mode selection have merit and are able to identify many of the modes of significance to the spacecraft, there are 'critical modes' which may be missed by conventional application of these methods. The use of different thresholds to select potential target modes from these parameters would enable identification of many of these missed modes. Ultimately, some consideration of the expected excitations is required to predict all modes likely to contribute to the response of the spacecraft in operation.

Novel method to control antenna currents based on theory of characteristic modes

NASA Astrophysics Data System (ADS)

Elghannai, Ezdeen Ahmed

Characteristic Mode Theory is one of the very few numerical methods that provide a great deal of physical insight because it allows us to determine the natural modes of the radiating structure. The key feature of these modes is that the total induced antenna current, input impedance/admittance and radiation pattern can be expressed as a linear weighted combination of individual modes. Using this decomposition method, it is possible to study the behavior of the individual modes, understand them and therefore control the antennas behavior; in other words, control the currents induced on the antenna structure. This dissertation advances the topic of antenna design by carefully controlling the antenna currents over the desired frequency band to achieve the desired performance specifications for a set of constraints. Here, a systematic method based on the Theory of Characteristic Modes (CM) and lumped reactive loading to achieve the goal of current control is developed. The lumped reactive loads are determined based on the desired behavior of the antenna currents. This technique can also be used to impedance match the antenna to the source/generator connected to it. The technique is much more general than the traditional impedance matching. Generally, the reactive loads that properly control the currents exhibit a combination of Foster and non-Foster behavior. The former can be implemented with lumped passive reactive components, while the latter can be implemented with lumped non-Foster circuits (NFC). The concept of current control is applied to design antennas with a wide band (impedance/pattern) behavior using reactive loads. We successfully applied this novel technique to design multi band and wide band antennas for wireless applications. The technique was developed to match the antenna to resistive and/or complex source impedance and control the radiation pattern at these frequency bands, considering size and volume constraints. A wide band patch antenna was achieved using the developed technique. In addition, the technique was applied to multi band wire less Universal Serial Bus (USB) dongle antenna that serves for WLAN IEEE 802.11 a/b/g/n band applications and Radio Frequency Identification (RFID) tag antenna for 915MHz band applications with superior performance compared to previous published results. This dissertation also discusses the total Q of an antenna from the CM standpoint. A new expression as well as additional physical information about each mode's individual contribution to the total antenna Q are provided. Finally, the theory is used to an analyze the antenna in both radiation and/or scattering modes. In the antenna scattering mode, the field scattered by an antenna contains a component that is the short circuit scattered field, and a second component that is proportional to the radiation field. In this dissertation, an analytical study of this phenomena from the CM standpoint is performed aiming to shed some light on antenna scattering phenomenon where additional physical insight is obtained and thus used to reach desire results.

Structural insight into RNA recognition motifs: versatile molecular Lego building blocks for biological systems.

PubMed

Muto, Yutaka; Yokoyama, Shigeyuki

2012-01-01

'RNA recognition motifs (RRMs)' are common domain-folds composed of 80-90 amino-acid residues in eukaryotes, and have been identified in many cellular proteins. At first they were known as RNA binding domains. Through discoveries over the past 20 years, however, the RRMs have been shown to exhibit versatile molecular recognition activities and to behave as molecular Lego building blocks to construct biological systems. Novel RNA/protein recognition modes by RRMs are being identified, and more information about the molecular recognition by RRMs is becoming available. These RNA/protein recognition modes are strongly correlated with their biological significance. In this review, we would like to survey the recent progress on these versatile molecular recognition modules. Copyright © 2012 John Wiley & Sons, Ltd.

Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals

NASA Astrophysics Data System (ADS)

Tian, Zhen; Liu, Jiyuan; Zhang, Yalin

2016-03-01

Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses.

Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals

PubMed Central

Tian, Zhen; Liu, Jiyuan; Zhang, Yalin

2016-01-01

Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses. PMID:26928635

Proximity-interference wake-induced vibration at subcritical Re: Mechanism analysis using a linear dynamic model

NASA Astrophysics Data System (ADS)

Li, Xintao; Zhang, Weiwei; Gao, Chuanqiang

2018-03-01

Wake-induced vibration (WIV) contains rich and complex phenomena due to the flow interference between cylinders. The aim of the present study is to gain physical insight into the intrinsic dynamics of WIV via linear stability analysis (LSA) of the fluid-structure interaction (FSI) system. A reduced-order-model-based linear dynamic model, combined with the direct computational fluid dynamics/computational structural dynamics simulation method, is adopted to investigate WIV in two identical tandem cylinders at low Re. The spacing ratio L/D, with L as the center-to-center distance and D as the diameter of cylinders, is selected as 2.0 to consider the effect of proximity flow interference. Results show that extensive WIV along with the vortex shedding could occur at subcritical Re conditions due to the instability of one coupled mode (i.e., coupled mode I, CM-I) of the FSI system. The eigenfrequency of CM-I transfers smoothly from close to the reduced natural frequency of structure to the eigenfrequency of uncoupled wake mode as the reduced velocity U* increases. Thus, CM-I characterizes as the structure mode (SM) at low U*, while it characterizes as the wake mode (WM) at large U*. Mode conversion of CM-I is the primary cause of the "frequency transition" phenomenon observed in WIV responses. Furthermore, LSA indicates that there exists a critical mass ratio mcr*, below which no upper instability boundary of CM-I exists (Uup p e r *→∞ ). The unbounded instability of CM-I ultimately leads to the "infinite WIV" phenomenon. The neutral stability boundaries for WIV in the (Re, U*) plane are determined through LSA. It is shown that the lowest Re possible for WIV regarding the present configuration is R el o w e s t≈34 . LSA accurately captures the dynamics of WIV at subcritical Re and reveals that it is essentially a fluid-elastic instability problem. This work lays a good foundation for the investigation of WIV at supercritical high Re and gives enlightenment to the understanding of more complex WIV phenomena therein.

WEBnm@ v2.0: Web server and services for comparing protein flexibility.

PubMed

Tiwari, Sandhya P; Fuglebakk, Edvin; Hollup, Siv M; Skjærven, Lars; Cragnolini, Tristan; Grindhaug, Svenn H; Tekle, Kidane M; Reuter, Nathalie

2014-12-30

Normal mode analysis (NMA) using elastic network models is a reliable and cost-effective computational method to characterise protein flexibility and by extension, their dynamics. Further insight into the dynamics-function relationship can be gained by comparing protein motions between protein homologs and functional classifications. This can be achieved by comparing normal modes obtained from sets of evolutionary related proteins. We have developed an automated tool for comparative NMA of a set of pre-aligned protein structures. The user can submit a sequence alignment in the FASTA format and the corresponding coordinate files in the Protein Data Bank (PDB) format. The computed normalised squared atomic fluctuations and atomic deformation energies of the submitted structures can be easily compared on graphs provided by the web user interface. The web server provides pairwise comparison of the dynamics of all proteins included in the submitted set using two measures: the Root Mean Squared Inner Product and the Bhattacharyya Coefficient. The Comparative Analysis has been implemented on our web server for NMA, WEBnm@, which also provides recently upgraded functionality for NMA of single protein structures. This includes new visualisations of protein motion, visualisation of inter-residue correlations and the analysis of conformational change using the overlap analysis. In addition, programmatic access to WEBnm@ is now available through a SOAP-based web service. Webnm@ is available at http://apps.cbu.uib.no/webnma . WEBnm@ v2.0 is an online tool offering unique capability for comparative NMA on multiple protein structures. Along with a convenient web interface, powerful computing resources, and several methods for mode analyses, WEBnm@ facilitates the assessment of protein flexibility within protein families and superfamilies. These analyses can give a good view of how the structures move and how the flexibility is conserved over the different structures.

Structural insights into the oligomerization mode of the human receptor for advanced glycation end-products.

PubMed

Yatime, Laure; Andersen, Gregers R

2013-12-01

The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor sensing endogenous stress signals associated with the development of various diseases, including diabetes, vascular complications, Alzheimer's disease and cancer. RAGE ligands include advanced glycation end-products, S100 proteins, high mobility group box 1 protein and amyloid β-peptides/fibrils. Their signalling through RAGE induces a sustained inflammation that accentuates tissue damage, thereby participating in disease progression. Receptor oligomerization appears to be a crucial parameter for the formation of active signalling complexes, although the precise mode of oligomerization remains unclear in the context of these various ligands. In the present study, we report the first crystal structure of the VC1C2 fragment of the RAGE ectodomain. This structure provides the first description of the C2 domain in the context of the entire ectodomain and supports the observation of its conformational freedom relative to the rigid VC1 domain tandem. In addition, we have obtained a new crystal structure of the RAGE VC1 fragment. The packing in both crystal structures reveals an association of the RAGE molecules through contacts between two V domains and the physiological relevance of this homodimerization mode is discussed. Based on homology with single-pass transmembrane receptors, we also suggest RAGE dimerization through a conserved GxxxG motif within its transmembrane domain. A multimodal homodimerization strategy of RAGE is proposed to form the structural basis for ligand-specific complex formation and signalling functions, as well as for RAGE-mediated cell adhesion. hRAGE_VC1C2 and hRAGE_VC1C2 bind by x-ray crystallography (View interaction) hRAGE_VC1 and hRAGE_VC1 bind by x-ray crystallography (View interaction). © 2013 FEBS.

Tunneling Mode of Scanning Electrochemical Microscopy: Probing Electrochemical Processes at Single Nanoparticles.

PubMed

Sun, Tong; Wang, Dengchao; Mirkin, Michael V

2018-06-18

Electrochemical experiments at individual nanoparticles (NPs) can provide new insights into their structure-activity relationships. By using small nanoelectrodes as tips in a scanning electrochemical microscope (SECM), we recently imaged individual surface-bound 10-50 nm metal NPs. Herein, we introduce a new mode of SECM operation based on tunneling between the tip and a nanoparticle immobilized on the insulating surface. The obtained current vs. distance curves show the transition from the conventional feedback response to electron tunneling between the tip and the NP at separation distances of less than about 3 nm. In addition to high-resolution imaging of the NP topography, the tunneling mode enables measurement of the heterogeneous kinetics at a single NP without making an ohmic contact with it. The developed method should be useful for studying the effects of nanoparticle size and geometry on electrocatalytic activity in real-world applications. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Constraints on the structure of the core of subgiants via mixed modes: the case of HD 49385

NASA Astrophysics Data System (ADS)

Deheuvels, S.; Michel, E.

2011-11-01

Context. The solar-like pulsator HD 49385 was observed with the CoRoT satellite over a period of 137 days. The analysis of its oscillation spectrum yielded precise estimates of the mode frequencies over nine radial orders and distinguished some unusual characteristics, such as some modes outside the identified ridges in the échelle diagram and that the curvature of the ℓ = 1 ridge differs significantly from that of the ℓ = 0 ridge. Aims: We search for stellar models that can reproduce the peculiar features of the oscillation spectrum of HD 49385. After showing that they can be accounted for only by a low-frequency ℓ = 1 avoided crossing, we investigate the information provided by the mixed modes about the structure of the core of HD 49385. Methods: We propose a toy-model to study the case of avoided crossings with a strong coupling between the p-mode and g-mode cavities in order to establish the presence of mixed modes in the spectrum of HD 49385. We then show that traditional optimization techniques are ill-suited to stars with mixed modes in avoided crossing. We propose a new approach to the computation of grids of models that we apply to HD 49385. Results: The detection of mixed modes leads us to establish the post-main-sequence status of HD 49385. The mixed mode frequencies suggest that there is a strong coupling between the p-mode and g-mode cavities. As a result, we show that the amount of core overshooting in HD 49385 is either very small (0 < αov < 0.05) or moderate (0.18 < αov < 0.20). The mixing length parameter is found to be significantly lower than the solar one (αCGM = 0.55 ± 0.04 compared to the solar value α⊙ = 0.64). Finally, we show that the revised solar abundances of Asplund ensure closer agreement with the observations than the classical ones of Grevesse & Noels. At each step, we investigate the origin and meaning of these seismic diagnostics in terms of the physical structure of the star. Conclusions: The subgiant HD 49385 is the first star for which a thorough modeling has been attempted to reproduce all the properties of an avoided crossing. It has provided the opportunity to show that the study of the coupling between the cavities in these stars can provide valuable insight into open questions such as core overshooting, the efficiency of convection, and the abundances of heavy elements in stars.

Continuous-Flow MOVPE of Ga-Polar GaN Column Arrays and Core-Shell LED Structures

NASA Astrophysics Data System (ADS)

Wang, Xue; Li, Shunfeng; Mohajerani, Matin Sadat; Ledig, Johannes; Wehmann, Hergo-Heinrich; Mandl, Martin; Strassburg, Martin; Steegmüller, Ulrich; Jahn, Uwe; Lähnemann, Jonas; Riechert, Henning; Griffiths, Ian; Cherns, David; Waag, Andreas

2013-06-01

Arrays of dislocation free uniform Ga-polar GaN columns have been realized on patterned SiOx/GaN/sapphire templates by metal organic vapor phase epitaxy using a continuous growth mode. The key parameters and the physical principles of growth of Ga-polar GaN three-dimensional columns are identified, and their potential for manipulating the growth process is discussed. High aspect ratio columns have been achieved using silane during the growth, leading to n-type columns. The vertical growth rate increases with increasing silane flow. In a core-shell columnar LED structure, the shells of InGaN/GaN multi quantum wells and p-GaN have been realized on a core of n-doped GaN column. Cathodoluminescence gives insight into the inner structure of these core-shell LED structures.

Penetration of filamentary structures in the x-point region of spherical tokamaks

NASA Astrophysics Data System (ADS)

Baver, D. A.; Myra, J. R.; Scotti, F.; Zweben, S. J.; Militello, F.; Walkden, N.

2017-10-01

ArbiTER is a flexible eigenvalue code designed for plasma physics applications. It is used here to gain insight into the spatial dependence of filamentary structures in the scrape-off layer of spherical tokamaks. In particular, observations on MAST reveal the presence of a quiescent x-point region. Observations in NSTX similarly reveal a reduction in divertor fluctuations near the separatrix and a loss of midplane correlation. We will report on the penetration of filamentary structures into the vicinity of the x-point, as well as growth rate trends, for a variety of profiles and toroidal mode numbers. This will determine whether linear properties of these structures can explain experimental observations. Work supported by the U.S. Department of Energy Office of Science, Office of Fusion Energy Sciences, under Award Number DE-FG02-02ER54678.

Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators.

PubMed

Bohl, Casey E; Wu, Zengru; Chen, Jiyun; Mohler, Michael L; Yang, Jun; Hwang, Dong Jin; Mustafa, Suni; Miller, Duane D; Bell, Charles E; Dalton, James T

2008-10-15

Selective androgen receptor modulators (SARMs) are essentially prostate sparing androgens, which provide therapeutic potential in osteoporosis, male hormone replacement, and muscle wasting. Herein we report crystal structures of the androgen receptor (AR) ligand-binding domain (LBD) complexed to a series of potent synthetic nonsteroidal SARMs with a substituted pendant arene referred to as the B-ring. We found that hydrophilic B-ring para-substituted analogs exhibit an additional region of hydrogen bonding not seen with steroidal compounds and that multiple halogen substitutions affect the B-ring conformation and aromatic interactions with Trp741. This information elucidates interactions important for high AR binding affinity and provides new insight for structure-based drug design.

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2

DOE PAGES

Qiu, Wei; Lam, Robert; Voytyuk, Oleksandr; ...

2014-07-31

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, themore » high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.« less

Structure resonances due to space charge in periodic focusing channels

NASA Astrophysics Data System (ADS)

Li, Chao; Jameson, R. A.

2018-02-01

The Vlasov-Poisson model is one of the most effective methods to study the space charge dominated beam evolution self-consistently in a periodic focusing channel. Since the approach to get the solution with this model is not trivial, previous studies are limited in degenerated conditions, either in smoothed channel (constant focusing) [I. Hofmann, Phys. Rev. E 57, 4713 (1998)] or in alternating gradient focusing channel with equal initial beam emittance condition in the degrees of freedom [I. Hofmann et al., Part. Accel. 13, 145 (1983); Chao Li et al., THOBA02, IPAC2016]. To establish a basis, we intentionally limit this article to the study of the pure transverse periodic focusing lattice with arbitrary initial beam condition, and the same lattice structure in both degrees of freedom, but with possibility of different focusing strengths. This will show the extension of the existing work. The full Hamiltonian is invoked for a pure transverse focusing lattice in various initial beam conditions, revealing different mode structure and additional modes beyond those of the degenerated cases. Application of the extended method to realistic lattices (including longitudinal accelerating elements) and further details will then reveal many new insights, and will be presented in later work.

Elastic strain and twist analysis of protein structural data and allostery of the transmembrane channel KcsA

NASA Astrophysics Data System (ADS)

Mitchell, Michael R.; Leibler, Stanislas

2018-05-01

The abundance of available static protein structural data makes the more effective analysis and interpretation of this data a valuable tool to supplement the experimental study of protein mechanics. Structural displacements can be difficult to analyze and interpret. Previously, we showed that strains provide a more natural and interpretable representation of protein deformations, revealing mechanical coupling between spatially distinct sites of allosteric proteins. Here, we demonstrate that other transformations of displacements yield additional insights. We calculate the divergence and curl of deformations of the transmembrane channel KcsA. Additionally, we introduce quantities analogous to bend, splay, and twist deformation energies of nematic liquid crystals. These transformations enable the decomposition of displacements into different modes of deformation, helping to characterize the type of deformation a protein undergoes. We apply these calculations to study the filter and gating regions of KcsA. We observe a continuous path of rotational deformations physically coupling these two regions, and, we propose, underlying the allosteric interaction between these regions. Bend, splay, and twist distinguish KcsA gate opening, filter opening, and filter-gate coupling, respectively. In general, physically meaningful representations of deformations (like strain, curl, bend, splay, and twist) can make testable predictions and yield insights into protein mechanics, augmenting experimental methods and more fully exploiting available structural data.

The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation

PubMed Central

Mueller-Dieckmann, Christoph; Kernstock, Stefan; Lisurek, Michael; von Kries, Jens Peter; Haag, Friedrich; Weiss, Manfred S.; Koch-Nolte, Friedrich

2006-01-01

Posttranslational modifications are used by cells from all kingdoms of life to control enzymatic activity and to regulate protein function. For many cellular processes, including DNA repair, spindle function, and apoptosis, reversible mono- and polyADP-ribosylation constitutes a very important regulatory mechanism. Moreover, many pathogenic bacteria secrete toxins which ADP-ribosylate human proteins, causing diseases such as whooping cough, cholera, and diphtheria. Whereas the 3D structures of numerous ADP-ribosylating toxins and related mammalian enzymes have been elucidated, virtually nothing is known about the structure of protein de-ADP-ribosylating enzymes. Here, we report the 3Dstructure of human ADP-ribosylhydrolase 3 (hARH3). The molecular architecture of hARH3 constitutes the archetype of an all-α-helical protein fold and provides insights into the reversibility of protein ADP-ribosylation. Two magnesium ions flanked by highly conserved amino acids pinpoint the active-site crevice. Recombinant hARH3 binds free ADP-ribose with micromolar affinity and efficiently de-ADP-ribosylates poly- but not monoADP-ribosylated proteins. Docking experiments indicate a possible binding mode for ADP-ribose polymers and suggest a reaction mechanism. Our results underscore the importance of endogenous ADP-ribosylation cycles and provide a basis for structure-based design of ADP-ribosylhydrolase inhibitors. PMID:17015823

Femtosecond manipulation of spins, charges, and ions in nanostructures, thin films, and surfaces

PubMed Central

Carbone, F.; Hengsberger, M.; Castiglioni, L.; Osterwalder, J.

2017-01-01

Modern ultrafast techniques provide new insights into the dynamics of ions, charges, and spins in photoexcited nanostructures. In this review, we describe the use of time-resolved electron-based methods to address specific questions such as the ordering properties of self-assembled nanoparticles supracrystals, the interplay between electronic and structural dynamics in surfaces and adsorbate layers, the light-induced control of collective electronic modes in nanowires and thin films, and the real-space/real-time evolution of the skyrmion lattice in topological magnets. PMID:29308416

Ideas That Work! The Midnight Audit

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

Parker, Steven A.

The midnight audit provides valuable insight toward identifying opportunities to reduce energy consumption—insight that can be easily overlooked during the normal (daytime) energy auditing process. The purpose of the midnight audit is to observe after-hour operation with the mindset of seeking ways to further minimize energy consumption during the unoccupied mode and minimize energy waste by reducing unnecessary operation. The midnight audit should be used to verify that equipment is off when it is supposed to be, or operating in set-back mode when applicable. Even a facility that operates 2 shifts per day, 5 days per week experiences fewer annualmore » hours in occupied mode than it does during unoccupied mode. Minimizing energy loads during unoccupied hours can save significant energy, which is why the midnight audit is an Idea That Works.« less

Structural Characterization of CO-Inhibited Mo-Nitrogenase by Combined Application of Nuclear Resonance Vibrational Spectroscopy, Extended X-ray Absorption Fine Structure, and Density Functional Theory: New Insights into the Effects of CO Binding and the Role of the Interstitial Atom

DOE PAGES

Scott, Aubrey D.; Pelmenschikov, Vladimir; Guo, Yisong; ...

2014-10-02

The properties of CO-inhibited Azotobacter vinelandii (Av) Mo-nitrogenase (N 2ase) have been examined by the combined application of nuclear resonance vibrational spectroscopy (NRVS), extended X-ray absorption fine structure (EXAFS), and density functional theory (DFT). Dramatic changes in the NRVS are seen under high-CO conditions, especially in a 188 cm –1 mode associated with symmetric breathing of the central cage of the FeMo-cofactor. Similar changes are reproduced with the α-H195Q N 2ase variant. In the frequency region above 450 cm –1, additional features are seen that are assigned to Fe-CO bending and stretching modes (confirmed by 13CO isotope shifts). The EXAFSmore » for wild-type N 2ase shows evidence for a significant cluster distortion under high-CO conditions, most dramatically in the splitting of the interaction between Mo and the shell of Fe atoms originally at 5.08 Å in the resting enzyme. A DFT model with both a terminal ₋CO and a partially reduced ₋CHO ligand bound to adjacent Fe sites is consistent with both earlier FT-IR experiments, and the present EXAFS and NRVS observations for the wild-type enzyme. Another DFT model with two terminal CO ligands on the adjacent Fe atoms yields Fe-CO bands consistent with the α-H195Q variant NRVS. The calculations also shed light on the vibrational “shake” modes of the interstitial atom inside the central cage, and their interaction with the Fe-CO modes. We discuss implications for the CO and N 2 reactivity of N 2ase.« less

Femtosecond coherent nuclear dynamics of excited tetraphenylethylene: Ultrafast transient absorption and ultrafast Raman loss spectroscopic studies

NASA Astrophysics Data System (ADS)

Kayal, Surajit; Roy, Khokan; Umapathy, Siva

2018-01-01

Ultrafast torsional dynamics plays an important role in the photoinduced excited state dynamics. Tetraphenylethylene (TPE), a model system for the molecular motor, executes interesting torsional dynamics upon photoexcitation. The photoreaction of TPE involves ultrafast internal conversion via a nearly planar intermediate state (relaxed state) that further leads to a twisted zwitterionic state. Here, we report the photoinduced structural dynamics of excited TPE during the course of photoisomerization in the condensed phase by ultrafast Raman loss (URLS) and femtosecond transient absorption (TA) spectroscopy. TA measurements on the S1 state reveal step-wise population relaxation from the Franck-Condon (FC) state → relaxed state → twisted state, while the URLS study provides insights on the vibrational dynamics during the course of the reaction. The TA spectral dynamics and vibrational Raman amplitudes within 1 ps reveal vibrational wave packet propagating from the FC state to the relaxed state. Fourier transformation of this oscillation leads to a ˜130 cm-1 low-frequency phenyl torsional mode. Two vibrational marker bands, Cet=Cet stretching (˜1512 cm-1) and Cph=Cph stretching (˜1584 cm-1) modes, appear immediately after photoexcitation in the URLS spectra. The initial red-shift of the Cph=Cph stretching mode with a time constant of ˜400 fs (in butyronitrile) is assigned to the rate of planarization of excited TPE. In addition, the Cet=Cet stretching mode shows initial blue-shift within 1 ps followed by frequency red-shift, suggesting that on the sub-picosecond time scale, structural relaxation is dominated by phenyl torsion rather than the central Cet=Cet twist. Furthermore, the effect of the solvent on the structural dynamics is discussed in the context of ultrafast nuclear dynamics and solute-solvent coupling.

Femtosecond coherent nuclear dynamics of excited tetraphenylethylene: Ultrafast transient absorption and ultrafast Raman loss spectroscopic studies.

PubMed

Kayal, Surajit; Roy, Khokan; Umapathy, Siva

2018-01-14

Ultrafast torsional dynamics plays an important role in the photoinduced excited state dynamics. Tetraphenylethylene (TPE), a model system for the molecular motor, executes interesting torsional dynamics upon photoexcitation. The photoreaction of TPE involves ultrafast internal conversion via a nearly planar intermediate state (relaxed state) that further leads to a twisted zwitterionic state. Here, we report the photoinduced structural dynamics of excited TPE during the course of photoisomerization in the condensed phase by ultrafast Raman loss (URLS) and femtosecond transient absorption (TA) spectroscopy. TA measurements on the S 1 state reveal step-wise population relaxation from the Franck-Condon (FC) state → relaxed state → twisted state, while the URLS study provides insights on the vibrational dynamics during the course of the reaction. The TA spectral dynamics and vibrational Raman amplitudes within 1 ps reveal vibrational wave packet propagating from the FC state to the relaxed state. Fourier transformation of this oscillation leads to a ∼130 cm -1 low-frequency phenyl torsional mode. Two vibrational marker bands, C et =C et stretching (∼1512 cm -1 ) and C ph =C ph stretching (∼1584 cm -1 ) modes, appear immediately after photoexcitation in the URLS spectra. The initial red-shift of the C ph =C ph stretching mode with a time constant of ∼400 fs (in butyronitrile) is assigned to the rate of planarization of excited TPE. In addition, the C et =C et stretching mode shows initial blue-shift within 1 ps followed by frequency red-shift, suggesting that on the sub-picosecond time scale, structural relaxation is dominated by phenyl torsion rather than the central C et =C et twist. Furthermore, the effect of the solvent on the structural dynamics is discussed in the context of ultrafast nuclear dynamics and solute-solvent coupling.

Design and Experimental Study of an Over-Under TBCC Exhaust System.

PubMed

Mo, Jianwei; Xu, Jinglei; Zhang, Liuhuan

2014-01-01

Turbine-based combined-cycle (TBCC) propulsion systems have been a topic of research as a means for more efficient flight at supersonic and hypersonic speeds. The present study focuses on the fundamental physics of the complex flow in the TBCC exhaust system during the transition mode as the turbine exhaust is shut off and the ramjet exhaust is increased. A TBCC exhaust system was designed using methods of characteristics (MOC) and subjected to experimental and computational study. The main objectives of the study were: (1) to identify the interactions between the two exhaust jet streams during the transition mode phase and their effects on the whole flow-field structure; (2) to determine and verify the aerodynamic performance of the over-under TBCC exhaust nozzle; and (3) to validate the simulation ability of the computational fluid dynamics (CFD) software according to the experimental conditions. Static pressure taps and Schlieren apparatus were employed to obtain the wall pressure distributions and flow-field structures. Steady-state tests were performed with the ramjet nozzle cowl at six different positions at which the turbine flow path were half closed and fully opened, respectively. Methods of CFD were used to simulate the exhaust flow and they complemented the experimental study by providing greater insight into the details of the flow field and a means of verifying the experimental results. Results indicated that the flow structure was complicated because the two exhaust jet streams interacted with each other during the exhaust system mode transition. The exhaust system thrust coefficient varied from 0.9288 to 0.9657 during the process. The CFD simulation results agree well with the experimental data, which demonstrated that the CFD methods were effective in evaluating the aerodynamic performance of the TBCC exhaust system during the mode transition.

The molecular structure of the phosphate mineral beraunite Fe2+Fe53+(PO4)4(OH)5ṡ4H2O - A vibrational spectroscopic study

NASA Astrophysics Data System (ADS)

Frost, Ray L.; López, Andrés; Scholz, Ricardo; Xi, Yunfei; Lana, Cristiano

2014-07-01

The mineral beraunite from Boca Rica pegmatite in Minas Gerais with theoretical formula Fe2+Fe53+(PO4)4(OH)5ṡ4H2O has been studied using a combination of electron microscopy with EDX and vibrational spectroscopic techniques. Raman spectroscopy identifies an intense band at 990 cm-1 and 1011 cm-1. These bands are attributed to the PO43- ν1 symmetric stretching mode. The ν3 antisymmetric stretching modes are observed by a large number of Raman bands. The Raman bands at 1034, 1051, 1058, 1069 and 1084 together with the Raman bands at 1098, 1116, 1133, 1155 and 1174 cm-1 are assigned to the ν3 antisymmetric stretching vibrations of PO43- and the HOPO32- units. The observation of these multiple Raman bands in the symmetric and antisymmetric stretching region gives credence to the concept that both phosphate and hydrogen phosphate units exist in the structure of beraunite. The series of Raman bands at 567, 582, 601, 644, 661, 673, and 687 cm-1 are assigned to the PO43- ν2 bending modes. The series of Raman bands at 437, 468, 478, 491, 503 cm-1 are attributed to the PO43- and HOPO32- ν4 bending modes. No Raman bands of beraunite which could be attributed to the hydroxyl stretching unit were observed. Infrared bands at 3511 and 3359 cm-1 are ascribed to the OH stretching vibration of the OH units. Very broad bands at 3022 and 3299 cm-1 are attributed to the OH stretching vibrations of water. Vibrational spectroscopy offers insights into the molecular structure of the phosphate mineral beraunite.

Structural characterization of CO-inhibited Mo-nitrogenase by combined application of nuclear resonance vibrational spectroscopy, extended X-ray absorption fine structure, and density functional theory: new insights into the effects of CO binding and the role of the interstitial atom.

PubMed

Scott, Aubrey D; Pelmenschikov, Vladimir; Guo, Yisong; Yan, Lifen; Wang, Hongxin; George, Simon J; Dapper, Christie H; Newton, William E; Yoda, Yoshitaka; Tanaka, Yoshihito; Cramer, Stephen P

2014-11-12

The properties of CO-inhibited Azotobacter vinelandii (Av) Mo-nitrogenase (N2ase) have been examined by the combined application of nuclear resonance vibrational spectroscopy (NRVS), extended X-ray absorption fine structure (EXAFS), and density functional theory (DFT). Dramatic changes in the NRVS are seen under high-CO conditions, especially in a 188 cm(-1) mode associated with symmetric breathing of the central cage of the FeMo-cofactor. Similar changes are reproduced with the α-H195Q N2ase variant. In the frequency region above 450 cm(-1), additional features are seen that are assigned to Fe-CO bending and stretching modes (confirmed by (13)CO isotope shifts). The EXAFS for wild-type N2ase shows evidence for a significant cluster distortion under high-CO conditions, most dramatically in the splitting of the interaction between Mo and the shell of Fe atoms originally at 5.08 Å in the resting enzyme. A DFT model with both a terminal -CO and a partially reduced -CHO ligand bound to adjacent Fe sites is consistent with both earlier FT-IR experiments, and the present EXAFS and NRVS observations for the wild-type enzyme. Another DFT model with two terminal CO ligands on the adjacent Fe atoms yields Fe-CO bands consistent with the α-H195Q variant NRVS. The calculations also shed light on the vibrational "shake" modes of the interstitial atom inside the central cage, and their interaction with the Fe-CO modes. Implications for the CO and N2 reactivity of N2ase are discussed.

Stationary zonal flows during the formation of the edge transport barrier in the JET tokamak

DOE PAGES

Hillesheim, J. C.; Meyer, H.; Maggi, C. F.; ...

2016-02-10

In this study, high spatial resolution Doppler backscattering measurements in JET have enabled new insights into the development of the edge E r. We observe fine-scale spatial structures in the edge E r well with a wave number k rρi ≈ 0.4-0.8, consistent with stationary zonal flows, the characteristics of which vary with density. The zonal flow amplitude and wavelength both decrease with local collisionality, such that the zonal flow E x B shear increases. Above the minimum of the L-H transition power threshold dependence on density, the zonal flows are present during L mode and disappear following the H-modemore » transition, while below the minimum they are reduced below measurable amplitude during L mode, before the L-H transition.« less

Statistical discovery of site inter-dependencies in sub-molecular hierarchical protein structuring

PubMed Central

2012-01-01

Background Much progress has been made in understanding the 3D structure of proteins using methods such as NMR and X-ray crystallography. The resulting 3D structures are extremely informative, but do not always reveal which sites and residues within the structure are of special importance. Recently, there are indications that multiple-residue, sub-domain structural relationships within the larger 3D consensus structure of a protein can be inferred from the analysis of the multiple sequence alignment data of a protein family. These intra-dependent clusters of associated sites are used to indicate hierarchical inter-residue relationships within the 3D structure. To reveal the patterns of associations among individual amino acids or sub-domain components within the structure, we apply a k-modes attribute (aligned site) clustering algorithm to the ubiquitin and transthyretin families in order to discover associations among groups of sites within the multiple sequence alignment. We then observe what these associations imply within the 3D structure of these two protein families. Results The k-modes site clustering algorithm we developed maximizes the intra-group interdependencies based on a normalized mutual information measure. The clusters formed correspond to sub-structural components or binding and interface locations. Applying this data-directed method to the ubiquitin and transthyretin protein family multiple sequence alignments as a test bed, we located numerous interesting associations of interdependent sites. These clusters were then arranged into cluster tree diagrams which revealed four structural sub-domains within the single domain structure of ubiquitin and a single large sub-domain within transthyretin associated with the interface among transthyretin monomers. In addition, several clusters of mutually interdependent sites were discovered for each protein family, each of which appear to play an important role in the molecular structure and/or function. Conclusions Our results demonstrate that the method we present here using a k-modes site clustering algorithm based on interdependency evaluation among sites obtained from a sequence alignment of homologous proteins can provide significant insights into the complex, hierarchical inter-residue structural relationships within the 3D structure of a protein family. PMID:22793672

Statistical discovery of site inter-dependencies in sub-molecular hierarchical protein structuring.

PubMed

Durston, Kirk K; Chiu, David Ky; Wong, Andrew Kc; Li, Gary Cl

2012-07-13

Much progress has been made in understanding the 3D structure of proteins using methods such as NMR and X-ray crystallography. The resulting 3D structures are extremely informative, but do not always reveal which sites and residues within the structure are of special importance. Recently, there are indications that multiple-residue, sub-domain structural relationships within the larger 3D consensus structure of a protein can be inferred from the analysis of the multiple sequence alignment data of a protein family. These intra-dependent clusters of associated sites are used to indicate hierarchical inter-residue relationships within the 3D structure. To reveal the patterns of associations among individual amino acids or sub-domain components within the structure, we apply a k-modes attribute (aligned site) clustering algorithm to the ubiquitin and transthyretin families in order to discover associations among groups of sites within the multiple sequence alignment. We then observe what these associations imply within the 3D structure of these two protein families. The k-modes site clustering algorithm we developed maximizes the intra-group interdependencies based on a normalized mutual information measure. The clusters formed correspond to sub-structural components or binding and interface locations. Applying this data-directed method to the ubiquitin and transthyretin protein family multiple sequence alignments as a test bed, we located numerous interesting associations of interdependent sites. These clusters were then arranged into cluster tree diagrams which revealed four structural sub-domains within the single domain structure of ubiquitin and a single large sub-domain within transthyretin associated with the interface among transthyretin monomers. In addition, several clusters of mutually interdependent sites were discovered for each protein family, each of which appear to play an important role in the molecular structure and/or function. Our results demonstrate that the method we present here using a k-modes site clustering algorithm based on interdependency evaluation among sites obtained from a sequence alignment of homologous proteins can provide significant insights into the complex, hierarchical inter-residue structural relationships within the 3D structure of a protein family.

Characterizing the structure-function relationship reveals the mode of action of a novel antimicrobial peptide, P1, from jumper ant Myrmecia pilosula.

PubMed

Tseng, Tien-Sheng; Tsai, Keng-Chang; Chen, Chinpan

2017-06-01

Microbial infections of antibiotic-resistant strains cause serious diseases and have a significant impact on public health worldwide, so novel antimicrobial drugs are urgently needed. Insect venoms, a rich source of bioactive components containing antimicrobial peptides (AMPs), are attractive candidates for new therapeutic agents against microbes. Recently, a novel peptide, P1, identified from the venom of the Australian jumper ant Myrmecia pilosula, showed potent antimicrobial activities against both Gram-negative and Gram-positive bacteria, but its structure-function relationship is unknown. Here, we used biochemical and biophysical techniques coupled with computational simulations to explore the mode of action of P1 interaction with dodecylphosphocholine (DPC) micelles as a model membrane system. Our circular dichroism (CD) and NMR studies revealed an amphipathic α-helical structure for P1 upon interaction with DPC micelles. A paramagnetic relaxation enhancement approach revealed that P1 orients its α-helix segment (F6-G14) into DPC micelles. In addition, the α-helix segment could be essential for membrane permeabilization and antimicrobial activity. Moreover, the arginine residues R8, R11, and R15 significantly contribute to helix formation and membrane-binding affinity. The lysine residue K19 of the C-terminus functionally guides P1 to interact with DPC micelles in the early interaction stage. Our study provides insights into the mode of action of P1, which is valuable in modifying and developing potent AMPs as antibiotic drugs.

Combined EXAFS and DFT Structure Calculations Provide Structural Insights into the 1:1 Multi-Histidine Complexes of CuII, CuI and ZnII with the Tandem Octarepeats of the Mammalian Prion Protein

PubMed Central

Pushie, M. Jake; Nienaber, Kurt H.; McDonald, Alex; Millhauser, Glenn L.; George, Graham N.

2014-01-01

The metal coordinating properties of the prion protein (PrP) have been the subject of intense focus and debate since the first reports of copper interaction with PrP just before the turn of the century. The picture of metal coordination to PrP has been improved and refined over the past decade, and yet the structural details of the various metal coordination modes have not been fully elucidated in some cases. Herein we employ X-ray absorption near edge spectroscopy as well as extended X-ray absorption fine structure (EXAFS) spectroscopy to structurally characterize the dominant 1:1 coordination modes for CuII, CuI and ZnII with an N-terminal fragment of PrP. The PrP fragment constitutes four tandem repeats representative of the mammalian octarepeat domain, designated OR4, which is also the most studied PrP fragment for metal interactions, making our findings applicable to a large body of previous work. Density functional theory (DFT) calculations provide additional structural and thermodynamic data, and candidate structures are used to inform EXAFS data analysis. The optimized geometries from DFT calculations are used to identify potential coordination complexes for multi-histidine coordination of CuII, CuI and ZnII in an aqueous medium, modeled using 4-methylimidazole to represent the histidine side chain. Through a combination of in silico coordination chemistry as well as rigorous EXAFS curve fitting, using full multiple scattering on candidate structures from DFT calculations, we have characterized the predominant coordination modes for the 1:1 complexes of CuII, CuI and ZnII with the OR4 peptide at pH 7.4 at atomic resolution, which are best represented as a square planar [CuII(His)4]2+, digonal [CuI(His)2]+ and tetrahedral [ZnII(His)3(OH2)]2+, respectively. PMID:25042361

The molecular structure of the phosphate mineral kidwellite NaFe93+(PO4)6(OH)11ṡ3H2O - A vibrational spectroscopic study

NASA Astrophysics Data System (ADS)

Frost, Ray L.; López, Andrés; Theiss, Frederick L.; Scholz, Ricardo; Souza, Larissa

2014-09-01

The mineral kidwellite, a hydrated hydroxy phosphate of ferric iron and sodium of approximate formula NaFe93+(PO4)6(OH)11ṡ3H2O, has been studied using a combination of electron microscopy with EDX and vibrational spectroscopic techniques. Raman spectroscopy identifies an intense band at 978 cm-1 and 1014 cm-1. These bands are attributed to the PO43- ν1 symmetric stretching mode. The ν3 antisymmetric stretching modes are observed by a large number of Raman bands. The series of Raman bands at 1034, 1050, 1063, 1082, 1129, 1144 and 1188 cm-1 are attributed to the ν3 antisymmetric stretching bands of the PO43- and HOPO32- units. The observation of these multiple Raman bands in the symmetric and antisymmetric stretching region gives credence to the concept that both phosphate and hydrogen phosphate units exist in the structure of kidwellite. The series of Raman bands at 557, 570, 588, 602, 631, 644 and 653 cm-1are assigned to the PO43- ν2 bending modes. The series of Raman bands at 405, 444, 453, 467, 490 and 500 cm-1 are attributed to the PO43- and HOPO32- ν4 bending modes. The spectrum is quite broad but Raman bands may be resolved at 3122, 3231, 3356, 3466 and 3580 cm-1. These bands are assigned to water stretching vibrational modes. The number and position of these bands suggests that water is in different molecular environments with differing hydrogen bond distances. Infrared bands at 3511 and 3359 cm-1 are ascribed to the OH stretching vibration of the OH units. Very broad bands at 3022 and 3299 cm-1 are attributed to the OH stretching vibrations of water. Vibrational spectroscopy offers insights into the molecular structure of the phosphate mineral kidwellite.

Structural asymmetry in the Thermus thermophilus RuvC dimer suggests a basis for sequential strand cleavages during Holliday junction resolution.

PubMed

Chen, Luan; Shi, Ke; Yin, Zhiqi; Aihara, Hideki

2013-01-07

Holliday junction (HJ) resolvases are structure-specific endonucleases that cleave four-way DNA junctions (HJs) generated during DNA recombination and repair. Bacterial RuvC, a prototypical HJ resolvase, functions as homodimer and nicks DNA strands precisely across the junction point. To gain insights into the mechanisms underlying symmetrical strand cleavages by RuvC, we performed crystallographic and biochemical analyses of RuvC from Thermus thermophilus (T.th. RuvC). The crystal structure of T.th. RuvC shows an overall protein fold similar to that of Escherichia coli RuvC, but T.th. RuvC has a more tightly associated dimer interface possibly reflecting its thermostability. The binding mode of a HJ-DNA substrate can be inferred from the shape/charge complementarity between the T.th. RuvC dimer and HJ-DNA, as well as positions of sulfate ions bound on the protein surface. Unexpectedly, the structure of T.th. RuvC homodimer refined at 1.28 Å resolution shows distinct asymmetry near the dimer interface, in the region harboring catalytically important aromatic residues. The observation suggests that the T.th. RuvC homodimer interconverts between two asymmetric conformations, with alternating subunits switched on for DNA strand cleavage. This model provides a structural basis for the 'nick-counter-nick' mechanism in HJ resolution, a mode of HJ processing shared by prokaryotic and eukaryotic HJ resolvases.

A Novel Cofactor-binding Mode in Bacterial IMP Dehydrogenases Explains Inhibitor Selectivity*

PubMed Central

Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia; Osipiuk, Jerzy; Gu, Minyi; Zhang, Minjia; Mandapati, Kavitha; Gollapalli, Deviprasad R.; Gorla, Suresh Kumar; Hedstrom, Lizbeth; Joachimiak, Andrzej

2015-01-01

The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5′-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD+, which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD+ and XMP/NAD+. In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD+ adenosine moiety. More importantly, this new NAD+-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD+-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. These findings offer a potential strategy for further ligand optimization. PMID:25572472

Polymorphism in molecular solids: an extraordinary system of red, orange, and yellow crystals.

PubMed

Yu, Lian

2010-09-21

Diamond and graphite are polymorphs of each other: they have the same composition but different structures and properties. Many other substances exhibit polymorphism: inorganic and organic, natural and manmade. Polymorphs are encountered in studies of crystallization, phase transition, materials synthesis, and biomineralization and in the manufacture of specialty chemicals. Polymorphs can provide valuable insights into crystal packing and structure-property relationships. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, known as ROY for its red, orange, and yellow crystals, has seven polymorphs with solved structures, the largest number in the Cambridge Structural Database. First synthesized by medicinal chemists, ROY has attracted attention from solid-state chemists because it demonstrates the remarkable diversity possible in organic solids. Many structures of ROY polymorphs and their thermodynamic properties are known, making ROY an important model system for testing computational models. Though not the most polymorphic substance on record, ROY is extraordinary in that many of its polymorphs can crystallize simultaneously from the same liquid and are kinetically stable under the same conditions. Studies of ROY polymorphs have revealed a new crystallization mechanism that invalidates the common view that nucleation defines the polymorph of crystallization. A slow-nucleating polymorph can still dominate the product if it grows rapidly and nucleates on another polymorph. Studies of ROY have also helped understand a new, surprisingly fast mode of crystal growth in organic liquids cooled to the glass transition temperature. This growth mode exists only for those polymorphs that have more isotropic, and perhaps more liquid-like, packing. The rich polymorphism of ROY results from a combination of favorable thermodynamics and kinetics. Not only must there be many polymorphs of comparable energies or free energies, many polymorphs must be kinetically stable and crystallize at comparable rates to be observed. This system demonstrates the unique insights that polymorphism provides into solid-state structures and properties, as well as the inadequacy of our current understanding of the phenomenon. Despite many studies of ROY, it is still impossible to predict the next molecule that is equally or more polymorphic. ROY is a lucky gift from medicinal chemists.

Structural insights of a PI3K/mTOR dual inhibitor with the morpholino-triazine scaffold

NASA Astrophysics Data System (ADS)

Takeda, Takako; Wang, Yanli; Bryant, Stephen H.

2016-04-01

Stimulation of the PI3K/Akt/mTOR pathway, which controls cell proliferation and growth, is often observed in cancer cell. Inhibiting both PI3K and mTOR in this pathway can switch off Akt activation and hence, plays a powerful role for modulating this pathway. PKI-587, a drug containing the structure of morpholino-triazines, shows a dual and nano-molar inhibition activity and is currently in clinical trial. To provide an insight into the mechanism of this dual inhibition, pharmacophore and QSAR models were developed in this work using compounds based on the morpholino-triazines scaffold, followed by a docking study. Pharmacophore model suggested the mechanism of the inhibition of PI3Kα and mTOR by the compounds were mostly the same, which was supported by the docking study showing similar docking modes. The analysis also suggested the importance of the flat plane shape of the ligands, the space surrounding the ligands in the binding pocket, and the slight difference in the shape of the binding sites between PI3Kα and mTOR.

Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1

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

Lewis-Ballester, Ariel; Pham, Khoa N.; Batabyal, Dipanwita

Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination ofmore » an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.« less

Photonic crystal slab waveguides in moderate index contrast media: Generalized transverse Bragg waveguides

NASA Astrophysics Data System (ADS)

Burckel, David Bruce

One of the anticipated advantages of photonic crystal waveguides is the ability to tune waveguide dispersion and propagation characteristics to achieve desired properties. The majority of research into photonic crystal waveguides centers around high index contrast photonic crystal waveguides with complete in-plane bandgaps in the photonic crystal cladding. This work focuses on linear photonic crystal waveguides in moderate index materials, with insufficient index contrast to guarantee a complete in-plane bandgap. Using a technique called Interferometric Lithography (IL) as well as standard semiconductor processing steps, a process flow for creating large area (˜cm 2), linear photonic crystal waveguides in a spin-deposited photocurable polymer is outlined. The study of such low index contrast photonic crystal waveguides offers a unique opportunity to explore the mechanisms governing waveguide confinement and photonic crystal behavior in general. Results from two optical characterization experiments are provided. In the first set of experiments, rhodamine 590 organic laser dye was incorporated into the polymer prior to fabrication of the photonic crystal slab. Emission spectra from waveguide core modes exhibit no obvious spectral selectivity owing to variation in the periodicity or geometry of the photonic crystal. In addition, grating coupled waveguides were fabricated, and a single frequency diode laser was coupled into the waveguide in order to study the transverse mode structure. To this author's knowledge, the optical mode profile images are the first taken of photonic crystal slab waveguides, exhibiting both simple low order mode structure as well as complex high order mode structure inconsistent with effective index theory. However, no obvious correlation between the mode structure and photonic crystal period or geometry was evident. Furthermore, in both the laser dye-doped and grating coupled waveguides, low loss waveguiding was observed regardless of wavelength to period ratio. These optical results indicated a need for a deeper understanding of the confinement/guiding mechanisms in such waveguide structures. A simplification of the full 2-D problem to a more tractable "tilted 1-D" geometry led to the proposal of a new waveguide geometry, Generalized Transverse Bragg Waveguides (GTBW), as well as a new propagation mode characterized by spatial variation in both the transverse direction as well as the direction of propagation. GTBW demonstrate many of the same dispersion tunability traits exhibited in complete bandgap photonic crystal waveguides, under more modest fabrication demands, and moreover provide much insight into photonic crystal waveguide modes of all types. Generalized Transverse Bragg Waveguides are presented in terms of the standard physical properties associated with waveguides, including the dispersion relation, expressions for the spatial field profile, and the concepts of phase and group velocity. In addition, the proposal of at least one obvious application, semiconductor optical amplifiers, is offered.

Twisting phonons in complex crystals with quasi-one-dimensional substructures [Twisting Phonons in Higher Manganese Silicides with a Complex Nowotny Chimney Ladder Structure

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

Abernathy, Douglas L.; Ma, Jie; Yan, Jiaqiang

A variety of crystals contain quasi-one-dimensional substructures, which yield distinctive electronic, spintronic, optical and thermoelectric properties. There is a lack of understanding of the lattice dynamics that influences the properties of such complex crystals. Here we employ inelastic neutron scatting measurements and density functional theory calculations to show that numerous low-energy optical vibrational modes exist in higher manganese silicides, an example of such crystals. These optical modes, including unusually low-frequency twisting motions of the Si ladders inside the Mn chimneys, provide a large phase space for scattering acoustic phonons. A hybrid phonon and diffuson model is proposed to explain themore » low and anisotropic thermal conductivity of higher manganese silicides and to evaluate nanostructuring as an approach to further suppress the thermal conductivity and enhance the thermoelectric energy conversion efficiency. This discovery offers new insights into the structure-property relationships of a broad class of materials with quasi-one-dimensional substructures for various applications.« less

Infrared and Raman Study of the Recluse Spider Silk

NASA Astrophysics Data System (ADS)

Wang, S. L.; Wang, Qijue; Xing, Zhen; Schniepp, H. C.; Qazilbash, M. M.

Spider silk exhibits remarkable mechanical properties, such as high tensile strength and toughness. We want to gain insight into the composition and structure of spider silk to discover the origin of these properties. We are especially interested in the organization of the crystalline beta sheets that are expected to contribute to the high strength of the silk from the recluse spider, Loxosceles laeta. The recluse spider produces a silk that has a unique geometry amongst arachnids. We measure the silk's optical properties, particularly the infrared-active and Raman-active vibrations. Broadband infrared transmission spectra were collected in the spectral range between 600 cm-1 and 4000 cm-1, with light polarized parallel and perpendicular to the long axis of the silk. Raman micro-spectroscopy was performed in the spectral range 500 cm-1 and 4000 cm- 1 with a 514 nm laser. The infrared and Raman vibrational modes are fit with Lorentzian and pseudo-Voigt functions. The vibrational modes are assigned to specific structures and electronic bonds in the silk. This work was supported by NASA/ Virginia Space Grant Consortium.

Lagrangian single-particle turbulent statistics through the Hilbert-Huang transform.

PubMed

Huang, Yongxiang; Biferale, Luca; Calzavarini, Enrico; Sun, Chao; Toschi, Federico

2013-04-01

The Hilbert-Huang transform is applied to analyze single-particle Lagrangian velocity data from numerical simulations of hydrodynamic turbulence. The velocity trajectory is described in terms of a set of intrinsic mode functions C(i)(t) and of their instantaneous frequency ω(i)(t). On the basis of this decomposition we define the ω-conditioned statistical moments of the C(i) modes, named q-order Hilbert spectra (HS). We show that such quantities have enhanced scaling properties as compared to traditional Fourier transform- or correlation-based (structure functions) statistical indicators, thus providing better insights into the turbulent energy transfer process. We present clear empirical evidence that the energylike quantity, i.e., the second-order HS, displays a linear scaling in time in the inertial range, as expected from a dimensional analysis. We also measure high-order moment scaling exponents in a direct way, without resorting to the extended self-similarity procedure. This leads to an estimate of the Lagrangian structure function exponents which are consistent with the multifractal prediction in the Lagrangian frame as proposed by Biferale et al. [Phys. Rev. Lett. 93, 064502 (2004)].

Twisting phonons in complex crystals with quasi-one-dimensional substructures [Twisting Phonons in Higher Manganese Silicides with a Complex Nowotny Chimney Ladder Structure

DOE PAGES

Abernathy, Douglas L.; Ma, Jie; Yan, Jiaqiang; ...

2015-04-15

A variety of crystals contain quasi-one-dimensional substructures, which yield distinctive electronic, spintronic, optical and thermoelectric properties. There is a lack of understanding of the lattice dynamics that influences the properties of such complex crystals. Here we employ inelastic neutron scatting measurements and density functional theory calculations to show that numerous low-energy optical vibrational modes exist in higher manganese silicides, an example of such crystals. These optical modes, including unusually low-frequency twisting motions of the Si ladders inside the Mn chimneys, provide a large phase space for scattering acoustic phonons. A hybrid phonon and diffuson model is proposed to explain themore » low and anisotropic thermal conductivity of higher manganese silicides and to evaluate nanostructuring as an approach to further suppress the thermal conductivity and enhance the thermoelectric energy conversion efficiency. This discovery offers new insights into the structure-property relationships of a broad class of materials with quasi-one-dimensional substructures for various applications.« less

Estimating thermal conductivity and thermoelectricity in PbTiO3 from first principles

NASA Astrophysics Data System (ADS)

Roy, Anindya

A combination of density functional theory and Boltzmann transport equation is used in this study to calculate the lattice thermal conductivity (κL) of PbTiO3 (PTO). We cannot apply this procedure to determine κL in presence of imaginary phonon modes (''soft modes''). Hence the tetragonal structure of PTO is used in these calculations, and the predicted κL is extrapolated to higher temperature using insights from experiments. The computed κL of PTO is low, possibly due to the anharmonicity associated with the ferroelectric/paraelectric transition. Electronic transport parameters such as the Seebeck coefficient and the electrical conductivity are also determined (under constant scattering time approximation in semiclassical Boltzmann theory) for PTO. The low κL and the electronic transport parameters together indicate excellent thermoelectric properties of PTO (zT > 1.5 at 1000 K). As a technologically important ferroelectric/piezoelectric material, PTO is used in alloys and in layered structures. These morphologies could bring down the κL further, improving its thermoelectric performance. Synthesis of electrically conducting samples of PTO would allows us to verify the above predictions.

Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

NASA Astrophysics Data System (ADS)

Sheng, Chunquan; Ji, Haitao; Miao, Zhenyuan; Che, Xiaoyin; Yao, Jianzhong; Wang, Wenya; Dong, Guoqiang; Guo, Wei; Lü, Jiaguo; Zhang, Wannian

2009-06-01

Myristoyl-CoA:protein N-myristoyltransferase (NMT) is a cytosolic monomeric enzyme that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the N-terminal glycine of a number of eukaryotic cellular and viral proteins. Recent experimental data suggest NMT from parasites could be a promising new target for the design of novel antiparasitic agents with new mode of action. However, the active site topology and inhibitor specificity of these enzymes remain unclear. In this study, three-dimensional models of NMT from Plasmodium falciparum (PfNMT), Leishmania major (LmNMT) and Trypanosoma brucei (TbNMT) were constructed on the basis of the crystal structures of fungal NMTs using homology modeling method. The models were further refined by energy minimization and molecular dynamics simulations. The active sites of PfNMT, LmNMT and TbNMT were characterized by multiple copy simultaneous search (MCSS). MCSS functional maps reveal that PfNMT, LmNMT and TbNMT share a similar active site topology, which is defined by two hydrophobic pockets, a hydrogen-bonding (HB) pocket, a negatively-charged HB pocket and a positively-charged HB pocket. Flexible docking approaches were then employed to dock known inhibitors into the active site of PfNMT. The binding mode, structure-activity relationships and selectivity of inhibitors were investigated in detail. From the results of molecular modeling, the active site architecture and certain key residues responsible for inhibitor binding were identified, which provided insights for the design of novel inhibitors of parasitic NMTs.

Global and local molecular dynamics of a bacterial carboxylesterase provide insight into its catalytic mechanism

PubMed Central

Yu, Xiaozhen; Sigler, Sara C.; Hossain, Delwar; Wierdl, Monika; Gwaltney, Steven R.; Potter, Philip M.; Wadkins, Randy M.

2013-01-01

Carboxylesterases (CEs) are ubiquitous enzymes responsible for the detoxification of xenobiotics. In humans, substrates for these enzymes are far-ranging, and include the street drug heroin and the anticancer agent irinotecan. Hence, their ability to bind and metabolize substrates is of broad interest to biomedical science. In this study, we focused our attention on dynamic motions of a CE from B. subtilis (pnbCE), with emphasis on the question of what individual domains of the enzyme might contribute to its catalytic activity. We used a 10 ns all-atom molecular dynamics simulation, normal mode calculations, and enzyme kinetics to understand catalytic consequences of structural changes within this enzyme. Our results shed light on how molecular motions are coupled with catalysis. During molecular dynamics, we observed a distinct C-C bond rotation between two conformations of Glu310. Such a bond rotation would alternately facilitate and impede protonation of the active site His399 and act as a mechanism by which the enzyme alternates between its active and inactive conformation. Our normal mode results demonstrate that the distinct low-frequency motions of two loops in pnbCE, coil_5 and coil_21, are important in substrate conversion and seal the active site. Mutant CEs lacking these external loops show significantly reduced rates of substrate conversion, suggesting this sealing motion prevents escape of substrate. Overall, the results of our studies give new insight into the structure-function relationship of CEs and have implications for the entire family of α/β fold family of hydrolases, of which this CE is a member. PMID:22127613

Structural virology. Near-atomic cryo-EM structure of the helical measles virus nucleocapsid.

PubMed

Gutsche, Irina; Desfosses, Ambroise; Effantin, Grégory; Ling, Wai Li; Haupt, Melina; Ruigrok, Rob W H; Sachse, Carsten; Schoehn, Guy

2015-05-08

Measles is a highly contagious human disease. We used cryo-electron microscopy and single particle-based helical image analysis to determine the structure of the helical nucleocapsid formed by the folded domain of the measles virus nucleoprotein encapsidating an RNA at a resolution of 4.3 angstroms. The resulting pseudoatomic model of the measles virus nucleocapsid offers important insights into the mechanism of the helical polymerization of nucleocapsids of negative-strand RNA viruses, in particular via the exchange subdomains of the nucleoprotein. The structure reveals the mode of the nucleoprotein-RNA interaction and explains why each nucleoprotein of measles virus binds six nucleotides, whereas the respiratory syncytial virus nucleoprotein binds seven. It provides a rational basis for further analysis of measles virus replication and transcription, and reveals potential targets for drug design. Copyright © 2015, American Association for the Advancement of Science.

New insights into globoids of protein storage vacuoles in wheat aleurone using synchrotron soft X-ray microscopy

PubMed Central

Regvar, Marjana; Eichert, Diane; Kaulich, Burkhard; Gianoncelli, Alessandra; Pongrac, Paula; Vogel-Mikuš, Katarina; Kreft, Ivan

2011-01-01

Mature developed seeds are physiologically and biochemically committed to store nutrients, principally as starch, protein, oils, and minerals. The composition and distribution of elements inside the aleurone cell layer reflect their biogenesis, structural characteristics, and physiological functions. It is therefore of primary importance to understand the mechanisms underlying metal ion accumulation, distribution, storage, and bioavailability in aleurone subcellular organelles for seed fortification purposes. Synchrotron radiation soft X-ray full-field imaging mode (FFIM) and low-energy X-ray fluorescence (LEXRF) spectromicroscopy were applied to characterize major structural features and the subcellular distribution of physiologically important elements (Zn, Fe, Na, Mg, Al, Si, and P). These direct imaging methods reveal the accumulation patterns between the apoplast and symplast, and highlight the importance of globoids with phytic acid mineral salts and walls as preferential storage structures. C, N, and O chemical topographies are directly linked to the structural backbone of plant substructures. Zn, Fe, Na, Mg, Al, and P were linked to globoid structures within protein storage vacuoles with variable levels of co-localization. Si distribution was atypical, being contained in the aleurone apoplast and symplast, supporting a physiological role for Si in addition to its structural function. These results reveal that the immobilization of metals within the observed endomembrane structures presents a structural and functional barrier and affects bioavailability. The combination of high spatial and chemical X-ray microscopy techniques highlights how in situ analysis can yield new insights into the complexity of the wheat aleurone layer, whose precise biochemical composition, morphology, and structural characteristics are still not unequivocally resolved. PMID:21447756

The effect of a dominant initial single mode on the Kelvin–Helmholtz instability evolution: New insights on previous experimental results

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

Shimony, Assaf; Shvarts, Dov; Malamud, Guy

2016-04-12

This paper brings new insights on an experiment, measuring the Kelvin–Helmholtz (KH) instability evolution, performed on the OMEGA-60 laser facility. Experimental radiographs show that the initial seed perturbations in the experiment are of multimode spectrum with a dominant single-mode of 16 μm wavelength. In single-mode-dominated KH instability flows, the mixing zone (MZ) width saturates to a constant value comparable to the wavelength. However, the experimental MZ width at late times has exceeded 100 μm, an order of magnitude larger. In this work, we use numerical simulations and a statistical model in order to investigate the vortex dynamics of the KHmore » instability for the experimental initial spectrum. Here, we conclude that the KH instability evolution in the experiment is dominated by multimode, vortex-merger dynamics, overcoming the dominant initial mode.« less

Spatial Variations of Poloidal and Toroidal Mode Field Line Resonances Observed by MMS

NASA Astrophysics Data System (ADS)

Le, G.; Chi, P. J.; Strangeway, R. J.; Russell, C. T.; Slavin, J. A.; Anderson, B. J.; Kepko, L.; Nakamura, R.; Plaschke, F.; Torbert, R. B.

2017-12-01

Field line resonances (FLRs) are magnetosphere's responses to solar wind forcing and internal instabilities generated by solar wind-magnetospheric interactions. They are standing waves along the Earth's magnetic field lines oscillating in either poloidal or toroidal modes. The two types of waves have their unique frequency characteristics. The eigenfrequency of FLRs is determined by the length of the field line and the plasma density, and thus gradually changes with L. For toroidal mode oscillations with magnetic field perturbations in the azimuthal direction, ideal MHD predicts that each field line oscillates independently with its own eigenfrequency. For poloidal mode waves with field lines oscillating radially, their frequency cannot change with L easily as L shells need to oscillate in sync to avoid efficient damping due to phase mixing. Observations, mainly during quiet times, indeed show that poloidal mode waves often exhibit nearly constant frequency across L shells. Our recent observations, on the other hand, reveal a clear L-dependent frequency trend for a long lasting storm-time poloidal wave event, indicating the wave can maintain its power with changing frequencies for an extended period [Le et al., 2017]. The spatial variation of the frequency shows discrete spatial structures. The frequency remains constant within each discrete structure that spans about 1 REalong L, and changes discretely. We present a follow-up study to investigate spatial variations of wave frequencies using the Wigner-Ville distribution. We examine both poloidal and toroidal waves under different geomagnetic conditions using multipoint observations from MMS, and compare their frequency and occurrence characteristics for insights into their generation mechanisms. Reference: Le, G., et al. (2017), Global observations of magnetospheric high-m poloidal waves during the 22 June 2015 magnetic storm, Geophys. Res. Lett., 44, 3456-3464, doi:10.1002/2017GL073048.

Consistent assignment of the vibrations of symmetric and asymmetric meta-disubstituted benzenes

NASA Astrophysics Data System (ADS)

Kemp, David J.; Tuttle, William D.; Jones, Florence M. S.; Gardner, Adrian M.; Andrejeva, Anna; Wakefield, Jonathan C. A.; Wright, Timothy G.

2018-04-01

The assignment of vibrational structure in spectra gives valuable insights into geometric and electronic structure changes upon electronic excitation or ionization; particularly when such information is available for families of molecules. We give a description of the phenyl-ring-localized vibrational modes of the ground (S0) electronic states of sets of meta-disubstituted benzene molecules including both symmetrically- and asymmetrically-substituted cases. As in our earlier work on monosubstituted benzenes (Gardner and Wright, 2011), para-disubstituted benzenes (Andrejeva et al., 2016), and ortho-disubstituted benzenes (Tuttle et al., 2018), we conclude that the use of the commonly-used Wilson or Varsányi mode labels, which are based on the vibrational motions of benzene itself, is misleading and ambiguous. Instead, we label the phenyl-ring-localized modes consistently based upon the Mulliken (Herzberg) method for the modes of meta-difluorobenzene (mDFB) under Cs symmetry, since we wish the labelling scheme to cover both symmetrically- and asymmetrically-substituted molecules. By studying the vibrational wavenumbers obtained from the same force-field while varying the mass of the substituent, we are able to follow the evolving modes across a wide range of molecules and hence provide consistent assignments. We assign the vibrations of the following sets of molecules: the symmetric meta-dihalobenzenes, meta-xylene and resorcinol (meta-dihydroxybenzene); and the asymmetric meta-dihalobenzenes, meta-halotoluenes, meta-halophenols and meta-cresol. In the symmetrically-substituted species, we find two pairs of in-phase and out-of-phase carbon-substituent stretches, and this motion persists in asymmetrically-substituted molecules for heavier substituents; however, when at least one of the substituents is light, then we find that these evolve into localized carbon-substituent stretches.

Health in All Policies (HiAP) governance: lessons from network governance.

PubMed

Khayatzadeh-Mahani, Akram; Ruckert, Arne; Labonté, Ronald; Kenis, Patrick; Akbari-Javar, Mohammad Reza

2018-05-25

The Health in All Policies (HiAP) approach requires formal and sustained governance structures and mechanisms to ensure that the policies of various non-health sectors maximize positive and minimize negative impacts on population health. In this paper, we demonstrate the usefulness of a network perspective in understanding and contributing to the effectiveness of HiAP. We undertook an exploratory, qualitative case study of a HiAP structure in Iran, the Kerman province Council of Health and Food Security (CHFS) with diverse members from health and non-health sectors. We analyzed relevant policy texts and interviewed 32 policy actors involved in the CHFS. Data were analyzed using within-case analysis and constant comparative methodology. Our findings suggest that CHFS governance from a network perspective drew in practice on elements of two competing network governance modes: the network administrative organization (NAO) and the lead organization mode. Our results also show that a shift from a hierarchical and market-based mode of interaction to a network logic within CHFS has not yet taken place. In addition, CHFS suffers from large membership and an inability to address complex 'wicked problems', as well as low trust, legitimacy and goal consensus among its members. Drawing on other HiAP studies and commentaries, insights from organization network theory, and in-depth findings from our case study, we conclude that a NAO may be the most effective mode of governance for tackling complex social problems in HiAP structures. Since similar studies are limited, and our single case study may not be transferable across all contexts, we suggest that further research be undertaken to explore HiAP structures from a network perspective in different institutional and cultural settings. With increasing emphasis given to HiAP approaches in national and international health policy discourse, it is important that comparative knowledge about the effectiveness of HiAP governance arrangements be developed.

Effective Communication Modes in Multilingual Encounters: Comparing Alternatives in Computer Mediated Communication (CMC)

ERIC Educational Resources Information Center

van Mulken, Margot; Hendriks, Berna

2017-01-01

This paper reports on an experimental study investigating alternative communication modes to English as a Lingua Franca. The purpose was to examine the effectiveness of different modes of communication and to gain insight in communication strategies used by interlocutors to solve referential conflicts. Findings show that ELF may not necessarily be…

Dynamics of Student Interactions: An Empirical Study of Orienteering Lessons in Physical Education

ERIC Educational Resources Information Center

Jourand, Clément; Adé, David; Sève, Carole; Komar, John; Thouvarecq, Régis

2018-01-01

Introduction: Many studies in physical education (PE) have sought to identify and categorize the modes of student interaction in order to gain greater insight into the nature of cooperative activity. More others recent studies have examined how modes of interaction evolve on the basis of the modes of collective activity that they generate. These…

Seismic sensitivity to sub-surface solar activity from 18 yr of GOLF/SoHO observations

NASA Astrophysics Data System (ADS)

Salabert, D.; García, R. A.; Turck-Chièze, S.

2015-06-01

Solar activity has significantly changed over the last two Schwabe cycles. After a long and deep minimum at the end of Cycle 23, the weaker activity of Cycle 24 contrasts with the previous cycles. In this work, the response of the solar acoustic oscillations to solar activity is used in order to provide insights into the structural and magnetic changes in the sub-surface layers of the Sun during this on-going unusual period of low activity. We analyze 18 yr of continuous observations of the solar acoustic oscillations collected by the Sun-as-a-star GOLF instrument on board the SoHO spacecraft. From the fitted mode frequencies, the temporal variability of the frequency shifts of the radial, dipolar, and quadrupolar modes are studied for different frequency ranges that are sensitive to different layers in the solar sub-surface interior. The low-frequency modes show nearly unchanged frequency shifts between Cycles 23 and 24, with a time evolving signature of the quasi-biennial oscillation, which is particularly visible for the quadrupole component revealing the presence of a complex magnetic structure. The modes at higher frequencies show frequency shifts that are 30% smaller during Cycle 24, which is in agreement with the decrease observed in the surface activity between Cycles 23 and 24. The analysis of 18 yr of GOLF oscillations indicates that the structural and magnetic changes responsible for the frequency shifts remained comparable between Cycle 23 and Cycle 24 in the deeper sub-surface layers below 1400 km as revealed by the low-frequency modes. The frequency shifts of the higher-frequency modes, sensitive to shallower regions, show that Cycle 24 is magnetically weaker in the upper layers of Sun. Appendices are available in electronic form at http://www.aanda.orgThe following 68 GOLF frequency tables are available and Table A.1 is also available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/578/A137

Structure and Mechanism of a Eukaryotic FMN Adenylyltransferase

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

Huerta, Carlos; Borek, Dominika; Machius, Mischa

2009-12-01

Flavin mononucleotide adenylyltransferase (FMNAT) catalyzes the formation of the essential flavocoenzyme flavin adenine dinucleotide (FAD) and plays an important role in flavocoenzyme homeostasis regulation. By sequence comparison, bacterial and eukaryotic FMNAT enzymes belong to two different protein superfamilies and apparently utilize different sets of active-site residues to accomplish the same chemistry. Here we report the first structural characterization of a eukaryotic FMNAT from the pathogenic yeast Candida glabrata. Four crystal structures of C. glabrata FMNAT in different complexed forms were determined at 1.20-1.95 A resolutions, capturing the enzyme active-site states prior to and after catalysis. These structures reveal a novelmore » flavin-binding mode and a unique enzyme-bound FAD conformation. Comparison of the bacterial and eukaryotic FMNATs provides a structural basis for understanding the convergent evolution of the same FMNAT activity from different protein ancestors. Structure-based investigation of the kinetic properties of FMNAT should offer insights into the regulatory mechanisms of FAD homeostasis by FMNAT in eukaryotic organisms.« less

Structure of the inositol-1-phosphate cytidylyltransferase from Thermotoga maritima.

PubMed

Kurnasov, Oleg V; Luk, Hung-Jie Daniel; Roberts, Mary F; Stec, Boguslaw

2013-09-01

The unique steps in the synthesis of an unusual osmolyte in hyperthermophiles, di-myo-inositol-1,1'-phosphate (DIP), involve the production of CDP-inositol and its condensation with an inositol-1-phosphate molecule to form phosphorylated DIP. While many organisms fuse both activities into a single enzyme, the two are separate in Thermotoga maritima. The crystal structure of the T. maritima inositol-1-phosphate cytidylyltransferase, which as a soluble protein may transiently associate with its membrane-embedded partner phospho-DIP synthase (P-DIPS), has now been obtained. The structure shows a conserved motif of sugar nucleotide transferases (COG1213) with a structurally reinforced C-terminal Cys bonded to the core of the protein. A bound arsenosugar identifies the location of the active site for inositol 1-phosphate. Based on homologous structures from several species and the identification of the crucial conserved aspartate residue, a catalytic mechanism for this enzyme is proposed as well as a mode for its association with P-DIPS. This structure imposes constraints on the mode of association, communication and temperature activation of two separate enzymes in T. maritima. For the first time, a working model for the membrane-bound P-DIPS unit has been constructed. This sheds light on the functioning of the phosphatidylserine and phosphatidylinositol synthases involved in many physiological processes that are homologous to P-DIPS. This work provides fresh insights into the synthesis of the unusual thermoprotective compound DIP in hyperthermophiles.

A fermionic de Finetti theorem

NASA Astrophysics Data System (ADS)

Krumnow, Christian; Zimborás, Zoltán; Eisert, Jens

2017-12-01

Quantum versions of de Finetti's theorem are powerful tools, yielding conceptually important insights into the security of key distribution protocols or tomography schemes and allowing one to bound the error made by mean-field approaches. Such theorems link the symmetry of a quantum state under the exchange of subsystems to negligible quantum correlations and are well understood and established in the context of distinguishable particles. In this work, we derive a de Finetti theorem for finite sized Majorana fermionic systems. It is shown, much reflecting the spirit of other quantum de Finetti theorems, that a state which is invariant under certain permutations of modes loses most of its anti-symmetric character and is locally well described by a mode separable state. We discuss the structure of the resulting mode separable states and establish in specific instances a quantitative link to the quality of the Hartree-Fock approximation of quantum systems. We hint at a link to generalized Pauli principles for one-body reduced density operators. Finally, building upon the obtained de Finetti theorem, we generalize and extend the applicability of Hudson's fermionic central limit theorem.

Elucidating Duramycin's Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope.

PubMed

Hasim, Sahar; Allison, David P; Mendez, Berlin; Farmer, Abigail T; Pelletier, Dale A; Retterer, Scott T; Campagna, Shawn R; Reynolds, Todd B; Doktycz, Mitchel J

2018-01-01

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus -derived bacterial isolates to determine species selectivity. Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin's mode of action and a better understanding of its selectivity.

Modal split model considering carpool mode

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

Lyles, R.W.

1979-03-01

Modal split remains a primary concern of transportation planners as the state-of-the art has developed from diversion curves to behavioral models. The approach taken here is to formulate the mode-choice decision for the work trip as a linear combination of real and perceived characteristics of the modes considered. The logit formulation is used with three modes being considered: two automobile modes (drive-alone and carpool) and a public transit mode (bus). The final model provides insight into which factors are important in travel decisions among these three modes and the importance of examining traveler's perceptions of the differences among modes relativemore » to actual measurable differences.« less

Emergent patterns of collective cell migration under tubular confinement.

PubMed

Xi, Wang; Sonam, Surabhi; Beng Saw, Thuan; Ladoux, Benoit; Teck Lim, Chwee

2017-11-15

Collective epithelial behaviors are essential for the development of lumens in organs. However, conventional assays of planar systems fail to replicate cell cohorts of tubular structures that advance in concerted ways on out-of-plane curved and confined surfaces, such as ductal elongation in vivo. Here, we mimic such coordinated tissue migration by forming lumens of epithelial cell sheets inside microtubes of 1-10 cell lengths in diameter. We show that these cell tubes reproduce the physiological apical-basal polarity, and have actin alignment, cell orientation, tissue organization, and migration modes that depend on the extent of tubular confinement and/or curvature. In contrast to flat constraint, the cell sheets in a highly constricted smaller microtube demonstrate slow motion with periodic relaxation, but fast overall movement in large microtubes. Altogether, our findings provide insights into the emerging migratory modes for epithelial migration and growth under tubular confinement, which are reminiscent of the in vivo scenario.

Synapsis-defective mutants reveal a correlation between chromosome conformation and the mode of double-strand break repair during Caenorhabditis elegans meiosis.

PubMed

Smolikov, Sarit; Eizinger, Andreas; Hurlburt, Allison; Rogers, Eric; Villeneuve, Anne M; Colaiácovo, Mónica P

2007-08-01

SYP-3 is a new structural component of the synaptonemal complex (SC) required for the regulation of chromosome synapsis. Both chromosome morphogenesis and nuclear organization are altered throughout the germlines of syp-3 mutants. Here, our analysis of syp-3 mutants provides insights into the relationship between chromosome conformation and the repair of meiotic double-strand breaks (DSBs). Although crossover recombination is severely reduced in syp-3 mutants, the production of viable offspring accompanied by the disappearance of RAD-51 foci suggests that DSBs are being repaired in these synapsis-defective mutants. Our studies indicate that once interhomolog recombination is impaired, both intersister recombination and nonhomologous end-joining pathways may contribute to repair during germline meiosis. Moreover, our studies suggest that the conformation of chromosomes may influence the mode of DSB repair employed during meiosis.

Localized surface plasmon resonance properties of Ag nanorod arrays on graphene-coated Au substrate

NASA Astrophysics Data System (ADS)

Mu, Haiwei; Lv, Jingwei; Liu, Chao; Sun, Tao; Chu, Paul K.; Zhang, Jingping

2017-11-01

Localized surface plasmon resonance (LSPR) on silver nanorod (SNR) arrays deposited on a graphene-coated Au substrate is investigated by the discrete dipole approximation (DDA) method. The resonance peaks in the extinction spectra of the SNR/graphene/Au structure show significantly different profiles as SNR height, and refractive index of the surrounding medium are varied gradually. Numerical simulation reveals that the shifts in the resonance peaks arise from hybridization of multiple plasmon modes as a result of coupling between the SNR arrays and graphene-coated Au substrate. Moreover, the LSPR modes blue-shifts from 800 nm to 700 nm when the thickness of the graphene layer in the metal nanoparticle (NP) - graphene hybrid nanostructure increases from 1 nm to 5 nm, which attribute to charge transfer between the graphene layer and SNR arrays. The results provide insights into metal NP-graphene hybrid nanostructures which have potential applications in plasmonics.

Quasi-periodic Counter-propagating Fast Magnetosonic Wave Trains from Neighboring Flares: SDO/AIA Observations and 3D MHD Modeling

NASA Astrophysics Data System (ADS)

Ofman, Leon; Liu, Wei

2018-06-01

Since their discovery by the Solar Dynamics Observatory/Atmospheric Imaging Assembly (AIA) in the extreme ultraviolet, rapid (phase speeds of ∼1000 km s‑1), quasi-periodic, fast-mode propagating (QFP) wave trains have been observed accompanying many solar flares. They typically propagate in funnel-like structures associated with the expanding magnetic field topology of the active regions (ARs). The waves provide information on the associated flare pulsations and the magnetic structure through coronal seismology (CS). The reported waves usually originate from a single localized source associated with the flare. Here we report the first detection of counter-propagating QFPs associated with two neighboring flares on 2013 May 22, apparently connected by large-scale, trans-equatorial coronal loops. We present the first results of a 3D MHD model of counter-propagating QFPs in an idealized bipolar AR. We investigate the excitation, propagation, nonlinearity, and interaction of the counter-propagating waves for a range of key model parameters, such as the properties of the sources and the background magnetic structure. In addition to QFPs, we also find evidence of trapped fast- (kink) and slow-mode waves associated with the event. We apply CS to determine the magnetic field strength in an oscillating loop during the event. Our model results are in qualitative agreement with the AIA-observed counter-propagating waves and used to identify the various MHD wave modes associated with the observed event, providing insights into their linear and nonlinear interactions. Our observations provide the first direct evidence of counter-propagating fast magnetosonic waves that can potentially lead to turbulent cascade and carry significant energy flux for coronal heating in low-corona magnetic structures.

Real-space mapping of Fano interference in plasmonic metamolecules.

PubMed

Alonso-Gonzalez, Pablo; Schnell, Martin; Sarriugarte, Paulo; Sobhani, Heidar; Wu, Chihhui; Arju, Nihal; Khanikaev, Alexander; Golmar, Federico; Albella, Pablo; Arzubiaga, Libe; Casanova, Felix; Hueso, Luis E; Nordlander, Peter; Shvets, Gennady; Hillenbrand, Rainer

2011-09-14

An unprecedented control of the spectral response of plasmonic nanoantennas has recently been achieved by designing structures that exhibit Fano resonances. This new insight is paving the way for a variety of applications, such as biochemical sensing and surface-enhanced Raman spectroscopy. Here we use scattering-type near-field optical microscopy to map the spatial field distribution of Fano modes in infrared plasmonic systems. We observe in real space the interference of narrow (dark) and broad (bright) plasmonic resonances, yielding intensity and phase toggling between different portions of the plasmonic metamolecules when either their geometric sizes or the illumination wavelength is varied.

Molecular basis of human CD22 function and therapeutic targeting.

PubMed

Ereño-Orbea, June; Sicard, Taylor; Cui, Hong; Mazhab-Jafari, Mohammad T; Benlekbir, Samir; Guarné, Alba; Rubinstein, John L; Julien, Jean-Philippe

2017-10-02

CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause autoimmune diseases and blood cancers. Here we report the crystal structure of human CD22 at 2.1 Å resolution, which reveals that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin as a unique mode of recognition across sialic acid-binding immunoglobulin-type lectins. The CD22 ectodomain adopts an extended conformation that facilitates concomitant CD22 nanocluster formation on B cells and binding to trans ligands to avert autoimmunity in mammals. We structurally delineate the CD22 site targeted by the therapeutic antibody epratuzumab at 3.1 Å resolution and determine a critical role for CD22 N-linked glycosylation in antibody engagement. Our studies provide molecular insights into mechanisms governing B-cell inhibition and valuable clues for the design of immune modulators in B-cell dysfunction.The B-cell-specific co-receptor CD22 is a therapeutic target for depleting dysregulated B cells. Here the authors structurally characterize the ectodomain of CD22 and present its crystal structure with the bound therapeutic antibody epratuzumab, which gives insights into the mechanism of inhibition of B-cell activation.

Revealing the structure and dust content of debris disks on solar systems scales with GPI

NASA Astrophysics Data System (ADS)

Duchene, Gaspard; Fitzgerald, Michael P.; Kalas, Paul; Graham, James R.; Arriaga, Pauline; Bruzzone, Sebastian; Chen, Christine; Dawson, Rebekah Ilene; Dong, Ruobing; Draper, Zachary; Esposito, Thomas; Follette, Katherine; Hung, Li-Wei; Lawler, Samantha; Metchev, Stanimir; Millar-Blanchaer, Max; Murray-Clay, Ruth; Perrin, Marshall D.; Rameau, Julien; Wang, Jason; Wolff, Schuyler; Macintosh, Bruce; GPIES Team

2016-01-01

High contrast scattered light images offer the best prospect to assess the detailed geometry and structure of dusty debris disks. In turn, such images can yield profound insight on the architecture of the underlying planetary system as dust grains respond to the gravitational pull of planetary bodies. A new generation of extreme adaptive optics systems now enables an unprecedented exploration of circumstellar disks on solar system scales. Here we review the new science derived from over a dozen debris disks imaged with the Gemini Planet Imager (GPI) as part of the GPI Exoplanet Survey (GPIES). In addition to its exquisite imaging capability, GPI's polarimetric mode provides invaluable insight on the dust content of each disk, in most cases for the very first time. These early results typically reveal narrow belts of material with evacuated regions roughly 50-100 AU in radius, subtle asymmetries in structure and high degree of linear polarization. We will provide an overview of the disk observations made during the GPIES campaign to date and will discuss in more detail some of the most remarkable systems.This work is supported by grants NSF AST-0909188, -1411868, -1413718; NASA NNX-15AD95G, -14AJ80G, -11AD21G; and the NExSS research network.

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

DOE PAGES

Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; ...

2015-05-07

We report that angiotensin II type 1 receptor (AT 1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT 1R blockers (ARBs), the structural basis for AT 1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT 1R in complex with its selective antagonist ZD7155 atmore » 2.9 Å resolution. The AT 1R-ZD7155 complex structure revealed key structural features ofAT 1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT 1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT 1R structure-function relationship and structure-based drug design.« less

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

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

Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius

We report that angiotensin II type 1 receptor (AT 1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT 1R blockers (ARBs), the structural basis for AT 1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT 1R in complex with its selective antagonist ZD7155 atmore » 2.9 Å resolution. The AT 1R-ZD7155 complex structure revealed key structural features ofAT 1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT 1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT 1R structure-function relationship and structure-based drug design.« less

Using resolvent analysis for the design of separation control on a NACA 0012 airfoil

NASA Astrophysics Data System (ADS)

Yeh, Chi-An; Taira, Kunihiko

2017-11-01

A combined effort based on large-eddy simulation and resolvent analysis on the separated flow over a NACA 0012 airfoil is conducted to design active flow control for suppression of separation. This study considers the the airfoil at 6 deg. angle-of-attack and Reynolds number of 23000. The response mode obtained from the resolvent analysis about the baseline turbulent mean flow reveals modal structures that can be categorized into three families when sweeping through the resonant frequency: (1) von Karman wake structure for low frequency; (2) Kelvin-Helmholtz structure in the separation bubble for high frequency; (3) blended structure of (1) and (2) for the intermediate frequency. Leveraging the insights from resolvent analysis, unsteady thermal actuation is introduced to the flow near the leading-edge to examine the use of the frequencies from three families for separation control in LES. As indicated by the resolvent response modes, we find that the use of intermediate frequencies are most effective in suppressing the flow separation, since the shear layer over the separation bubble and the wake are both receptive to the perturbation at the these frequencies. The resolvent-analysis-based control strategy achieves 35% drag reduction and 9% lift increase with effective frequency. This work was supported by Office of Naval Research (N00014-15-R-FO13) and Army Research Office (W911NF-14-1-0224).

Structure-dependent vibrational dynamics of Mg(BH 4 ) 2 polymorphs probed with neutron vibrational spectroscopy and first-principles calculations

DOE PAGES

Dimitrievska, Mirjana; White, James L.; Zhou, Wei; ...

2016-08-19

We investigated the structure-dependent vibrational properties of different Mg(BH 4) 2 polymorphs (α, β, γ, and δ phases) with a combination of neutron vibrational spectroscopy (NVS) measurements and density functional theory (DFT) calculations, with emphasis placed on the effects of the local structure and orientation of the BH 4 - anions. DFT simulations closely match the neutron vibrational spectra. The main bands in the low-energy region (20–80 meV) are associated with the BH4 - librational modes. The features in the intermediate energy region (80–120 meV) are attributed to overtones and combination bands arising from the lower-energy modes. The features inmore » the high-energy region (120–200 meV) correspond to the BH 4 - symmetric and asymmetric bending vibrations, of which four peaks located at 140, 142, 160, and 172 meV are especially intense. There are noticeable intensity distribution variations in the vibrational bands for different polymorphs. We can explain these differences using the spatial distribution of BH 4 - anions within various structures. An example of the possible identification of products after the hydrogenation of MgB 2, using NVS measurements, is presented. Our results provide fundamental insights of benefit to researchers currently studying these promising hydrogen-storage materials.« less

State-plane analysis of parallel resonant converter

NASA Technical Reports Server (NTRS)

Oruganti, R.; Lee, F. C.

1985-01-01

A method for analyzing the complex operation of a parallel resonant converter is developed, utilizing graphical state-plane techniques. The comprehensive mode analysis uncovers, for the first time, the presence of other complex modes besides the continuous conduction mode and the discontinuous conduction mode and determines their theoretical boundaries. Based on the insight gained from the analysis, a novel, high-frequency resonant buck converter is proposed. The voltage conversion ratio of the new converter is almost independent of load.

Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin.

PubMed

Ali, Hassan Refat H; Alhalaweh, Amjad; Velaga, Sitaram P

2013-05-01

Identification of optimal solid form of an active pharmaceutical ingredient and form control are very important in drug development. Thus, the structural information of these forms and in-depth insight on the modes of molecular interactions are necessary, and vibrational spectroscopic methods are well suited for this purpose. In-depth structural analysis of different solid forms of indomethacin (IND) using Raman and infrared (IR) spectroscopy is the objective. We have investigated the modes of molecular interactions in polymorphs (α and γ), amorphous and discovered cocrystals of IND with nicotinamide (NIC) and trans-cinnamic acid (CIN) coformers. The solid forms of IND have been prepared; their purity has been verified by differential scanning calorimetry and powder X-ray diffractometry and then studied in the solid-state by Raman and IR spectroscopy. The modes of the interactions were closely investigated from the vibrational data. The key vibrational features of IND solid forms have been specified. The IR (C=O) band at 1713 cm(-1) attributed to cyclic acid dimer of γ IND has disappeared in IND-NIC/CIN whilst retained in IND-SAC cocrystal. IND cocrystallizes in different conformations and crystal lattices with different coformers. The cyclic acid dimer of IND has been kept on its cocrystallization with saccharin and it could have been broken with NIC and CIN. The complementary nature of Raman and IR spectroscopy allowed unambiguous investigation of the chemical composition of pharmaceutical materials which is of particular importance in the absence of detailed structural information, as in the case of IND-NIC and IND-CIN.

Atomic resolution crystal structure of VcLMWPTP-1 from Vibrio cholerae O395: Insights into a novel mode of dimerization in the low molecular weight protein tyrosine phosphatase family

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

Nath, Seema; Banerjee, Ramanuj; Sen, Udayaditya, E-mail: udayaditya.sen@saha.ac.in

Highlights: • VcLMWPTP-1 forms dimer in solution. • The dimer is catalytically active unlike other reported dimeric LMWPTPs. • The formation of extended dimeric surface excludes the active site pocket. • The surface bears closer resemblance to eukaryotic LMWPTPs. - Abstract: Low molecular weight protein tyrosine phosphatase (LMWPTP) is a group of phosphotyrosine phosphatase ubiquitously found in a wide range of organisms ranging from bacteria to mammals. Dimerization in the LMWPTP family has been reported earlier which follows a common mechanism involving active site residues leading to an enzymatically inactive species. Here we report a novel form of dimerization inmore » a LMWPTP from Vibrio cholera 0395 (VcLMWPTP-1). Studies in solution reveal the existence of the dimer in solution while kinetic study depicts the active form of the enzyme. This indicates that the mode of dimerization in VcLMWPTP-1 is different from others where active site residues are not involved in the process. A high resolution (1.45 Å) crystal structure of VcLMWPTP-1 confirms a different mode of dimerization where the active site is catalytically accessible as evident by a tightly bound substrate mimicking ligand, MOPS at the active site pocket. Although being a member of a prokaryotic protein family, VcLMWPTP-1 structure resembles very closely to LMWPTP from a eukaryote, Entamoeba histolytica. It also delineates the diverse surface properties around the active site of the enzyme.« less

The Oasis impact structure, Libya: geological characteristics from ALOS PALSAR-2 data interpretation

NASA Astrophysics Data System (ADS)

van Gasselt, Stephan; Kim, Jung Rack; Choi, Yun-Soo; Kim, Jaemyeong

2017-02-01

Optical and infrared remote sensing may provide first-order clues for the identification of potential impact structures on the Earth. Despite the free availability of at least optical image data at highest resolution, research has shown that remote sensing analysis always remains inconclusive and extensive groundwork is needed for the confirmation of the impact origin of such structures. Commonly, optical image data and digital terrain models have been employed mainly for such remote sensing studies of impact structures. With the advent of imaging radar data, a few excursions have been made to also employ radar datasets. Despite its long use, capabilities of imaging radar for studying surface and subsurface structures have not been exploited quantitatively when applied for the identification and description of such features due to the inherent complexity of backscatter processes. In this work, we make use of higher-level derived radar datasets in order to gain clearer qualitative insights that help to describe and identify potential impact structures. We make use of high-resolution data products from the ALOS PALSAR-1 and ALOS PALSAR-2 L-band sensors to describe the heavily eroded Oasis impact structure located in the Libyan Desert. While amplitude radar data with single polarization have usually been utilized to accompany the suite of remote sensing datasets when interpreting impact structures in the past, we conclude that the integration of amplitude data with HH/HV/HH-HV polarization modes in standard and, in particular, in Ultra-Fine mode, as well as entropy-alpha decomposition data, significantly helps to identify and discriminate surface units based on their consolidation. Based on the overarching structural pattern, we determined the diameter of the eroded Oasis structure at 15.6 ± 0.5 km.

Toward the fourth dimension of membrane protein structure: insight into dynamics from spin-labeling EPR spectroscopy.

PubMed

McHaourab, Hassane S; Steed, P Ryan; Kazmier, Kelli

2011-11-09

Trapping membrane proteins in the confines of a crystal lattice obscures dynamic modes essential for interconversion between multiple conformations in the functional cycle. Moreover, lattice forces could conspire with detergent solubilization to stabilize a minor conformer in an ensemble thus confounding mechanistic interpretation. Spin labeling in conjunction with electron paramagnetic resonance (EPR) spectroscopy offers an exquisite window into membrane protein dynamics in the native-like environment of a lipid bilayer. Systematic application of spin labeling and EPR identifies sequence-specific secondary structures, defines their topology and their packing in the tertiary fold. Long range distance measurements (60 Å-80 Å) between pairs of spin labels enable quantitative analysis of equilibrium dynamics and triggered conformational changes. This review highlights the contribution of spin labeling to bridging structure and mechanism. Efforts to develop methods for determining structures from EPR restraints and to increase sensitivity and throughput promise to expand spin labeling applications in membrane protein structural biology. Copyright © 2011 Elsevier Ltd. All rights reserved.

Magnetotelluric 2D Modelling Provides Insight on the Structural Characteristics of the Guadalajara (Mexico) Triple Junction Domains

NASA Astrophysics Data System (ADS)

Arboleda Zapata, M. D. J., Sr.; Arzate-Flores, J.; Guevara Betancourt, R. E., Sr.

2017-12-01

The Jalisco Block is a continental microplate produced by the extension along three large structures: the Tepic-Zacoalco rift (TZR), the Colima rift (CR) and the Chapala rift that converge in a triple junction 50 km southwest of Guadalajara, Mexico, with orientation NW-SE, N-S, and E-W respectively. The present study focuses on investigating the deep structure of the north Colima and eastern Zacoalco grabens close to the Guadalajara triple junction (GTJ). This is a first study of its type that provide insight on the grabens structures and crustal characteristics underneath. We measured along two magnetotellurics (MT) profiles that cut perpendicularly the TZR (profile ZAC), and the northern CR (profile SAY) comprising a total of 24 broad band MT soundings. The ZAC profile has 11 stations and has a NE orientation, and the SAY profile has 14 station aligned E-W. Standard processing and editing procedures were completed, and distortion analysis was applied to the data set in order to define the dimensionality and electric strike of the separated profiles. Static shift was corrected using geology information to distinguish the different types of soundings and later averaging for those soundings located over the same lithology. The Bahr dimensionality parameters showed that the medium is mainly 3D for the SAY profile and 2D for the ZAC profile; furthermore, the regional geoelectric strike azimuth calculated with Bahr methodology were -4° and -48° respectively, with good concordance with the main surface structures. The tipper analysis permitted validated these results, as the real induction vectors were nearly perpendicular to main fault structures. All soundings were rotated to the respective regional strike and a 2D simultaneous inversion of the transverse electric (TE) mode, the transvers magnetic (TM) mode and the Tipper was completed. The RMS fitting error yield 3.2% for ZAC profile and 3.7% for SAY profile. Both profiles show a shallow conductive zone at north of the Colima Rift and the south of the Zacoalco rift, which are interpreted as lacustrine and fluvial sediments having maximum thickness of 1.5 and 1.0 km respectively. The profiles show a faulted resistive upper crust, 35 to 40 km thick, that is reliably correlated with mapped surface structures and consistent with two types of extensional processes.

Dynamic Triple-Mode Sorption and Outgassing in Materials.

PubMed

Sharma, Hom N; Harley, Stephen J; Sun, Yunwei; Glascoe, Elizabeth A

2017-06-07

Moisture uptake and outgassing can be detrimental to a system by altering the chemical and mechanical properties of materials within the system over time. In this work, we conducted isotherm experiments to investigate dynamic moisture sorption and desorption in markedly different materials, i.e., a polymeric material, Sylgard-184 and a ceramic aluminosilicate material, Zircar RS-1200, at different temperatures (30 °C-70 °C) by varying the water activity (0.0-0.90). Sylgard-184 showed a linear sorption and outgassing behavior with no-hysteresis over the entire temperature and water activity range considered here. Whereas, the sorption and outgassing of Zircar RS-1200 was highly non-linear with significant hysteresis, especially at higher water activities, at all temperatures considered here. The type of hysteresis suggested the presence of mesopores in Zircar RS-1200, whereas the lack of hysteresis in Sylgard-184 indicates that it has a nonporous structure. A diffusion model coupled with a dynamic, triple-mode sorption (Langmuir, Henry, and pooling modes) model employed in this study matched our experimental data very well and provides mechanistic insight into the processes. Our triple-mode sorption model was adaptive enough to (1) model these distinctly different materials and (2) predict sorption and outgassing under conditions that are distinctly different from the parameterization experiments.

Dynamic Triple-Mode Sorption and Outgassing in Materials

DOE PAGES

Sharma, Hom N.; Harley, Stephen J.; Sun, Yunwei; ...

2017-06-07

Moisture uptake and outgassing can be detrimental to a system by altering the chemical and mechanical properties of materials within the system over time. In this work, we conducted isotherm experiments to investigate dynamic moisture sorption and desorption in markedly different materials, i.e., a polymeric material, Sylgard-184 and a ceramic aluminosilicate material, Zircar RS-1200, at different temperatures (30 °C–70 °C) by varying the water activity (0.0–0.90). Sylgard-184 showed a linear sorption and outgassing behavior with no-hysteresis over the entire temperature and water activity range considered here. Whereas, the sorption and outgassing of Zircar RS-1200 was highly non-linear with significant hysteresis,more » especially at higher water activities, at all temperatures considered here. The type of hysteresis suggested the presence of mesopores in Zircar RS-1200, whereas the lack of hysteresis in Sylgard-184 indicates that it has a nonporous structure. A diffusion model coupled with a dynamic, triple-mode sorption (Langmuir, Henry, and pooling modes) model employed in this study matched our experimental data very well and provides mechanistic insight into the processes. Our triple-mode sorption model was adaptive enough to (1) model these distinctly different materials and (2) predict sorption and outgassing under conditions that are distinctly different from the parameterization experiments.« less

Dynamic Triple-Mode Sorption and Outgassing in Materials

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

Sharma, Hom N.; Harley, Stephen J.; Sun, Yunwei

Moisture uptake and outgassing can be detrimental to a system by altering the chemical and mechanical properties of materials within the system over time. In this work, we conducted isotherm experiments to investigate dynamic moisture sorption and desorption in markedly different materials, i.e., a polymeric material, Sylgard-184 and a ceramic aluminosilicate material, Zircar RS-1200, at different temperatures (30 °C–70 °C) by varying the water activity (0.0–0.90). Sylgard-184 showed a linear sorption and outgassing behavior with no-hysteresis over the entire temperature and water activity range considered here. Whereas, the sorption and outgassing of Zircar RS-1200 was highly non-linear with significant hysteresis,more » especially at higher water activities, at all temperatures considered here. The type of hysteresis suggested the presence of mesopores in Zircar RS-1200, whereas the lack of hysteresis in Sylgard-184 indicates that it has a nonporous structure. A diffusion model coupled with a dynamic, triple-mode sorption (Langmuir, Henry, and pooling modes) model employed in this study matched our experimental data very well and provides mechanistic insight into the processes. Our triple-mode sorption model was adaptive enough to (1) model these distinctly different materials and (2) predict sorption and outgassing under conditions that are distinctly different from the parameterization experiments.« less

Weighted Fuzzy Risk Priority Number Evaluation of Turbine and Compressor Blades Considering Failure Mode Correlations

NASA Astrophysics Data System (ADS)

Gan, Luping; Li, Yan-Feng; Zhu, Shun-Peng; Yang, Yuan-Jian; Huang, Hong-Zhong

2014-06-01

Failure mode, effects and criticality analysis (FMECA) and Fault tree analysis (FTA) are powerful tools to evaluate reliability of systems. Although single failure mode issue can be efficiently addressed by traditional FMECA, multiple failure modes and component correlations in complex systems cannot be effectively evaluated. In addition, correlated variables and parameters are often assumed to be precisely known in quantitative analysis. In fact, due to the lack of information, epistemic uncertainty commonly exists in engineering design. To solve these problems, the advantages of FMECA, FTA, fuzzy theory, and Copula theory are integrated into a unified hybrid method called fuzzy probability weighted geometric mean (FPWGM) risk priority number (RPN) method. The epistemic uncertainty of risk variables and parameters are characterized by fuzzy number to obtain fuzzy weighted geometric mean (FWGM) RPN for single failure mode. Multiple failure modes are connected using minimum cut sets (MCS), and Boolean logic is used to combine fuzzy risk priority number (FRPN) of each MCS. Moreover, Copula theory is applied to analyze the correlation of multiple failure modes in order to derive the failure probabilities of each MCS. Compared to the case where dependency among multiple failure modes is not considered, the Copula modeling approach eliminates the error of reliability analysis. Furthermore, for purpose of quantitative analysis, probabilities importance weight from failure probabilities are assigned to FWGM RPN to reassess the risk priority, which generalize the definition of probability weight and FRPN, resulting in a more accurate estimation than that of the traditional models. Finally, a basic fatigue analysis case drawn from turbine and compressor blades in aeroengine is used to demonstrate the effectiveness and robustness of the presented method. The result provides some important insights on fatigue reliability analysis and risk priority assessment of structural system under failure correlations.

A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity

DOE PAGES

Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia; ...

2015-01-09

The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5'-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD +, which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexesmore » with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD + and XMP/NAD +. In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD+ adenosine moiety. More importantly, this new NAD +-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD +-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. As a result, these findings offer a potential strategy for further ligand optimization.« less

A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity.

PubMed

Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia; Osipiuk, Jerzy; Gu, Minyi; Zhang, Minjia; Mandapati, Kavitha; Gollapalli, Deviprasad R; Gorla, Suresh Kumar; Hedstrom, Lizbeth; Joachimiak, Andrzej

2015-02-27

The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5'-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD(+), which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD(+) and XMP/NAD(+). In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD(+) adenosine moiety. More importantly, this new NAD(+)-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD(+)-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. These findings offer a potential strategy for further ligand optimization. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Structural and functional connectivity underlying grey matter covariance: impact of developmental insult.

PubMed

Paquola, Casey; Bennett, Maxwell; Lagopoulos, Jim

2018-05-15

Structural covariance networks (SCNs) may offer unique insights into the developmental impact of childhood maltreatment because they are thought to reflect coordinated maturation of distinct grey matter regions. T1-weighted magnetic resonance images were acquired from 121 young people with emerging mental illness. Diffusion weighted and resting state functional imaging was also acquired from a random subset of the participants (n=62). Ten study-specific SCNs were identified using a whole brain grey matter independent component analysis. The effects of childhood maltreatment and age on average grey matter density and the expression of each SCN were calculated. Childhood maltreatment was linked to age-related decreases in grey matter density across a SCN that overlapped with the default mode and fronto-parietal networks. Resting state functional connectivity and structural connectivity were calculated in the study-specific SCN and across the whole brain. Grey matter covariance was significantly correlated with rsFC across the SCN, and rsFC fully mediated the relationship between grey matter covariance and structural connectivity in the non-maltreated group. A unique association of grey matter covariance with structural connectivity was detected amongst individuals with a history of childhood maltreatment. Perturbation of grey matter development across the default mode and fronto-parietal networks following childhood maltreatment may have significant implications for mental well-being, given the networks' roles in self-referential activity. Cross-modal comparisons suggest reduced grey matter following childhood maltreatment could arise from deficient functional activity earlier in life.

Combined wave propagation analysis of earthquake recordings from borehole and building sensors

NASA Astrophysics Data System (ADS)

Petrovic, B.; Parolai, S.; Dikmen, U.; Safak, E.; Moldobekov, B.; Orunbaev, S.

2015-12-01

In regions highly exposed to natural hazards, Early Warning Systems can play a central role in risk management and mitigation procedures. To improve at a relatively low cost the spatial resolution of regional earthquake early warning (EEW) systems, decentralized onsite EEW and building monitoring, a wireless sensing unit, the Self-Organizing Seismic Early Warning Information Network (SOSEWIN) was developed and further improved to include the multi-parameter acquisition. SOSEWINs working in continuous real time mode are currently tested on various sites. In Bishkek and Istanbul, an instrumented building is located close to a borehole equipped with downhole sensors. The joint data analysis of building and borehole earthquake recordings allows the study of the behavior of the building, characteristics of the soil, and soil-structure interactions. The interferometric approach applied to recordings of the building response is particularly suitable to characterize the wave propagation inside a building, including the propagation velocity of shear waves and attenuation. Applied to borehole sensors, it gives insights into velocity changes in different layers, reflections and mode conversion, and allows the estimation of the quality factor Qs. We used combined building and borehole data from the two test sites: 1) to estimate the characteristics of wave propagation through the building to the soil and back, and 2) to obtain an empirical insight into soil-structure interactions. The two test sites represent two different building and soil types, and soil structure impedance contrasts. The wave propagation through the soil to the building and back is investigated by the joint interferometric approach. The propagation of up and down-going waves through the building and soil is clearly imaged and the reflection of P and S waves from the earth surface and the top of the building identified. An estimate of the reflected and transmitted energy amounts is given, too.

GaAsBi Synthesis: From Band Structure Modification to Nanostructure Formation

NASA Astrophysics Data System (ADS)

Collar, Kristen N.

Research and development bismides have proven bismides to be a promising field for material science with important applications in optoelectronics. However, the development of a complete description of the electrical and material properties of bismide ternaries is not comprehensive or straightforward. One of the main benefits of this ternary system is the opportunity for bandgap tuning, which opens doors to new applications. Tuning the bandgap is achieved by means of varying the composition; this allows access to a wider energy spectrum with particular applications in long wavelength emitters and detectors. In addition to bandgap tuning, Bi provides an opportunity to decrease lasing threshold currents, the temperature sensitivity and a major loss mechanism of today's telecom lasers. We propose to characterize the electronic and chemical structure of GaAsBi grown by molecular beam epitaxy. We probe the binding structure using x-ray photoelectron spectroscopy. This provides insights into the antisite incorporation of Bi and the reactivity of the surface. Furthermore, we use XPS to track the energy variation in the valence band with dilute Bi incorporation into GaAs. These insights provide valuable perspective into improving the predictability of bandgaps and of heterostructure band offsets for the realization of bismides in future electronics. The stringent growth conditions required by GaAsBi and the surfactant properties of Bi provide a unique opportunity to study nanostructure formation and epitaxial growth control mechanisms. The GaAsBi epitaxial films under Ga-rich growth conditions self-catalyze Ga droplet seeds for Vapor-Liquid-Solid growth of embedded nanowires. We demonstrate a means to direct the nanowires unidirectionally along preferential crystallographic directions utilizing the step-flow growth mode. We mediated the step-flow growth by employing vicinal surfaces and Bi's surfactant-like properties to enhance the properties of the step-flow growth mode. Semiconductor nanostructures are becoming a cornerstone of future optoelectronics and the work presented herein exploits the power of a bottom-up architecture to self-assemble aligned unidirectional planar nanowires.

A Two-Dimensional 'Zigzag' Silica Polymorph on a Metal Support.

PubMed

Kuhness, David; Yang, Hyun Jin; Klemm, Hagen W; Prieto, Mauricio; Peschel, Gina; Fuhrich, Alexander; Menzel, Dietrich; Schmidt, Thomas; Yu, Xin; Shaikhutdinov, Shamil; Lewandowski, Adrian; Heyde, Markus; Kelemen, Anna; Włodarczyk, Radosław; Usvyat, Denis; Schütz, Martin; Sauer, Joachim; Freund, Hans-Joachim

2018-05-16

We present a new polymorph of the two-dimensional (2D) silica film with a characteristic 'zigzag' line structure and a rectangular unit cell which forms on a Ru(0001) metal substrate. This new silica polymorph may allow for important insights into growth modes and transformations of 2D silica films as a model system for the study of glass transitions. Based on scanning tunneling microscopy, low energy electron diffraction, infrared reflection absorption spectroscopy, and X-ray photoelectron spectroscopy measurements on the one hand, and density functional theory calculations on the other, a structural model for the 'zigzag' polymorph is proposed. In comparison to established monolayer and bilayer silica, this 'zigzag' structure system has intermediate characteristics in terms of coupling to the substrate and stoichiometry. The silica 'zigzag' phase is transformed upon reoxidation at higher annealing temperature into a SiO 2 silica bilayer film which is chemically decoupled from the substrate.

Clerodane diterpenes: sources, structures, and biological activities†

PubMed Central

Li, Rongtao; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

2016-01-01

The clerodane diterpenoids are a widespread class of secondary metabolites and have been found in several hundreds of plant species from various families and in organisms from other taxonomic groups. These substances have attracted interest in recent years due to their notable biological activities, particularly insect antifeedant properties. In addition, the major active clerodanes of Salvia divinorum can be used as novel opioid receptor probes, allowing greater insight into opioid receptor-mediated phenomena, as well as opening additional areas for chemical investigation. This article provides extensive coverage of naturally occurring clerodane diterpenes discovered from 1990 until 2015, and follows up on the 1992 review by Merritt and Ley in this same journal. The distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes are summarized. In the cases where sufficient information is available, structure activity relationship (SAR) correlations and mode of action of active clerodanes have been presented. PMID:27433555

ULTRAFAST CHEMISTRY: Using Time-Resolved Vibrational Spectroscopy for Interrogation of Structural Dynamics

NASA Astrophysics Data System (ADS)

Nibbering, Erik T. J.; Fidder, Henk; Pines, Ehud

2005-05-01

Time-resolved infrared (IR) and Raman spectroscopy elucidates molecular structure evolution during ultrafast chemical reactions. Following vibrational marker modes in real time provides direct insight into the structural dynamics, as is evidenced in studies on intramolecular hydrogen transfer, bimolecular proton transfer, electron transfer, hydrogen bonding during solvation dynamics, bond fission in organometallic compounds and heme proteins, cis-trans isomerization in retinal proteins, and transformations in photochromic switch pairs. Femtosecond IR spectroscopy monitors the site-specific interactions in hydrogen bonds. Conversion between excited electronic states can be followed for intramolecular electron transfer by inspection of the fingerprint IR- or Raman-active vibrations in conjunction with quantum chemical calculations. Excess internal vibrational energy, generated either by optical excitation or by internal conversion from the electronic excited state to the ground state, is observable through transient frequency shifts of IR-active vibrations and through nonequilibrium populations as deduced by Raman resonances.

Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations.

PubMed

Capoferri, Luigi; Leth, Rasmus; ter Haar, Ernst; Mohanty, Arun K; Grootenhuis, Peter D J; Vottero, Eduardo; Commandeur, Jan N M; Vermeulen, Nico P E; Jørgensen, Flemming Steen; Olsen, Lars; Geerke, Daan P

2016-03-01

Cytochrome P450 BM3 (CYP102A1) mutant M11 is able to metabolize a wide range of drugs and drug-like compounds. Among these, M11 was recently found to be able to catalyze formation of human metabolites of mefenamic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, single active-site mutations such as V87I were reported to invert regioselectivity in NSAID hydroxylation. In this work, we combine crystallography and molecular simulation to study the effect of single mutations on binding and regioselective metabolism of mefenamic acid by M11 mutants. The heme domain of the protein mutant M11 was expressed, purified, and crystallized, and its X-ray structure was used as template for modeling. A multistep approach was used that combines molecular docking, molecular dynamics (MD) simulation, and binding free-energy calculations to address protein flexibility. In this way, preferred binding modes that are consistent with oxidation at the experimentally observed sites of metabolism (SOMs) were identified. Whereas docking could not be used to retrospectively predict experimental trends in regioselectivity, we were able to rank binding modes in line with the preferred SOMs of mefenamic acid by M11 and its mutants by including protein flexibility and dynamics in free-energy computation. In addition, we could obtain structural insights into the change in regioselectivity of mefenamic acid hydroxylation due to single active-site mutations. Our findings confirm that use of MD and binding free-energy calculation is useful for studying biocatalysis in those cases in which enzyme binding is a critical event in determining the selective metabolism of a substrate. © 2016 Wiley Periodicals, Inc.

The prokaryotic zinc-finger: structure, function and comparison with the eukaryotic counterpart.

PubMed

Malgieri, Gaetano; Palmieri, Maddalena; Russo, Luigi; Fattorusso, Roberto; Pedone, Paolo V; Isernia, Carla

2015-12-01

Classical zinc finger (ZF) domains were thought to be confined to the eukaryotic kingdom until the transcriptional regulator Ros protein was identified in Agrobacterium tumefaciens. The Ros Cys2 His2 ZF binds DNA in a peculiar mode and folds in a domain significantly larger than its eukaryotic counterpart consisting of 58 amino acids (the 9-66 region) arranged in a βββαα topology, and stabilized by a conserved, extensive, 15-residue hydrophobic core. The prokaryotic ZF domain, then, shows some intriguing new features that make it interestingly different from its eukaryotic counterpart. This review will focus on the prokaryotic ZFs, summarizing and discussing differences and analogies with the eukaryotic domains and providing important insights into their structure/function relationships. © 2015 FEBS.

In-operando high-speed tomography of lithium-ion batteries during thermal runaway

PubMed Central

Finegan, Donal P.; Scheel, Mario; Robinson, James B.; Tjaden, Bernhard; Hunt, Ian; Mason, Thomas J.; Millichamp, Jason; Di Michiel, Marco; Offer, Gregory J.; Hinds, Gareth; Brett, Dan J.L.; Shearing, Paul R.

2015-01-01

Prevention and mitigation of thermal runaway presents one of the greatest challenges for the safe operation of lithium-ion batteries. Here, we demonstrate for the first time the application of high-speed synchrotron X-ray computed tomography and radiography, in conjunction with thermal imaging, to track the evolution of internal structural damage and thermal behaviour during initiation and propagation of thermal runaway in lithium-ion batteries. This diagnostic approach is applied to commercial lithium-ion batteries (LG 18650 NMC cells), yielding insights into key degradation modes including gas-induced delamination, electrode layer collapse and propagation of structural degradation. It is envisaged that the use of these techniques will lead to major improvements in the design of Li-ion batteries and their safety features. PMID:25919582

Anisotropic Ripple Deformation in Phosphorene.

PubMed

Kou, Liangzhi; Ma, Yandong; Smith, Sean C; Chen, Changfeng

2015-05-07

Two-dimensional materials tend to become crumpled according to the Mermin-Wagner theorem, and the resulting ripple deformation may significantly influence electronic properties as observed in graphene and MoS2. Here, we unveil by first-principles calculations a new, highly anisotropic ripple pattern in phosphorene, a monolayer black phosphorus, where compression-induced ripple deformation occurs only along the zigzag direction in the strain range up to 10%, but not the armchair direction. This direction-selective ripple deformation mode in phosphorene stems from its puckered structure with coupled hinge-like bonding configurations and the resulting anisotropic Poisson ratio. We also construct an analytical model using classical elasticity theory for ripple deformation in phosphorene under arbitrary strain. The present results offer new insights into the mechanisms governing the structural and electronic properties of phosphorene crucial to its device applications.

Further characterization of Bacillus subtilis antibiotic biosensors and their use for antibacterial mode-of-action studies.

PubMed

Mariner, Katherine R; Ooi, Nicola; Roebuck, Deborah; O'Neill, Alex J; Chopra, Ian

2011-04-01

We further examined the usefulness of previously reported Bacillus subtilis biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8-hydroxyquinoline, and juglone.

Comparative transcriptomic analysis of Clostridium perfringens biofilms and planktonic cells.

PubMed

Charlebois, Audrey; Jacques, Mario; Archambault, Marie

2016-10-01

Clostridium perfringens is an opportunistic pathogen that can cause food poisoning in humans and various enterotoxaemias in animal species. Recently, C. perfringens was shown to form biofilms, a structured community of bacterial cells enclosed in a self-produced extracellular matrix. However, very little is known on the subject and no information is available on gene expression in C. perfringens biofilms. To gain insights into the differences between free-living C. perfringens cells and those in biofilms, we used RNA sequencing. In total, 25.7% of genes showed differential expression in the two growth modes; about 12.8% of genes were up-regulated and about 12.9% were down-regulated in biofilms. We show that 772 genes were significantly differentially expressed between biofilms and planktonic cells from the supernatant of biofilms. Genes that were down-regulated in biofilm cells, relative to planktonic cells, included those involved in virulence, energy production, amino acid, nucleotide and carbohydrate metabolism, and in translation and ribosomal structure. Genes up-regulated in biofilm cells were mainly involved in amino acid and carbohydrate metabolism, transcription, inorganic ion metabolism and in defence mechanisms. This study provides new insights into the transcriptomic response of C. perfringens during biofilm formation.

INSIGHTS INTO THE CARCINOGENIC MODE OF ACTION OF ARSENIC

EPA Science Inventory

That arsenic can induce cancer in humans has been known since the late 17th century, yet how arsenic induces cancer has been the subject of numerous scientific publications. Various modes of action (MOA) have been proposed for arsenic's carcinogenicity. In this paper we review o...

Confirmation of high-throughput screening data and novel mechanistic insights into VDR-xenobiotic interactions by orthogonal assays.

PubMed

Mahapatra, Debabrata; Franzosa, Jill A; Roell, Kyle; Kuenemann, Melaine Agnes; Houck, Keith A; Reif, David M; Fourches, Denis; Kullman, Seth W

2018-06-11

High throughput screening (HTS) programs have demonstrated that the Vitamin D receptor (VDR) is activated and/or antagonized by a wide range of structurally diverse chemicals. In this study, we examined the Tox21 qHTS data set generated against VDR for reproducibility and concordance and elucidated functional insights into VDR-xenobiotic interactions. Twenty-one potential VDR agonists and 19 VDR antagonists were identified from a subset of >400 compounds with putative VDR activity and examined for VDR functionality utilizing select orthogonal assays. Transient transactivation assay (TT) using a human VDR plasmid and Cyp24 luciferase reporter construct revealed 20/21 active VDR agonists and 18/19 active VDR antagonists. Mammalian-2-hybrid assay (M2H) was then used to evaluate VDR interactions with co-activators and co-regulators. With the exception of a select few compounds, VDR agonists exhibited significant recruitment of co-regulators and co-activators whereas antagonists exhibited considerable attenuation of recruitment by VDR. A unique set of compounds exhibiting synergistic activity in antagonist mode and no activity in agonist mode was identified. Cheminformatics modeling of VDR-ligand interactions were conducted and revealed selective ligand VDR interaction. Overall, data emphasizes the molecular complexity of ligand-mediated interactions with VDR and suggest that VDR transactivation may be a target site of action for diverse xenobiotics.

Insights into the dynamics of planetary interiors obtained through the study of global distribution of volcanoes I: Empirical calibration on Earth

NASA Astrophysics Data System (ADS)

Cañon-Tapia, Edgardo; Mendoza-Borunda, Ramón

2014-06-01

The distribution of volcanic features is ultimately controlled by processes taking place beneath the surface of a planet. For this reason, characterization of volcano distribution at a global scale can be used to obtain insights concerning dynamic aspects of planetary interiors. Until present, studies of this type have focused on volcanic features of a specific type, or have concentrated on relatively small regions. In this paper, (the first of a series of three papers) we describe the distribution of volcanic features observed over the entire surface of the Earth, combining an extensive database of submarine and subaerial volcanoes. The analysis is based on spatial density contours obtained with the Fisher kernel. Based on an empirical approach that makes no a priori assumptions concerning the number of modes that should characterize the density distribution of volcanism we identified the most significant modes. Using those modes as a base, the relevant distance for the formation of clusters of volcanoes is constrained to be on the order of 100 to 200 km. In addition, it is noted that the most significant modes lead to the identification of clusters that outline the most important tectonic margins on Earth without the need of making any ad hoc assumptions. Consequently, we suggest that this method has the potential of yielding insights about the probable occurrence of tectonic features within other planets.

Vibrational spectroscopy and theoretical studies on 2,4-dinitrophenylhydrazine

NASA Astrophysics Data System (ADS)

Chiş, V.; Filip, S.; Miclăuş, V.; Pîrnău, A.; Tănăselia, C.; Almăşan, V.; Vasilescu, M.

2005-06-01

In this work, we will report a combined experimental and theoretical study on molecular and vibrational structure of 2,4-dinitrophenylhydrazine. FT-IR, FT-IR/ATR and Raman spectra of normal and deuterated DNPH have been recorded and analyzed in order to get new insights into molecular structure and properties of this molecule, with particular emphasize on its intra- and intermolecular hydrogen bonds (HB's). For computational purposes we used density functional theory (DFT) methods, with B3LYP and BLYP exchange-correlation functionals, in conjunction with 6-31G(d) basis set. All experimental vibrational bands have been discussed and assigned to normal modes on the basis of DFT calculations and isotopic shifts and by comparison to other dinitro- substituted compounds [V. Chiş, Chem. Phys., 300 (2004) 1]. To aid in mode assignments, we based on the direct comparison between experimental and calculated spectra by considering both the frequency sequence and the intensity pattern of the experimental and computed vibrational bands. It is also shown that semiempirical AM1 method predicts geometrical parameters and vibrational frequencies related to the HB in a pleasant agreement with experiment, being surprisingly accurate from this perspective.

Atomic force microscopy as an advanced tool in neuroscience

PubMed Central

Jembrek, Maja Jazvinšćak; Šimić, Goran; Hof, Patrick R.; Šegota, Suzana

2015-01-01

This review highlights relevant issues about applications and improvements of atomic force microscopy (AFM) toward a better understanding of neurodegenerative changes at the molecular level with the hope of contributing to the development of effective therapeutic strategies for neurodegenerative illnesses. The basic principles of AFM are briefly discussed in terms of evaluation of experimental data, including the newest PeakForce Quantitative Nanomechanical Mapping (QNM) and the evaluation of Young’s modulus as the crucial elasticity parameter. AFM topography, revealed in imaging mode, can be used to monitor changes in live neurons over time, representing a valuable tool for high-resolution detection and monitoring of neuronal morphology. The mechanical properties of living cells can be quantified by force spectroscopy as well as by new AFM. A variety of applications are described, and their relevance for specific research areas discussed. In addition, imaging as well as non-imaging modes can provide specific information, not only about the structural and mechanical properties of neuronal membranes, but also on the cytoplasm, cell nucleus, and particularly cytoskeletal components. Moreover, new AFM is able to provide detailed insight into physical structure and biochemical interactions in both physiological and pathophysiological conditions. PMID:28123795

Structural insight into the TFIIE–TFIIH interaction: TFIIE and p53 share the binding region on TFIIH

PubMed Central

Okuda, Masahiko; Tanaka, Aki; Satoh, Manami; Mizuta, Shoko; Takazawa, Manabu; Ohkuma, Yoshiaki; Nishimura, Yoshifumi

2008-01-01

RNA polymerase II and general transcription factors (GTFs) assemble on a promoter to form a transcription preinitiation complex (PIC). Among the GTFs, TFIIE recruits TFIIH to complete the PIC formation and regulates enzymatic activities of TFIIH. However, the mode of binding between TFIIE and TFIIH is poorly understood. Here, we demonstrate the specific binding of the C-terminal acidic domain (AC-D) of the human TFIIEα subunit to the pleckstrin homology domain (PH-D) of the human TFIIH p62 subunit and describe the solution structures of the free and PH-D-bound forms of AC-D. Although the flexible N-terminal acidic tail from AC-D wraps around PH-D, the core domain of AC-D also interacts with PH-D. AC-D employs an entirely novel binding mode, which differs from the amphipathic helix method used by many transcriptional activators. So the binding surface between PH-D and AC-D is much broader than the specific binding surface between PH-D and the p53 acidic fragments. From our in vitro studies, we demonstrate that this interaction could be a switch to replace p53 with TFIIE on TFIIH in transcription. PMID:18354501

Fish Pectoral Fin Hydrodynamics; Part III: Low Dimensional Models via POD Analysis

NASA Astrophysics Data System (ADS)

Bozkurttas, M.; Madden, P.

2005-11-01

The highly complex kinematics of the pectoral fin and the resulting hydrodynamics does not lend itself easily to analysis based on simple notions of pitching/heaving/paddling kinematics or lift/drag based propulsive mechanisms. A more inventive approach is needed to dissect the fin gait and gain insight into the hydrodynamic performance of the pectoral fin. The focus of the current work is on the hydrodynamics of the pectoral fin of a bluegill sunfish in steady forward motion. The 3D, time-dependent fin kinematics is obtained via a stereo-videographic technique. We employ proper orthogonal decomposition to extract the essential features of the fin gait and then use CFD to examine the hydrodynamics of simplified gaits synthesized from the POD modes. The POD spectrum shows that the first two, three and five POD modes capture 55%, 67%, and 80% of the motion respectively. The first three modes are in particular highly distinct: Mode-1 is a ``cupping'' motion where the fin cups forward as it is abducted; Mode-2 is an ``expansion'' motion where the fin expands to present a larger area during adduction and finally Mode-3 involves a ``spanwise flick'' of the dorsal edge of the fin. Numerical simulation of flow past fin gaits synthesized from these modes lead to insights into the mechanisms of thrust production; these are discussed in detail.

Relation Between Crustal Deformations Caused by the 2000 Miyake-Kozu Seismovolcanic Activity and the 2000 Tokai Slow-Slip Event -- Which Crustal Deformation Occurred Earlier? --

NASA Astrophysics Data System (ADS)

Kawamura, M.; Yamaoka, K.

2006-12-01

The 2000 seismovolcanic activity between the Miyakejima and Kozushima islands, which are located south of the Japanese main island, and the 2000 slow-slip event, which was initiated on the plate boundary between the subducting Philippine Sea Plate and its overriding Eurasian (Amurian) Plate just beneath the Hamana Lake in the Tokai district, are typical overlapping geophysical processes in space and time around the Japanese islands. Which process affected the other one is an issue which is difficult to clear even now. It is important to resolve the issue in order to get insight into the tectonics of central Japan. For this purpose, we applied two statistical approaches, principal component analysis and mode rotation procedure, to the displacement field of central Japan to obtain the spatiotemporal crustal deformation structures characteristic of the above two processes. We divided time period into two spans: from 26th June, 1999 to 25th June, 2000 and from 26th June, 2000 to 26th June 2001. Secular and periodic components for each station were excluded beforehand by evaluating these components using the data of each station from 26th June, 1999 to 25th June, 2000. All of the spatial and temporal modes for the first half period didn't reveal any significant spatiotemporal changes accompanied by the two processes. This indicates that this time period didn't experience any nonstationary crustal deformations. On the contrary, the modes for the latter half period included the changes due to these processes. The 1st and 2nd modes corresponded to the spatiotemporal structures of the first and latter half periods of the Miyake-Kozu seismovolcanic activity, respectively. The 3rd mode, which was prominent later than the beginning of the Miyake-Kozu seismovolcanic activity, was characteristic of the structure of the Tokai slow-slip event. These results allow us to conclude that crustal deformation due to the Tokai slow-slip event was preceded by that due to the Miyake-Kozu seismovolcanic activity.

Performance Evaluation and Durability Studies of Adhesive Bonds

NASA Astrophysics Data System (ADS)

Ranade, Shantanu Rajendra

In this thesis, four test approaches were developed to characterize the adhesion performance and durability of adhesive bonds for specific applications in areas spanning from structural adhesive joints to popular confectionaries such as chewing gum. In the first chapter, a double cantilever beam (DCB) specimen geometry is proposed for combinatorial fracture studies of structural adhesive bonds. This specimen geometry enabled the characterization of fracture energy vs. bondline thickness trends through fewer tests than those required during a conventional "one at a time" characterization approach, potentially offering a significant reduction in characterization times. The second chapter investigates the adhesive fracture resistance and crack path selection in adhesive joints containing patterns of discreet localized weak interfaces created using physical vapor deposition of copper. In a DCB specimen tested under mode-I conditions, fracture energy within the patterned regions scaled according to a simple rule of mixture, while reverse R-curve and R-curve type trends were observed in the regions surrounding weak interface patterns. Under mixed mode conditions such that bonding surface with patterns is subjected to axial tension, fracture energy did not show R-curve type trends while it was observed that a crack could be made to avoid exceptionally weak interfaces when loaded such that bonding surface with defects is subjected to axial compression. In the third chapter, an adaptation of the probe tack test is proposed to characterize the adhesion behavior of gum cuds. This test method allowed the introduction of substrates with well-defined surface energies and topologies to study their effects on gum cud adhesion. This approach and reported insights could potentially be useful in developing chewing gum formulations that facilitate easy removal of improperly discarded gum cuds from adhering surfaces. In the fourth chapter we highlight a procedure to obtain insights into the long-term performance of silicone sealants designed for load-bearing applications such as solar panel support sealants. Using small strain constitutive tests and time-temperature-superposition principle, thermal shift factors were obtained and successfully used to characterize the creep rupture master curves for specific joint configurations, leading to insights into delayed failures corresponding to three years through experiments carried out in one month.

Military Design Insights for Online Education Program Evaluation: A Revised Theoretical Construct

ERIC Educational Resources Information Center

Culkin, David T.

2017-01-01

This theoretical development article examines how design methodology currently applied in United States military doctrine can offer insights into the increasingly complex arena of program evaluations of online modes for adult distance education. The article presents key themes that emerge from a multidisciplinary literature review. These themes…

Structural analysis of a putative SAM-dependent methyltransferase, YtqB, from Bacillus subtilis.

PubMed

Park, Sun Cheol; Song, Wan Seok; Yoon, Sung-il

2014-04-18

S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases) methylate diverse biological molecules using a SAM cofactor. The ytqB gene of Bacillus subtilis encodes a putative MTase and its biological function has never been characterized. To reveal the structural features and the cofactor binding mode of YtqB, we have determined the crystal structures of YtqB alone and in complex with its cofactor, SAM, at 1.9 Å and 2.2 Å resolutions, respectively. YtqB folds into a β-sheet sandwiched by two α-helical layers, and assembles into a dimeric form. Each YtqB monomer contains one SAM binding site, which shapes SAM into a slightly curved conformation and exposes the reactive methyl group of SAM potentially to a substrate. Our comparative structural analysis of YtqB and its homologues indicates that YtqB is a SAM-dependent class I MTase, and provides insights into the substrate binding site of YtqB. Copyright © 2014 Elsevier Inc. All rights reserved.

Hybrid Methods Reveal Multiple Flexibly Linked DNA Polymerases within the Bacteriophage T7 Replisome

DOE PAGES

Wallen, Jamie R.; Zhang, Hao; Weis, Caroline; ...

2017-01-03

The physical organization of DNA enzymes at a replication fork enables efficient copying of two antiparallel DNA strands, yet dynamic protein interactions within the replication complex complicate replisome structural studies. We employed a combination of crystallographic, native mass spectrometry and small-angle X-ray scattering experiments to capture alternative structures of a model replication system encoded by bacteriophage T7. then, the two molecules of DNA polymerase bind the ring-shaped primase-helicase in a conserved orientation and provide structural insight into how the acidic C-terminal tail of the primase-helicase contacts the DNA polymerase to facilitate loading of the polymerase onto DNA. A third DNA polymerasemore » binds the ring in an offset manner that may enable polymerase exchange during replication. Alternative polymerase binding modes are also detected by small-angle X-ray scattering with DNA substrates present. The collective results unveil complex motions within T7 replisome higher-order structures that are underpinned by multivalent protein-protein interactions with functional implications.« less

Structure of D-AKAP2:PKA RI complex: Insights into AKAP specificity and selectivity

PubMed Central

Sarma, Ganapathy N.; Kinderman, Francis S.; Kim, Choel; von Daake, Sventja; Chen, Lirong; Wang, Bi-Cheng; Taylor, Susan S.

2011-01-01

Summary A-kinase anchoring proteins (AKAPs) regulate cyclic AMP-dependent protein kinase (PKA) signaling in space and time. Dual-specific AKAP 2 (D-AKAP2) binds to the dimerization/docking (D/D) domain of both RI and RII regulatory subunits of PKA with high affinity. Here, we have determined the structures of the RIα D/D domain alone and in complex with D-AKAP2. The D/D domain presents an extensive surface for binding through a well-formed N-termina helix and this surface restricts the diversity of AKAPs that can interact. The structures also underscore the importance of a redox-sensitive disulfide in affecting AKAP binding. An unexpected shift in the helical register of D-AKAP2 compared to the RIIα:D-AKAP2 complex structure makes the mode of binding to RIα novel. Finally, the comparison allows us to deduce a molecular explanation for the sequence and spatial determinants of AKAP specificity. PMID:20159461

Fragmentation studies of fulvic acids using collision induced dissociation fourier transform ion cyclotron resonance mass spectrometry.

PubMed

Witt, Matthias; Fuchser, Jens; Koch, Boris P

2009-04-01

The complex natural organic matter standard Suwannee river fulvic acid (SRFA) was analyzed by negative ion mode electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FTICR MS) using on-resonance collision induced dissociation (CID) of single ultrahigh resolved mass peaks in the ICR cell. Molecular formula assignment of precursor masses resulted in exactly one molecular formula for each of the peaks. Analyses of the corresponding fragment spectra and comparison to different standard substances revealed specific neutral losses and fragmentation patterns which result in structures consisting of a high degree of carboxyl- and fewer hydroxyl groups. The comparison of fragmented mass peaks within different pseudohomologous series (CH(2)-series, and CH(4) vs O exchange) suggested structurally based differences between these series. CID FTICR MS allowed isolating single mass peaks in a very complex natural organic matter spectrum. Subsequently, fragmentation gave structural insights into this material. Our results suggest that the structural diversity in complex humic substances is not as high as expected.

Hybrid Methods Reveal Multiple Flexibly Linked DNA Polymerases within the Bacteriophage T7 Replisome

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

Wallen, Jamie R.; Zhang, Hao; Weis, Caroline

The physical organization of DNA enzymes at a replication fork enables efficient copying of two antiparallel DNA strands, yet dynamic protein interactions within the replication complex complicate replisome structural studies. We employed a combination of crystallographic, native mass spectrometry and small-angle X-ray scattering experiments to capture alternative structures of a model replication system encoded by bacteriophage T7. then, the two molecules of DNA polymerase bind the ring-shaped primase-helicase in a conserved orientation and provide structural insight into how the acidic C-terminal tail of the primase-helicase contacts the DNA polymerase to facilitate loading of the polymerase onto DNA. A third DNA polymerasemore » binds the ring in an offset manner that may enable polymerase exchange during replication. Alternative polymerase binding modes are also detected by small-angle X-ray scattering with DNA substrates present. The collective results unveil complex motions within T7 replisome higher-order structures that are underpinned by multivalent protein-protein interactions with functional implications.« less

Parsesciencing: A Basic Science Mode of Inquiry.

PubMed

Parse, Rosemarie Rizzo

2016-10-01

The purpose of this article is to introduce the language for the mode of inquiry, now known as Parsesciencing. The language for the Humanbecoming Hermeneutic Sciencing was introduced in an earlier volume of Nursing Science Quarterly. Language both reflects and cocreates meaning. The language of sciencing is everchanging; it is an evolutionary emergent, shifting as new ideas cocreate horizons beyond. The language set forth here is to articulate more explicitly meanings of the modes of inquiry consistent with the humanbecoming paradigm and distinct from modes of inquiry in other disciplines. In dwelling with the findings of published and unpublished studies that were guided by humanbecoming, new insights arose, and with creative conceptualizing these new insights gave birth to new meanings, thus different language. The language introduced here includes the following: Parsesciencing as coming to know the meanings of universal humanuniverse living experiences, horizon of inquiry, foreknowings, inquiry stance, mode of inquiry, historians, dialoging-engaging, scholar, distilling-fusing, discerning extant moment, transmogrifying, transsubstantiating, and newknowings. Note: an example of the new language with a Parsesciencing inquiry on the universal humanuniverse living experience of feeling unsure by Sandra Bunkers appears later in this issue. © The Author(s) 2016.

Measurement of nonlinear normal modes using multi-harmonic stepped force appropriation and free decay

NASA Astrophysics Data System (ADS)

Ehrhardt, David A.; Allen, Matthew S.

2016-08-01

Nonlinear Normal Modes (NNMs) offer tremendous insight into the dynamic behavior of a nonlinear system, extending many concepts that are familiar in linear modal analysis. Hence there is interest in developing methods to experimentally and numerically determine a system's NNMs for model updating or simply to characterize its dynamic response. Previous experimental work has shown that a mono-harmonic excitation can be used to isolate a system's dynamic response in the neighborhood of a NNM along the main backbones of a system. This work shows that a multi-harmonic excitation is needed to isolate a NNM when well separated linear modes of a structure couple to produce an internal resonance. It is shown that one can tune the multiple harmonics of the input excitation using a plot of the input force versus the response velocity until the area enclosed by the force-velocity curve is minimized. Once an appropriated NNM is measured, one can increase the force level and retune the frequency to obtain a NNM at a higher amplitude or remove the excitation and measure the structure's decay down a NNM backbone. This work explores both methods using simulations and measurements of a nominally-flat clamped-clamped beam excited at a single point with a magnetic force. Numerical simulations are used to validate the method in a well defined environment and to provide comparison with the experimentally measured NNMs. The experimental results seem to produce a good estimate of two NNMs along their backbone and part of an internal resonance branch. Full-field measurements are then used to further explore the couplings between the underlying linear modes along the identified NNMs.

Design and synthesis of alkoxyindolyl-3-acetic acid analogs as peroxisome proliferator-activated receptor-γ/δ agonists.

PubMed

Gim, Hyo Jin; Li, Hua; Lee, Eun; Ryu, Jae-Ha; Jeon, Raok

2013-01-15

A series of carbazole or phenoxazine containing alkoxyindole-3-acetic acid analogs were prepared as PPARγ/δ agonists and their transactivation activities for PPAR receptor subtypes (α, γ and δ) were investigated. Structure-activity relationship studies disclosed the effect of the lipophilic tail, attaching position of the alkoxy group and N-benzyl substitution at indole. Compound 1b was the most potent for PPARδ and 3b for PPARγ. Molecular modeling suggested two different binding modes of our alkoxyindole-3-acetic acid analogs providing the insight into their PPAR activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Peculiarities of the third natural frequency vibrations of a cantilever for the improvement of energy harvesting.

PubMed

Ostasevicius, Vytautas; Janusas, Giedrius; Milasauskaite, Ieva; Zilys, Mindaugas; Kizauskiene, Laura

2015-05-28

This paper focuses on several aspects extending the dynamical efficiency of a cantilever beam vibrating in the third mode. A few ways of producing this mode stimulation, namely vibro-impact or forced excitation, as well as its application for energy harvesting devices are proposed. The paper presents numerical and experimental analyses of novel structural dynamics effects along with an optimal configuration of the cantilever beam. The peculiarities of a cantilever beam vibrating in the third mode are related to the significant increase of the level of deformations capable of extracting significant additional amounts of energy compared to the conventional harvester vibrating in the first mode. Two types of a piezoelectric vibrating energy harvester (PVEH) prototype are analysed in this paper: the first one without electrode segmentation, while the second is segmented using electrode segmentation at the strain nodes of the third vibration mode to achieve effective operation at the third resonant frequency. The results of this research revealed that the voltage generated by any segment of the segmented PVEH prototype excited at the third resonant frequency demonstrated a 3.4-4.8-fold increase in comparison with the non-segmented prototype. Simultaneously, the efficiency of the energy harvester prototype also increased at lower resonant frequencies from 16% to 90%. The insights presented in the paper may serve for the development and fabrication of advanced piezoelectric energy harvesters which would be able to generate a considerably increased amount of electrical energy independently of the frequency of kinematical excitation.

Elucidating Duramycin’s Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope

DOE PAGES

Hasim, Sahar; Allison, David P.; Mendez, Berlin; ...

2018-02-14

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus-derived bacterial isolates to determine species selectivity.more » Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin’s mode of action and a better understanding of its selectivity.« less

Elucidating Duramycin’s Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope

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

Hasim, Sahar; Allison, David P.; Mendez, Berlin

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus-derived bacterial isolates to determine species selectivity.more » Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin’s mode of action and a better understanding of its selectivity.« less

Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

PubMed

Sakkal, Leon A; Rajkowski, Kyle Z; Armen, Roger S

2017-06-05

Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A 1 R, A 2A R, A 3 R) and muscarinic acetylcholine (M 1 R, M 5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M 1 R PAMs were predicted to bind in the analogous M 2 R PAM LY2119620 binding site. The M 5 R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Gradual plasmon evolution and huge infrared near-field enhancement of metallic bridged nanoparticle dimers.

PubMed

Huang, Yu; Ma, Lingwei; Hou, Mengjing; Xie, Zheng; Zhang, Zhengjun

2016-01-28

By three-dimensional (3D) finite element method (FEM) plasmon mapping, gradual plasmon evolutions of both bonding dipole plasmon (BDP) and charge transfer plasmon (CTP) modes are visualized. In particular, the evolved BDP mode provides a physical insight into the rapid degeneration of electromagnetic hot spots in practical applications, while the rising CTP mode enables a huge near-field enhancement for potential plasmonic devices at infrared wavelengths.

Spectroscopic Ellipsometry Studies of n-i-p Hydrogenated Amorphous Silicon Based Photovoltaic Devices

PubMed Central

Karki Gautam, Laxmi; Junda, Maxwell M.; Haneef, Hamna F.; Collins, Robert W.; Podraza, Nikolas J.

2016-01-01

Optimization of thin film photovoltaics (PV) relies on characterizing the optoelectronic and structural properties of each layer and correlating these properties with device performance. Growth evolution diagrams have been used to guide production of materials with good optoelectronic properties in the full hydrogenated amorphous silicon (a-Si:H) PV device configuration. The nucleation and evolution of crystallites forming from the amorphous phase were studied using in situ near-infrared to ultraviolet spectroscopic ellipsometry during growth of films prepared as a function of hydrogen to reactive gas flow ratio R = [H2]/[SiH4]. In conjunction with higher photon energy measurements, the presence and relative absorption strength of silicon-hydrogen infrared modes were measured by infrared extended ellipsometry measurements to gain insight into chemical bonding. Structural and optical models have been developed for the back reflector (BR) structure consisting of sputtered undoped zinc oxide (ZnO) on top of silver (Ag) coated glass substrates. Characterization of the free-carrier absorption properties in Ag and the ZnO + Ag interface as well as phonon modes in ZnO were also studied by spectroscopic ellipsometry. Measurements ranging from 0.04 to 5 eV were used to extract layer thicknesses, composition, and optical response in the form of complex dielectric function spectra (ε = ε1 + iε2) for Ag, ZnO, the ZnO + Ag interface, and undoped a-Si:H layer in a substrate n-i-p a-Si:H based PV device structure. PMID:28773255

Insight into the enzyme-inhibitor interactions of the first experimentally determined human aromatase.

PubMed

Punetha, Ankita; Shanmugam, Karthi; Sundar, Durai

2011-04-01

Aromatase is an important pharmacological target in the anti-cancer therapy as the intratumoral aromatase is the source of local estrogen production in breast cancer tissues. Suppression of estrogen biosynthesis by aromatase inhibition represents an effective approach for the treatment of hormone-sensitive breast cancer. Because of the membrane-bound character and heme-binding instability, no crystal structure of aromatase was reported for a long time, until recently when crystal structure of human placental aromatase cytochrome P450 in complex with androstenedione was deposited in PDB. The present study is towards understanding the structural and functional characteristics of aromatase to address unsolved mysteries about this enzyme and elucidate the exact mode of binding of aromatase inhibitors. We have performed molecular docking simulation with twelve different inhibitors (ligands), which includes four FDA approved drugs; two flavonoids; three herbal compounds and three compounds having biphenyl motif with known IC(50) values into the active site of the human aromatase enzyme. All ligands showed favorable interactions and most of them seemed to interact to hydrophobic amino acids Ile133, Phe134, Phe221, Trp224, Ala306, Val370, Val373, Met374 and Leu477 and hydrophilic Arg115 and neutral Thr310 residues. The elucidation of the actual structure-function relationship of aromatase and the exact binding mode described in this study will be of significant interest as its inhibitors have shown great promise in fighting breast cancer.

Structure and Dynamics of the M3 Muscarinic Acetylcholine Receptor

PubMed Central

Kruse, Andrew C.; Hu, Jianxin; Pan, Albert C.; Arlow, Daniel H.; Rosenbaum, Daniel M.; Rosemond, Erica; Green, Hillary F.; Liu, Tong; Chae, Pil Seok; Dror, Ron O.; Shaw, David E.; Weis, William I.; Wess, Jurgen; Kobilka, Brian

2012-01-01

Acetylcholine (ACh), the first neurotransmitter to be identified1, exerts many of its physiological actions via activation of a family of G protein-coupled receptors (GPCRs) known as muscarinic ACh receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G protein coupling preference and the physiological responses they mediate.2–4 Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences.5–6 We describe here the structure of the Gq/11-coupled M3 mAChR bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the Gi/o-coupled M2 receptor, offers new possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows the first structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and raise additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer new insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors. PMID:22358844

An alternative to Guyan reduction of finite-element models

NASA Technical Reports Server (NTRS)

Lin, Jiguan Gene

1988-01-01

Structural modeling is a key part of structural system identification for large space structures. Finite-element structural models are commonly used in practice because of their general applicability and availability. The initial models generated by using a standard computer program such as NASTRAN, ANSYS, SUPERB, STARDYNE, STRUDL, etc., generally contain tens of thousands of degrees of freedom. The models must be reduced for purposes of identification. Not only does the magnitude of the identification effort grow exponentially as a function of the number of degrees of freedom, but numerical procedures may also break down because of accumulated round-off errors. Guyan reduction is usually applied after a static condensation. Misapplication of Guyan reduction can lead to serious modeling errors. It is quite unfortunate and disappointing, since the accuracy of the original detailed finite-element model one tries very hard to achieve is lost by the reduction. First, why and how Guyan reduction always causes loss of accuracy is examined. An alternative approach is then introduced. The alternative can be thought of as an improvement of Guyan reduction, the Rayleigh-Ritz method, and in particular the recent algorithm of Wilson, Yuan, and Dickens. Unlike Guyan reduction, the use of the alternative does not need any special insight, experience, or skill for partitioning the structural degrees of freedom. In addition to model condensation, this alternative approach can also be used for predicting analytically, quickly, and economically, what are those structural modes that are excitable by a force actuator at a given trial location. That is, in the excitation of the structural modes for identification, it can be used for guiding the placement of the force actuators.

Structure and dynamics of the M3 muscarinic acetylcholine receptor

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

Kruse, Andrew C.; Hu, Jianxin; Pan, Albert C.

2012-03-01

Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G{sub q/11}-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify themore » binding mode for this clinically important drug. This structure, together with that of the G{sub i/o}-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.« less

A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms

NASA Astrophysics Data System (ADS)

Jones, Alan M.; Westwood, Isaac M.; Osborne, James D.; Matthews, Thomas P.; Cheeseman, Matthew D.; Rowlands, Martin G.; Jeganathan, Fiona; Burke, Rosemary; Lee, Diane; Kadi, Nadia; Liu, Manjuan; Richards, Meirion; McAndrew, Craig; Yahya, Norhakim; Dobson, Sarah E.; Jones, Keith; Workman, Paul; Collins, Ian; van Montfort, Rob L. M.

2016-10-01

The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.

Visualizing Flutter Mechanism as Traveling Wave Through Animation of Simulation Results for the Semi-Span Super-Sonic Transport Wind-Tunnel Model

NASA Technical Reports Server (NTRS)

Christhilf, David M.

2014-01-01

It has long been recognized that frequency and phasing of structural modes in the presence of airflow play a fundamental role in the occurrence of flutter. Animation of simulation results for the long, slender Semi-Span Super-Sonic Transport (S4T) wind-tunnel model demonstrates that, for the case of mass-ballasted nacelles, the flutter mode can be described as a traveling wave propagating downstream. Such a characterization provides certain insights, such as (1) describing the means by which energy is transferred from the airflow to the structure, (2) identifying airspeed as an upper limit for speed of wave propagation, (3) providing an interpretation for a companion mode that coalesces in frequency with the flutter mode but becomes very well damped, (4) providing an explanation for bursts of response to uniform turbulence, and (5) providing an explanation for loss of low frequency (lead) phase margin with increases in dynamic pressure (at constant Mach number) for feedback systems that use sensors located upstream from active control surfaces. Results from simulation animation, simplified modeling, and wind-tunnel testing are presented for comparison. The simulation animation was generated using double time-integration in Simulink of vertical accelerometer signals distributed over wing and fuselage, along with time histories for actuated control surfaces. Crossing points for a zero-elevation reference plane were tracked along a network of lines connecting the accelerometer locations. Accelerometer signals were used in preference to modal displacement state variables in anticipation that the technique could be used to animate motion of the actual wind-tunnel model using data acquired during testing. Double integration of wind-tunnel accelerometer signals introduced severe drift even with removal of both position and rate biases such that the technique does not currently work. Using wind-tunnel data to drive a Kalman filter based upon fitting coefficients to analytical mode shapes might provide a better means to animate the wind tunnel data.

Selective coherent perfect absorption of subradiant mode in ultrathin bi-layer metamaterials via antisymmetric excitation

NASA Astrophysics Data System (ADS)

Tan, Wei; Zhang, Caihong; Li, Chun; Zhou, Xiaoying; Jia, Xiaoqing; Feng, Zheng; Su, Juan; Jin, Biaobing

2017-05-01

We demonstrate that the subradiant mode in ultrathin bi-layer metamaterials can be exclusively excited under two-antisymmetric-beam illumination (or equivalently, at a node of the standing wave field), while the superradiant mode is fully suppressed due to their different mode symmetry. Coherent perfect absorption (CPA) with the Lorentzian lineshape can be achieved corresponding to the subradiant mode. A theoretical model is established to distinguish the different behaviors of these two modes and to elucidate the CPA condition. Terahertz ultrathin bi-layer metamaterials on flexible polyimide substrates are fabricated and tested, exhibiting excellent agreement with theoretical predictions. This work provides physical insight into how to selectively excite the antisymmetric subradiant mode via coherence incidence.

Designed to Fail: A Novel Mode of Collagen Fibril Disruption and Its Relevance to Tissue Toughness

PubMed Central

Veres, Samuel P.; Lee, J. Michael

2012-01-01

Collagen fibrils are nanostructured biological cables essential to the structural integrity of many of our tissues. Consequently, understanding the structural basis of their robust mechanical properties is of great interest. Here we present what to our knowledge is a novel mode of collagen fibril disruption that provides new insights into both the structure and mechanics of native collagen fibrils. Using enzyme probes for denatured collagen and scanning electron microscopy, we show that mechanically overloading collagen fibrils from bovine tail tendons causes them to undergo a sequential, two-stage, selective molecular failure process. Denatured collagen molecules—meaning molecules with a reduced degree of time-averaged helicity compared to those packed in undamaged fibrils—were first created within kinks that developed at discrete, repeating locations along the length of fibrils. There, collagen denaturation within the kinks was concentrated within certain subfibrils. Additional denatured molecules were then created along the surface of some disrupted fibrils. The heterogeneity of the disruption within fibrils suggests that either mechanical load is not carried equally by a fibril's subcomponents or that the subcomponents do not possess homogenous mechanical properties. Meanwhile, the creation of denatured collagen molecules, which necessarily involves the energy intensive breaking of intramolecular hydrogen bonds, provides a physical basis for the toughness of collagen fibrils. PMID:22735538

Homology modeling of Homo sapiens lipoic acid synthase: Substrate docking and insights on its binding mode.

PubMed

Krishnamoorthy, Ezhilarasi; Hassan, Sameer; Hanna, Luke Elizabeth; Padmalayam, Indira; Rajaram, Rama; Viswanathan, Vijay

2017-05-07

Lipoic acid synthase (LIAS) is an iron-sulfur cluster mitochondrial enzyme which catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. Recently there has been significant interest in its role in metabolic diseases and its deficiency in LIAS expression has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy, suggesting a strong inverse correlation between LIAS reduction and disease status. In this study we use a bioinformatics approach to predict its structure, which would be helpful to understanding its role. A homology model for LIAS protein was generated using X-ray crystallographic structure of Thermosynechococcus elongatus BP-1 (PDB ID: 4U0P). The predicted structure has 93% of the residues in the most favour region of Ramachandran plot. The active site of LIAS protein was mapped and docked with S-Adenosyl Methionine (SAM) using GOLD software. The LIAS-SAM complex was further refined using molecular dynamics simulation within the subsite 1 and subsite 3 of the active site. To the best of our knowledge, this is the first study to report a reliable homology model of LIAS protein. This study will facilitate a better understanding mode of action of the enzyme-substrate complex for future studies in designing drugs that can target LIAS protein. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel imaging technologies for characterization of microbial extracellular polysaccharides.

PubMed

Lilledahl, Magnus B; Stokke, Bjørn T

2015-01-01

Understanding of biology is underpinned by the ability to observe structures at various length scales. This is so in a historical context and is also valid today. Evolution of novel insight often emerges from technological advancement. Recent developments in imaging technologies that is relevant for characterization of extraceullar microbiological polysaccharides are summarized. Emphasis is on scanning probe and optical based techniques since these tools offers imaging capabilities under aqueous conditions more closely resembling the physiological state than other ultramicroscopy imaging techniques. Following the demonstration of the scanning probe microscopy principle, novel operation modes to increase data capture speed toward video rate, exploitation of several cantilever frequencies, and advancement of utilization of specimen mechanical properties as contrast, also including their mode of operation in liquid, have been developed on this platform. Combined with steps in advancing light microscopy with resolution beyond the far field diffraction limit, non-linear methods, and combinations of the various imaging modalities, the potential ultramicroscopy toolbox available for characterization of exopolysaccharides (EPS) are richer than ever. Examples of application of such ultramicroscopy strategies range from imaging of isolated microbial polysaccharides, structures being observed when they are involved in polyelectrolyte complexes, aspects of their enzymatic degradation, and cell surface localization of secreted polysaccharides. These, and other examples, illustrate that the advancement in imaging technologies relevant for EPS characterization supports characterization of structural aspects.

Dual-Mode Electro-Optical Techniques for Biosensing Applications: A Review

PubMed Central

Johnson, Steven

2017-01-01

The monitoring of biomolecular interactions is a key requirement for the study of complex biological processes and the diagnosis of disease. Technologies that are capable of providing label-free, real-time insight into these interactions are of great value for the scientific and clinical communities. Greater understanding of biomolecular interactions alongside increased detection accuracy can be achieved using technology that can provide parallel information about multiple parameters of a single biomolecular process. For example, electro-optical techniques combine optical and electrochemical information to provide more accurate and detailed measurements that provide unique insights into molecular structure and function. Here, we present a comparison of the main methods for electro-optical biosensing, namely, electrochemical surface plasmon resonance (EC-SPR), electrochemical optical waveguide lightmode spectroscopy (EC-OWLS), and the recently reported silicon-based electrophotonic approach. The comparison considers different application spaces, such as the detection of low concentrations of biomolecules, integration, the tailoring of light-matter interaction for the understanding of biomolecular processes, and 2D imaging of biointeractions on a surface. PMID:28880211

From Molecular Docking to 3D-Quantitative Structure-Activity Relationships (3D-QSAR): Insights into the Binding Mode of 5-Lipoxygenase Inhibitors.

PubMed

Eren, Gokcen; Macchiarulo, Antonio; Banoglu, Erden

2012-02-01

Pharmacological intervention with 5-Lipoxygenase (5-LO) is a promising strategy for treatment of inflammatory and allergic ailments, including asthma. With the aim of developing predictive models of 5-LO affinity and gaining insights into the molecular basis of ligand-target interaction, we herein describe QSAR studies of 59 diverse nonredox-competitive 5-LO inhibitors based on the use of molecular shape descriptors and docking experiments. These studies have successfully yielded a predictive model able to explain much of the variance in the activity of the training set compounds while predicting satisfactorily the 5-LO inhibitory activity of an external test set of compounds. The inspection of the selected variables in the QSAR equation unveils the importance of specific interactions which are observed from docking experiments. Collectively, these results may be used to design novel potent and selective nonredox 5-LO inhibitors. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The clpB gene of Bifidobacterium breve UCC 2003: transcriptional analysis and first insights into stress induction.

PubMed

Ventura, Marco; Kenny, John G; Zhang, Ziding; Fitzgerald, Gerald F; van Sinderen, Douwe

2005-09-01

The so-called clp genes, which encode components of the Clp proteolytic complex, are widespread among bacteria. The Bifidobacterium breve UCC 2003 genome contains a clpB gene with significant homology to predicted clpB genes from other members of the Actinobacteridae group. The heat- and osmotic-inducibility of the B. breve UCC 2003 clpB homologue was verified by slot-blot analysis, while Northern blot and primer extension analyses showed that the clpB gene is transcribed as a monocistronic unit with a single promoter. The role of a hspR homologue, known to control the regulation of clpB and dnaK gene expression in other high G+C content bacteria was investigated by gel mobility shift assays. Moreover the predicted 3D structure of HspR provides further insight into the binding mode of this protein to the clpB promoter region, and highlights the key amino acid residues believed to be involved in the protein-DNA interaction.

Dual-Mode Electro-Optical Techniques for Biosensing Applications: A Review.

PubMed

Juan-Colás, José; Johnson, Steven; Krauss, Thomas F

2017-09-07

The monitoring of biomolecular interactions is a key requirement for the study of complex biological processes and the diagnosis of disease. Technologies that are capable of providing label-free, real-time insight into these interactions are of great value for the scientific and clinical communities. Greater understanding of biomolecular interactions alongside increased detection accuracy can be achieved using technology that can provide parallel information about multiple parameters of a single biomolecular process. For example, electro-optical techniques combine optical and electrochemical information to provide more accurate and detailed measurements that provide unique insights into molecular structure and function. Here, we present a comparison of the main methods for electro-optical biosensing, namely, electrochemical surface plasmon resonance (EC-SPR), electrochemical optical waveguide lightmode spectroscopy (EC-OWLS), and the recently reported silicon-based electrophotonic approach. The comparison considers different application spaces, such as the detection of low concentrations of biomolecules, integration, the tailoring of light-matter interaction for the understanding of biomolecular processes, and 2D imaging of biointeractions on a surface.

Strain Rate Dependency of Fracture Toughness, Energy Release Rate and Geomechanical Attributes of Select Indian Shales

NASA Astrophysics Data System (ADS)

Mahanta, B.; Vishal, V.; Singh, T. N.; Ranjith, P.

2016-12-01

In addition to modern improved technology, it requires detailed understanding of rock fractures for the purpose of enhanced energy extraction through hydraulic fracturing of gas shales and geothermal energy systems. The understanding of rock fracture behavior, patterns and properties such as fracture toughness; energy release rate; strength and deformation attributes during fracturing hold significance. Environmental factors like temperature, pressure, humidity, water vapor and experimental condition such as strain rate influence the estimation of these properties. In this study, the effects of strain rates on fracture toughness, energy release rate as well as geomechanical properties like uniaxial compressive strength, Young's modulus, failure strain, tensile strength, and brittleness index of gas shales were investigated. In addition to the rock-mechanical parameters, the fracture toughness and the energy release rates were measured for three different modes viz. mode I, mixed mode (I-II) and mode II. Petrographic and X-ray diffraction (XRD) analyses were performed to identify the mineral composition of the shale samples. Scanning electron microscope (SEM) analyses were conducted to have an insight about the strain rate effects on micro-structure of the rock. The results suggest that the fracture toughness; the energy release rate as well as other geomechanical properties are a function of strain rates. At high strain rates, the strength and stiffness of shale increases which in turn increases the fracture toughness and the energy release rate of shale that may be due to stress redistribution during grain fracturing. The fracture toughness and the strain energy release rates for all the modes (I/I-II/II) are comparable at lower strain rates, but they vary considerably at higher strain rates. In all the cases, mode I and mode II fracturing requires minimum and maximum applied energy, respectively. Mode I energy release rate is maximum, compared to the other modes.

Evolutionary significance of osmoregulatory mechanisms in cyanobacteria

NASA Technical Reports Server (NTRS)

Yopp, J. H.; Pavlicek, J. H.; Sibley, M. H.

1986-01-01

Physiological processes of all life forms on this planet are intrinsically related to their intracellular water potential. The overall goal was the elucidation of the mechanism(s) whereby the first oxygenic phtoautotrophs (the cyanobacteria) adjust their water potential to that of a changing external water potential (that is, osmoregulate). Osmoregulation is achieved by intracellular adjustment of inorganic and/or organic solutes (osmolytes) involving specific biochemical mechanisms. Structural and biochemical evolution within the cyanobacteria is believed completed (and fixed in present day forms) by the end of the Precambrain eon. Therefore, research using cyanobacteria of all three structural types (unicellular, filamentous, and branched), each grown in the photoautotrophic (PA), photoheterotrophic (PG), and chemotrophic (CH) modes of nutrition, should provide insight into the origin and evolution of the photosynthetically related osmoregulatory mechanisms of eukaryotic organisms. The chloroplasts of these organisms are phylogenetically related to the cyanobacteria.

Anomalous stress response of ultrahard WB n compounds

DOE PAGES

Li, Quan; Zhou, Dan; Zheng, Weitao; ...

2015-10-29

Boron-rich tungsten borides are premier prototypes of a new class of ultrahard compounds. Here, we show by first-principles calculations that their stress-strain relations display surprisingly diverse and anomalous behavior under a variety of loading conditions. Most remarkable is the dramatically changing bonding configurations and deformation modes with rising boron concentration in WB n (n=2, 3, 4), resulting in significantly different stress responses and unexpected indentation strength variations. This novel phenomenon stems from the peculiar structural arrangements in tungsten borides driven by boron’s ability to form unusually versatile bonding states. Our results elucidate the intriguing deformation mechanisms that define a distinctmore » type of ultrahard material. Here, these new insights underscore the need to explore unconventional structure-property relations in a broad range of transition-metal light-element compounds.« less

Modal decomposition of turbulent supersonic cavity

NASA Astrophysics Data System (ADS)

Soni, R. K.; Arya, N.; De, A.

2018-06-01

Self-sustained oscillations in a Mach 3 supersonic cavity with a length-to-depth ratio of three are investigated using wall-modeled large eddy simulation methodology for ReD = 3.39× 105 . The unsteady data obtained through computation are utilized to investigate the spatial and temporal evolution of the flow field, especially the second invariant of the velocity tensor, while the phase-averaged data are analyzed over a feedback cycle to study the spatial structures. This analysis is accompanied by the proper orthogonal decomposition (POD) data, which reveals the presence of discrete vortices along the shear layer. The POD analysis is performed in both the spanwise and streamwise planes to extract the coherence in flow structures. Finally, dynamic mode decomposition is performed on the data sequence to obtain the dynamic information and deeper insight into the self-sustained mechanism.

Multimodal and self-healable interfaces enable strong and tough graphene-derived materials

NASA Astrophysics Data System (ADS)

Liu, Yilun; Xu, Zhiping

2014-10-01

Recent studies have shown that graphene-derived materials not only feature outstanding multifunctional properties, but also act as model materials to implant nanoscale structural engineering insights into their macroscopic performance optimization. In this work, we explore strengthening and toughening strategies of this class of materials by introducing multimodal crosslinks, including long, strong and short, self-healable ones. We identify two failure modes by fracturing functionalized graphene sheets or their crosslinks, and the role of brick-and-mortar hierarchy in mechanical enhancement. Theoretical analysis and atomistic simulation results show that multimodal crosslinks synergistically transfer tensile load to enhance the strength, whereas reversible rupture and formation of healable crosslinks improve the toughness. These findings lay the ground for future development of high-performance paper-, fiber- or film-like macroscopic materials from low-dimensional structures with engineerable interfaces.

Anisotropic ripple deformation in phosphorene

DOE PAGES

Kou, Liangzhi; Ma, Yandong; Smith, Sean C.; ...

2015-04-07

Here, two-dimensional materials tend to become crumpled according to the Mermin-Wagner theorem, and the resulting ripple deformation may significantly influence electronic properties as observed in graphene and MoS 2. Here, we unveil by first-principles calculations a new, highly anisotropic ripple pattern in phosphorene, a monolayer black phosphorus, where compression-induced ripple deformation occurs only along the zigzag direction in the strain range up to 10%, but not the armchair direction. This direction-selective ripple deformation mode in phosphorene stems from its puckered structure with coupled hinge-like bonding configurations and the resulting anisotropic Poisson ratio. We also construct an analytical model using classicalmore » elasticity theory for ripple deformation in phosphorene under arbitrary strain. The present results offer new insights into the mechanisms governing the structural and electronic properties of phosphorene crucial to its device applications.« less

Anisotropic ripple deformation in phosphorene

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

Kou, Liangzhi; Ma, Yandong; Smith, Sean C.

Here, two-dimensional materials tend to become crumpled according to the Mermin-Wagner theorem, and the resulting ripple deformation may significantly influence electronic properties as observed in graphene and MoS 2. Here, we unveil by first-principles calculations a new, highly anisotropic ripple pattern in phosphorene, a monolayer black phosphorus, where compression-induced ripple deformation occurs only along the zigzag direction in the strain range up to 10%, but not the armchair direction. This direction-selective ripple deformation mode in phosphorene stems from its puckered structure with coupled hinge-like bonding configurations and the resulting anisotropic Poisson ratio. We also construct an analytical model using classicalmore » elasticity theory for ripple deformation in phosphorene under arbitrary strain. The present results offer new insights into the mechanisms governing the structural and electronic properties of phosphorene crucial to its device applications.« less

Using Grey Relational Analysis to Evaluate Energy Consumption, CO2 Emissions and Growth Patterns in China’s Provincial Transportation Sectors

PubMed Central

Yuan, Changwei; Liu, Hongchao

2017-01-01

The transportation sector is a complex system. Collecting transportation activity and the associated emissions data is extremely expensive and time-consuming. Grey Relational Analysis provides a viable alternative to overcome data insufficiency and gives insights for decision makers into such a complex system. In this paper, we achieved three major goals: (i) we explored the inter-relationships among transportation development, energy consumption and CO2 emissions for 30 provincial units in China; (ii) we identified the transportation development mode for each individual province; and (iii) we revealed policy implications regarding the sustainable transportation development at the provincial level. We can classify the 30 provinces into eight development modes according to the calculated Grey Relational Grades. Results also indicated that energy consumption has the largest influence on CO2 emission changes. Lastly, sustainable transportation policies were discussed at the province level according to the level of economy, urbanization and transportation energy structure. PMID:29292779

From tunable core-shell nanoparticles to plasmonic drawbridges: Active control of nanoparticle optical properties

PubMed Central

Byers, Chad P.; Zhang, Hui; Swearer, Dayne F.; Yorulmaz, Mustafa; Hoener, Benjamin S.; Huang, Da; Hoggard, Anneli; Chang, Wei-Shun; Mulvaney, Paul; Ringe, Emilie; Halas, Naomi J.; Nordlander, Peter; Link, Stephan; Landes, Christy F.

2015-01-01

The optical properties of metallic nanoparticles are highly sensitive to interparticle distance, giving rise to dramatic but frequently irreversible color changes. By electrochemical modification of individual nanoparticles and nanoparticle pairs, we induced equally dramatic, yet reversible, changes in their optical properties. We achieved plasmon tuning by oxidation-reduction chemistry of Ag-AgCl shells on the surfaces of both individual and strongly coupled Au nanoparticle pairs, resulting in extreme but reversible changes in scattering line shape. We demonstrated reversible formation of the charge transfer plasmon mode by switching between capacitive and conductive electronic coupling mechanisms. Dynamic single-particle spectroelectrochemistry also gave an insight into the reaction kinetics and evolution of the charge transfer plasmon mode in an electrochemically tunable structure. Our study represents a highly useful approach to the precise tuning of the morphology of narrow interparticle gaps and will be of value for controlling and activating a range of properties such as extreme plasmon modulation, nanoscopic plasmon switching, and subnanometer tunable gap applications. PMID:26665175

Numerical investigation of combustion field of hypervelocity scramjet engine

NASA Astrophysics Data System (ADS)

Zhang, Shikong; Li, Jiang; Qin, Fei; Huang, Zhiwei; Xue, Rui

2016-12-01

A numerical study of the ground testing of a hydrogen-fueled scramjet engine was undertaken using the commercial computational-fluid-dynamics code CFD++. The simulated Mach number was 12. A 7-species, 9-reaction-step hydrogen-air chemistry kinetics system was adopted for the Reynolds-averaged Navier-Stokes simulation. The two-equation SST turbulence model, which takes into account the wall functions, was used to handle the turbulence-chemistry interactions. The results were validated by experimentally measuring the wall pressure distribution, and the values obtained proved to be in good agreement. The flow pattern at non-reaction/reaction is presented, as are the results of analyzing the supersonic premix/non-premix flame structure, the reaction heat release distribution in different modes, and the change in the equivalence ratio. In this study, we realize the working mode of a hypervelocity engine and provide some suggestions for the combustion organization of the engine as well as offer insight into the potential for exploiting the processes of combustion and flow.

High-pressure Raman spectra and DFT calculations of L-tyrosine hydrochloride crystal

NASA Astrophysics Data System (ADS)

dos Santos, C. A. A. S. S.; Carvalho, J. O.; da Silva Filho, J. G.; Rodrigues, J. L.; Lima, R. J. C.; Pinheiro, G. S.; Freire, P. T. C.; Façanha Filho, P. F.

2018-02-01

High-pressure Raman spectra of L-tyrosine hydrochloride crystal were obtained from 1.0 atm to 7.0 GPa in the 90-1800 cm-1 spectral region. At atmospheric pressure, the Raman spectrum was obtained in the 50-3200 cm-1 spectral range and the assignment of the normal modes based on density functional theory calculations was provided. We found good correspondence between the calculated and the observed intramolecular geometry parameters. This confirms the correct assignment of the normal modes, since it was crucial to understand the meaning of the changes observed in particular Raman active modes. Here we show that bands associated with internal modes undergo slight modifications during compression. However, an inversion of the relative intensity of bands around 125 cm-1 as well as a change of slope dω/dP from 1.0 to 1.5 GPa was understood as a conformational change involving a torsion of the L-tyrosine molecule. As a consequence, it is possible to conclude that the crystal remained in the same monoclinic structure in the 1 atm-7.0 GPa interval, although conformational change of the molecule was verified. A comparison of our results with other selected studies provided insights about the role of the amino acid side chain on the arrangement of hydrogen bonds. Finally, when the pressure was released back to 1 atm, the Raman spectrum was recovered and no hysteresis was observed.

Compression selective solid-state chemistry

NASA Astrophysics Data System (ADS)

Hu, Anguang

Compression selective solid-state chemistry refers to mechanically induced selective reactions of solids under thermomechanical extreme conditions. Advanced quantum solid-state chemistry simulations, based on density functional theory with localized basis functions, were performed to provide a remarkable insight into bonding pathways of high-pressure chemical reactions in all agreement with experiments. These pathways clearly demonstrate reaction mechanisms in unprecedented structural details, showing not only the chemical identity of reactive intermediates but also how atoms move along the reaction coordinate associated with a specific vibrational mode, directed by induced chemical stress occurred during bond breaking and forming. It indicates that chemical bonds in solids can break and form precisely under compression as we wish. This can be realized through strongly coupling of mechanical work to an initiation vibrational mode when all other modes can be suppressed under compression, resulting in ultrafast reactions to take place isothermally in a few femtoseconds. Thermodynamically, such reactions correspond to an entropy minimum process on an isotherm where the compression can force thermal expansion coefficient equal to zero. Combining a significantly brief reaction process with specific mode selectivity, both statistical laws and quantum uncertainty principle can be bypassed to precisely break chemical bonds, establishing fundamental principles of compression selective solid-state chemistry. Naturally this leads to understand the ''alchemy'' to purify, grow, and perfect certain materials such as emerging novel disruptive energetics.

Observation of microscopic dynamics of phase transition in ferroelectric crystals using fluorescence spectroscopy

NASA Astrophysics Data System (ADS)

Sedarous, Salah S.

1996-03-01

Despite the large quantity of data on the macroscopic changes in the physical properties of ferroelectric crystals during phase transition, there is a continued need for understanding their microscopic origin. Here we describe a novel method for examining the microscopic dynamics of the ferroelectric phase transition using time-resolved fluorescence spectroscopy. The fluorescence properties of organic chromophores embedded in the ferroelectric crystals triglycine sulfate and potassium dihydrogen phosphate are altered in response to the structural phase transitions. The lifetime and the fractional intensity decay show large changes around Tc and the order of the phase transition is readily recovered (first or second order). To explain the fluorescence lifetime data we present a novel theoretical model based on the concept of polaritons in these crystals. Deactivation of the excited state chromophore involves the participation of the vibrational modes of the chromophore. These modes are coupled to the polarization dispersion of the matrix and facilitate the coupling of the excited state to the collective modes in the crystal. The net result is the flow of energy from the excited state chromophore to the lattice phonon. The data indicate that changes in fluorescence lifetime can be used to examine directly the collective modes in these crystals. Our work provides important insight into the emergence of macroscopic phase transition behavior out of microscopic fluctuations.

Two distinct modes of metal ion binding in the nuclease active site of a viral DNA-packaging terminase: insight into the two-metal-ion catalytic mechanism

PubMed Central

Zhao, Haiyan; Lin, Zihan; Lynn, Anna Y.; Varnado, Brittany; Beutler, John A.; Murelli, Ryan P.; Le Grice, Stuart F. J.; Tang, Liang

2015-01-01

Many dsDNA viruses encode DNA-packaging terminases, each containing a nuclease domain that resolves concatemeric DNA into genome-length units. Terminase nucleases resemble the RNase H-superfamily nucleotidyltransferases in folds, and share a two-metal-ion catalytic mechanism. Here we show that residue K428 of a bacteriophage terminase gp2 nuclease domain mediates binding of the metal cofactor Mg2+. A K428A mutation allows visualization, at high resolution, of a metal ion binding mode with a coupled-octahedral configuration at the active site, exhibiting an unusually short metal-metal distance of 2.42 Å. Such proximity of the two metal ions may play an essential role in catalysis by generating a highly positive electrostatic niche to enable formation of the negatively charged pentacovalent phosphate transition state, and provides the structural basis for distinguishing Mg2+ from Ca2+. Using a metal ion chelator β-thujaplicinol as a molecular probe, we observed a second mode of metal ion binding at the active site, mimicking the DNA binding state. Arrangement of the active site residues differs drastically from those in RNase H-like nucleases, suggesting a drifting of the active site configuration during evolution. The two distinct metal ion binding modes unveiled mechanistic details of the two-metal-ion catalysis at atomic resolution. PMID:26450964

High Confinement Mode and Edge Localized Mode Characteristics in a Near-Unity Aspect Ratio Tokamak.

PubMed

Thome, K E; Bongard, M W; Barr, J L; Bodner, G M; Burke, M G; Fonck, R J; Kriete, D M; Perry, J M; Schlossberg, D J

2016-04-29

Tokamak experiments at near-unity aspect ratio A≲1.2 offer new insights into the self-organized H-mode plasma confinement regime. In contrast to conventional A∼3 plasmas, the L-H power threshold P_{LH} is ∼15× higher than scaling predictions, and it is insensitive to magnetic topology, consistent with modeling. Edge localized mode (ELM) instabilities shift to lower toroidal mode numbers as A decreases. These ultralow-A operations enable heretofore inaccessible J_{edge}(R,t) measurements through an ELM that show a complex multimodal collapse and the ejection of a current-carrying filament.

High confinement mode and edge localized mode characteristics in a near-unity aspect ratio tokamak

DOE PAGES

Thome, Kathreen E.; Bongard, Michael W.; Barr, Jayson L.; ...

2016-04-27

Tokamak experiments at near-unity aspect ratio A ≲ 1.2 offer new insights into the self-organized H-mode plasma confinement regime. In contrast to conventional A ~ 3 plasmas, the L–H power threshold P LH is ~15× higher than scaling predictions, and it is insensitive to magnetic topology, consistent with modeling. Edge localized mode (ELM) instabilities shift to lower toroidal mode numbers as A decreases. Furthermore, these ultralow-A operations enable heretofore inaccessible J edge(R,t) measurements through an ELM that show a complex multimodal collapse and the ejection of a current-carrying filament.

Do joints initiate as sharp mode I fractures or finite thickness dilatancy bands? Insights from laboratory experiments and field data

NASA Astrophysics Data System (ADS)

Petit, J.; Chemenda, A. I.; Jorand, C.

2011-12-01

Terminology on fracture and discontinuities in geological objects mainly relies on distinguishing between tabular and sharp forms of deformation localization/failure structures (Aydin et al, JSG 2006; Shultz and Fossen, AAPG, 2009). On this basis joints (considered as mode I fractures) and dilation bands (very rarely observed) are distinguished among extension discontinuities. The former propagate with the separation of the fracture walls due to strong stress concentration at the fracture tips. The plumose features or hackles typical of joints (these terms cover a wide variety of diverging fractographic features) are believed to result from the fracture front breakdown due to the loading mode change (the origin of this change remains unclear). This view is called into question by recent experimental results of extension tests conducted on a synthetic physical rock analogue (granular, frictional, cohesive and dilatant) material (GRAM1) and by field observations of embryonic (not yet open) joints in highly jointed dolomicrite Chemenda et al., JGR, 2011). The initial porosity and grain size of both materials are very different, but at SEM scale, both experimental and natural unopened discontinuities reveal a comparable dilatancy (dilation) band structure with a porosity increase over a width of several grains. This suggests that the distinction between tabular and sharp is a matter of observation scale. Both axisymetric and poly-axial extension tests show that dilatancy bands form at elevated mean stress and have plumose morphology. Mode I cracking occurs only at very low mean stres and the forming fractures do not bear plumose features. Thus the absence of plumose structures can be considered as the signature of mode I fracturing. Consequently, we propose that non- plumose bearing natural joints (provided their fractography is not eroded) could originate as mode I fractures and call them "mode I joints". We call the joints formed as closed dilatancy bands propagating at relatively high pressure (depth) conditions and generating the plumose fractography "dilatancy joints". These joints obtained in poly-axial experiments can be very tight as is also often observed in nature. Joint spacing was shown to depend on the loading conditions but not on the sample thickness, which is another argument against the mode I mechanism. There are two main reasons for which the dilatancy joints were not detected previously: (1) the dilatancy band tends to open during exhumation (it is a weakness zone) leading to the separation of the two walls with destruction of the dilatancy band texture and mineral infilling; (2) if no opening occurs, as soon as the band of increased permeability is formed, diagenetic/epigenetic processes can rapidly cancel the initial structure, the trace of the band appearing at great magnification as a tiny mineralized vein. Such transformation must be very frequent in sedimentary rocks, but it can be absent when the mineral solubility is limited, as for the dolomicrite example presented.

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

Candel, Arno; Li, Z.; Ng, C.

The Compact Linear Collider (CLIC) provides a path to a multi-TeV accelerator to explore the energy frontier of High Energy Physics. Its novel two-beam accelerator concept envisions rf power transfer to the accelerating structures from a separate high-current decelerator beam line consisting of power extraction and transfer structures (PETS). It is critical to numerically verify the fundamental and higher-order mode properties in and between the two beam lines with high accuracy and confidence. To solve these large-scale problems, SLAC's parallel finite element electromagnetic code suite ACE3P is employed. Using curvilinear conformal meshes and higher-order finite element vector basis functions, unprecedentedmore » accuracy and computational efficiency are achieved, enabling high-fidelity modeling of complex detuned structures such as the CLIC TD24 accelerating structure. In this paper, time-domain simulations of wakefield coupling effects in the combined system of PETS and the TD24 structures are presented. The results will help to identify potential issues and provide new insights on the design, leading to further improvements on the novel CLIC two-beam accelerator scheme.« less

SOME INSIGHTS INTO THE MODE OF ACTION OF BUTADIENE BY EXAMINING THE GENOTOXICITY OF ITS METABOLITES

EPA Science Inventory

1,3-Butadiene (BTD) is an important commodity chemical and air pollutant that has been shown to be a potent carcinogen in mice, and to a lesser extent, a carcinogen in rats. To better assess butadiene's carcinogenic risk to humans, it is important to understand its mode of action...

Virus-host interactions: insights from the replication cycle of the large Paramecium bursaria chlorella virus.

PubMed

Milrot, Elad; Mutsafi, Yael; Fridmann-Sirkis, Yael; Shimoni, Eyal; Rechav, Katya; Gurnon, James R; Van Etten, James L; Minsky, Abraham

2016-01-01

The increasing interest in cytoplasmic factories generated by eukaryotic-infecting viruses stems from the realization that these highly ordered assemblies may contribute fundamental novel insights to the functional significance of order in cellular biology. Here, we report the formation process and structural features of the cytoplasmic factories of the large dsDNA virus Paramecium bursaria chlorella virus 1 (PBCV-1). By combining diverse imaging techniques, including scanning transmission electron microscopy tomography and focused ion beam technologies, we show that the architecture and mode of formation of PBCV-1 factories are significantly different from those generated by their evolutionary relatives Vaccinia and Mimivirus. Specifically, PBCV-1 factories consist of a network of single membrane bilayers acting as capsid templates in the central region, and viral genomes spread throughout the host cytoplasm but excluded from the membrane-containing sites. In sharp contrast, factories generated by Mimivirus have viral genomes in their core, with membrane biogenesis region located at their periphery. Yet, all viral factories appear to share structural features that are essential for their function. In addition, our studies support the notion that PBCV-1 infection, which was recently reported to result in significant pathological outcomes in humans and mice, proceeds through a bacteriophage-like infection pathway. © 2015 John Wiley & Sons Ltd.

Interstellar PAH Emission in the 11-14 micron Region: New Insights and a Tracer of Ionized PAHs

NASA Technical Reports Server (NTRS)

Hudgins, Douglas M.; Allamandola, Louis J.; Mead, Susan (Technical Monitor)

1999-01-01

The Ames infrared spectral database of isolated, neutral and ionized polycyclic aromatic hydrocarbons (PAHs) shows that aromatic CH out-of-plane bending frequencies are significantly shifted upon ionization. For non-adjacent and doubly-adjacent CH groups, the shift is pronounced and consistently toward higher frequencies. The non-adjacent modes are blueshifted by an average of 27 per cm and the doubly-adjacent modes by an average of 17 per cm. For triply- and quadruply-adjacent CH out-of-plane modes the ionization shifts are more erratic and typically more modest. As a result of these ionization shifts, both the non-adjacent and doubly-adjacent CH out-of-plane modes move out of the regions classically associated with their respective vibrations in neutral PAHs. The doubly-adjacent modes of ionized PAHs tend to fall into the frequency range traditionally associated with the non-adjacent modes, while the non-adjacent modes are shifted to frequencies above those normally attributed to out-of-plane bending vibrations. Consequently, the origin of the interstellar infrared emission feature near 11.2 microns, traditionally attributed to the out-of-plane bending of non-adjacent CH groups on PAHs is rendered ambiguous. Instead, this feature likely reflects contributions from both non-adjacent CH units in neutral PAHs and doubly-adjacent CH units in PAH cations, the dominant charge state in the most energetic emission regions. This greatly relieves the structural constraints placed on the interstellar PAH population by the dominance of the 11.2 micron band in this region and eliminates the necessity to invoke extensive dehydrogenation of the emitting species. Furthermore, these results indicate that the emission between 926 and 904 per cm (10.8 and 11.1 microns) observed in many sources can be unambiguously attributed to the non-adjacent CH out-of-plane bending modes of moderately-sized (fewer than 50 carbon atom) PAH cations making this emission an unequivocal tracer of ionized interstellar PAHs.

Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors

PubMed Central

2016-01-01

Available crystal structures of opioid receptors provide a high-resolution picture of ligand binding at the primary (“orthosteric”) site, that is, the site targeted by endogenous ligands. Recently, positive allosteric modulators of opioid receptors have also been discovered, but their modes of binding and action remain unknown. Here, we use a metadynamics-based strategy to efficiently sample the binding process of a recently discovered positive allosteric modulator of the δ-opioid receptor, BMS-986187, in the presence of the orthosteric agonist SNC-80, and with the receptor embedded in an explicit lipid–water environment. The dynamics of BMS-986187 were enhanced by biasing the potential acting on the ligand–receptor distance and ligand–receptor interaction contacts. Representative lowest-energy structures from the reconstructed free-energy landscape revealed two alternative ligand binding poses at an allosteric site delineated by transmembrane (TM) helices TM1, TM2, and TM7, with some participation of TM6. Mutations of amino acid residues at these proposed allosteric sites were found to either affect the binding of BMS-986187 or its ability to modulate the affinity and/or efficacy of SNC-80. Taken together, these combined experimental and computational studies provide the first atomic-level insight into the modulation of opioid receptor binding and signaling by allosteric modulators. PMID:26841170

Spectroscopic and Computational Studies of (µ-Oxo)(µ-1,2-peroxo)diiron(III) Complexes of Relevance to Nonheme Diiron Oxygenase Intermediates

PubMed Central

Fiedler, Adam T.; Shan, Xiaopeng; Mehn, Mark P.; Kaizer, József; Torelli, Stéphane; Frisch, Jonathan R.; Kodera, Masahito; Que, Lawrence

2009-01-01

With the goal of gaining insight into the structures of peroxo intermediates observed for oxygen activating nonheme diiron enzymes, a series of metastable synthetic diiron(III)-peroxo complexes with [FeIII2(µ-O)(µ-1,2-O2)] cores has been characterized by X-ray absorption and resonance Raman spectroscopy. EXAFS analysis shows that this basic core structure gives rise to an Fe-Fe distance of ~3.15 Å; the distance is decreased by 0.1 Å upon introduction of an additional carboxylate bridge. In corresponding resonance Raman studies, vibrations arising from both the Fe-O-Fe and the Fe-O-O-Fe units can be observed. A change in the Fe-Fe distance affects the ν(O-O) mode, as well as the νsym(Fe-O-Fe) and the νasym(Fe-O-Fe) modes. Indeed a linear correlation can be discerned between the ν(O-O) frequency of a complex and its Fe-Fe distance among the subset of complexes with [FeIII2(µ-OR)(µ-1,2-O2)] cores (R = H, alkyl, aryl, or no substituent). These experimental studies are complemented by a normal coordinate analysis and DFT calculations. PMID:18811130

The hydrodynamics of linear accelerations in bluegill sunfish, Lepomis macrochirus

NASA Astrophysics Data System (ADS)

Wise, Tyler; Boden, Alex; Schwalbe, Margot; Tytell, Eric

2015-11-01

As fish swim, their body interacts with the fluid around them in order to generate thrust. In this study, we examined the hydrodynamics of linear acceleration by bluegill sunfish, Lepomis macrochirus, which swims using a carangiform mode. Carangiform swimmers primarily use their caudal fin and posterior body for propulsion, which is different from anguilliform swimmers, like eels, that undulate almost their whole body to swim. Most previous studies have examined steady swimming, but few have looked at linear accelerations, even though most fish do not often swim steadily. During steady swimming, thrust and drag forces are balanced, which makes it difficult to separate the two, but during acceleration, thrust exceeds drag, making it easier to measure; this may reveal insights into how thrust is produced. This study used particle image velocimetry (PIV) to compare the structure of the wake during steady swimming and acceleration and to estimate the axial force. Axial force increased during acceleration, but the orientation of the vortices did not differ between steady swimming and acceleration, which is different than anguilliform swimmers, whose wakes change structure during acceleration. This difference may point to fundamental differences between the two swimming modes. This material is based upon work supported by the U. S. Army Research Office under grant number W911NF-14-1-0494.

Quantitative analysis of the effect of environmental-scanning electron microscopy on collagenous tissues.

PubMed

Lee, Woowon; Toussaint, Kimani C

2018-05-31

Environmental-scanning electron microscopy (ESEM) is routinely applied to various biological samples due to its ability to maintain a wet environment while imaging; moreover, the technique obviates the need for sample coating. However, there is limited research carried out on electron-beam (e-beam) induced tissue damage resulting from using the ESEM. In this paper, we use quantitative second-harmonic generation (SHG) microscopy to examine the effects of e-beam exposure from the ESEM on collagenous tissue samples prepared as either fixed, frozen, wet or dehydrated. Quantitative SHG analysis of tissues, before and after ESEM e-beam exposure in low-vacuum mode, reveals evidence of cross-linking of collagen fibers, however there are no structural differences observed in fixed tissue. Meanwhile wet-mode ESEM appears to radically alter the structure from a regular fibrous arrangement to a more random fiber orientation. We also confirm that ESEM images of collagenous tissues show higher spatial resolution compared to SHG microscopy, but the relative tradeoff with collagen specificity reduces its effectiveness in quantifying collagen fiber organization. Our work provides insight on both the limitations of the ESEM for tissue imaging, and the potential opportunity to use as a complementary technique when imaging fine features in the non-collagenous regions of tissue samples.

Monitoring Interactions Inside Cells by Advanced Spectroscopies: Overview of Copper Transporters and Cisplatin.

PubMed

Lasorsa, Alessia; Natile, Giovanni; Rosato, Antonio; Tadini-Buoninsegni, Francesco; Arnesano, Fabio

2018-02-12

Resistance, either at the onset of the treatment or developed after an initial positive response, is a major limitation of antitumor therapy. In the case of platinum- based drugs, copper transporters have been found to interfere with drug trafficking by facilitating the import or favoring the platinum export and inactivation. The use of powerful spectroscopic, spectrometric and computational methods has allowed a deep structural insight into the mode of interaction of platinum drugs with the metal-binding domains of the transporter proteins. This review article focuses on the mode in which platinum drugs can compete with copper ion for binding to transport proteins and consequent structural and biological effects. Three types of transporters are discussed in detail: copper transporter 1 (Ctr1), the major responsible for Cu+ uptake; antioxidant-1 copper chaperone (Atox1), responsible for copper transfer within the cytoplasm; and copper ATPases (ATP7A/B), responsible for copper export into specific subcellular compartments and outside the cell. The body of knowledge summarized in this review can help in shaping current chemotherapy to optimize the efficacy of platinum drugs (particularly in relation to resistance) and to mitigate adverse effects on copper metabolism. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Understanding lattice thermal conductivity in thermoelectric clathrates: A density functional theory study on binary Si-based type-I clathrates

NASA Astrophysics Data System (ADS)

Euchner, Holger; Pailhès, Stéphane; Giordano, Valentina M.; de Boissieu, Marc

2018-01-01

Despite their crystalline nature, thermoelectric clathrates exhibit a strongly reduced lattice thermal conductivity. While the reason for this unexpected behavior is known to lie in the peculiarities of the complex crystal structure and the interplay of the underlying guest-host framework, their respective roles are still not fully disentangled and understood. Our ab initio study of the most simple type-I clathrate phase, the binary compound Ba8Si46 and its derivatives Ba8 -xSi46 seeks to identify these mechanisms and provides insight into their origin. Indeed, the strongly decreased lattice thermal conductivity in thermoelectric clathrates is a consequence of a reduction of the acoustic phonon bandwidth, a lowering of the acoustic phonon group velocities, and the amplification of three-phonon-scattering processes. While the complexity of the crystal structure is demonstrated not to be the leading factor, the reasons are manifold. A modified Si-Si interaction causes a first decrease of the sound velocity, whereas the presence of flat Ba modes results in an additional lowering. These modes correspond to confined Bloch states that are localized on the Ba atoms and significantly increase the scattering phase space and, together with an increased anharmonicity of the interatomic interactions, strongly affect the phonon lifetimes.

KOSMOS: a universal morph server for nucleic acids, proteins and their complexes.

PubMed

Seo, Sangjae; Kim, Moon Ki

2012-07-01

KOSMOS is the first online morph server to be able to address the structural dynamics of DNA/RNA, proteins and even their complexes, such as ribosomes. The key functions of KOSMOS are the harmonic and anharmonic analyses of macromolecules. In the harmonic analysis, normal mode analysis (NMA) based on an elastic network model (ENM) is performed, yielding vibrational modes and B-factor calculations, which provide insight into the potential biological functions of macromolecules based on their structural features. Anharmonic analysis involving elastic network interpolation (ENI) is used to generate plausible transition pathways between two given conformations by optimizing a topology-oriented cost function that guarantees a smooth transition without steric clashes. The quality of the computed pathways is evaluated based on their various facets, including topology, energy cost and compatibility with the NMA results. There are also two unique features of KOSMOS that distinguish it from other morph servers: (i) the versatility in the coarse-graining methods and (ii) the various connection rules in the ENM. The models enable us to analyze macromolecular dynamics with the maximum degrees of freedom by combining a variety of ENMs from full-atom to coarse-grained, backbone and hybrid models with one connection rule, such as distance-cutoff, number-cutoff or chemical-cutoff. KOSMOS is available at http://bioengineering.skku.ac.kr/kosmos.

Group II chaperonins: new TRiC(k)s and turns of a protein folding machine.

PubMed

Gutsche, I; Essen, L O; Baumeister, W

1999-10-22

In the past decade, the eubacterial group I chaperonin GroEL became the paradigm of a protein folding machine. More recently, electron microscopy and X-ray crystallography offered insights into the structure of the thermosome, the archetype of the group II chaperonins which also comprise the chaperonin from the eukaryotic cytosol TRiC. Some structural differences from GroEL were revealed, namely the existence of a built-in lid provided by the helical protrusions of the apical domains instead of a GroES-like co-chaperonin. These structural studies provide a framework for understanding the differences in the mode of action between the group II and the group I chaperonins. In vitro analyses of the folding of non-native substrates coupled to ATP binding and hydrolysis are progressing towards establishing a functional cycle for group II chaperonins. A protein complex called GimC/prefoldin has recently been found to cooperate with TRiC in vivo, and its characterization is under way. Copyright 1999 Academic Press.

Scanning superlens microscopy for non-invasive large field-of-view visible light nanoscale imaging

NASA Astrophysics Data System (ADS)

Wang, Feifei; Liu, Lianqing; Yu, Haibo; Wen, Yangdong; Yu, Peng; Liu, Zhu; Wang, Yuechao; Li, Wen Jung

2016-12-01

Nanoscale correlation of structural information acquisition with specific-molecule identification provides new insight for studying rare subcellular events. To achieve this correlation, scanning electron microscopy has been combined with super-resolution fluorescent microscopy, despite its destructivity when acquiring biological structure information. Here we propose time-efficient non-invasive microsphere-based scanning superlens microscopy that enables the large-area observation of live-cell morphology or sub-membrane structures with sub-diffraction-limited resolution and is demonstrated by observing biological and non-biological objects. This microscopy operates in both non-invasive and contact modes with ~200 times the acquisition efficiency of atomic force microscopy, which is achieved by replacing the point of an atomic force microscope tip with an imaging area of microspheres and stitching the areas recorded during scanning, enabling sub-diffraction-limited resolution. Our method marks a possible path to non-invasive cell imaging and simultaneous tracking of specific molecules with nanoscale resolution, facilitating the study of subcellular events over a total cell period.

Formation routes and structural details of the CaF1 layer on Si(111) from high-resolution noncontact atomic force microscopy data

NASA Astrophysics Data System (ADS)

Rahe, Philipp; Smith, Emily F.; Wollschläger, Joachim; Moriarty, Philip J.

2018-03-01

We investigate the CaF1/Si (111 ) interface using a combination of high-resolution scanning tunneling and noncontact atomic force microscopy operated at cryogenic temperature as well as x-ray photoelectron spectroscopy. Submonolayer CaF1 films grown at substrate temperatures between 550 and 600 ∘C on Si (111 ) surfaces reveal the existence of two island types that are distinguished by their edge topology, nucleation position, measured height, and inner defect structure. Our data suggest a growth model where the two island types are the result of two reaction pathways during CaF1 interface formation. A key difference between these two pathways is identified to arise from the excess species during the growth process, which can be either fluorine or silicon. Structural details as a result of this difference are identified by means of high-resolution noncontact atomic force microscopy and add insights into the growth mode of this heteroepitaxial insulator-on-semiconductor system.

Structural basis for gene regulation by a B12-dependent photoreceptor

PubMed Central

Jost, Marco; Fernández-Zapata, Jésus; Polanco, María Carmen; Ortiz-Guerrero, Juan Manuel; Chen, Percival Yang-Ting; Kang, Gyunghoon; Padmanabhan, S.; Elías-Arnanz, Montserrat; Drennan, Catherine L.

2015-01-01

Summary Photoreceptor proteins enable organisms to sense and respond to light. The newly discovered CarH-type photoreceptors use a vitamin B12 derivative, adenosylcobalamin, as the light-sensing chromophore to mediate light-dependent gene regulation. Here, we present crystal structures of Thermus thermophilus CarH in all three relevant states: in the dark, both free and bound to operator DNA, and after light exposure. These structures provide a visualization of how adenosylcobalamin mediates CarH tetramer formation in the dark, how this tetramer binds to the promoter −35 element to repress transcription, and how light exposure leads to a large-scale conformational change that activates transcription. In addition to the remarkable functional repurposing of adenosylcobalamin from an enzyme cofactor to a light sensor, we find that nature also repurposed two independent protein modules in assembling CarH. These results expand the biological role of vitamin B12 and provide fundamental insight into a new mode of light-dependent gene regulation. PMID:26416754

Structure and reactivity of a mononuclear gold(II) complex

NASA Astrophysics Data System (ADS)

Preiß, Sebastian; Förster, Christoph; Otto, Sven; Bauer, Matthias; Müller, Patrick; Hinderberger, Dariush; Hashemi Haeri, Haleh; Carella, Luca; Heinze, Katja

2017-12-01

Mononuclear gold(II) complexes are very rare labile species. Transient gold(II) species have been suggested in homogeneous catalysis and in medical applications, but their geometric and electronic structures have remained essentially unexplored: even fundamental data, such as the ionic radius of gold(II), are unknown. Now, an unprecedentedly stable neutral gold(II) complex of a porphyrin derivative has been isolated, and its structural and spectroscopic features determined. The gold atom adopts a 2+2 coordination mode in between those of gold(III) (four-coordinate square planar) and gold(I) (two-coordinate linear), owing to a second-order Jahn-Teller distortion enabled by the relativistically lowered 6s orbital of gold. The reactivity of this gold(II) complex towards dioxygen, nitrosobenzene and acids is discussed. This study provides insight on the ionic radius of gold(II), and allows it to be placed within the homologous series of nd9 Cu/Ag/Au divalent ions and the 5d8/9/10 Pt/Au/Hg 'relativistic' triad in the periodic table.

Structural basis for gene regulation by a B 12-dependent photoreceptor

DOE PAGES

Jost, Marco; Fernández-Zapata, Jésus; Polanco, María Carmen; ...

2015-09-28

Photoreceptor proteins enable organisms to sense and respond to light. The newly discovered CarH-type photoreceptors use a vitamin B 12 derivative, adenosylcobalamin, as the light-sensing chromophore to mediate light-dependent gene regulation. Here in this paper, we present crystal structures of Thermus thermophilus CarH in all three relevant states: in the dark, both free and bound to operator DNA, and after light exposure. These structures provide visualizations of how adenosylcobalamin mediates CarH tetramer formation in the dark, how this tetramer binds to the promoter -35 element to repress transcription, and how light exposure leads to a large-scale conformational change that activatesmore » transcription. In addition to the remarkable functional repurposing of adenosylcobalamin from an enzyme cofactor to a light sensor, we find that nature also repurposed two independent protein modules in assembling CarH. Finally, these results expand the biological role of vitamin B 12 and provide fundamental insight into a new mode of light-dependent gene regulation.« less

Probing the interaction of anticancer drug temsirolimus with human serum albumin: molecular docking and spectroscopic insight.

PubMed

Shamsi, Anas; Ahmed, Azaj; Bano, Bilqees

2018-05-01

The binding interaction between temsirolimus, an important antirenal cancer drug, and HSA, an important carrier protein was scrutinized making use of UV and fluorescence spectroscopy. Hyper chromaticity observed in UV spectroscopy in the presence of temsirolimus as compared to free HSA suggests the formation of complex between HSA and temsirolimus. Fluorescence quenching experiments clearly showed quenching in the fluorescence of HSA in the presence of temsirolimus confirming the complex formation and also confirmed that static mode of interaction is operative for this binding process. Binding constant values obtained through UV and fluorescence spectroscopy reveal strong interaction; temsirolimus binds to HSA at 298 K with a binding constant of 2.9 × 10 4  M -1 implying the strength of interaction. The negative Gibbs free energy obtained through Isothermal titration calorimetry as well as quenching experiments suggests that binding process is spontaneous. Molecular docking further provides an insight of various residues that are involved in this binding process; showing the binding energy to be -12.9 kcal/mol. CD spectroscopy was retorted to analyze changes in secondary structure of HSA; increased intensity in presence of temsirolimus showing changes in secondary structure of HSA induced by temsirolimus. This study is of importance as it provides an insight into the binding mechanism of an important antirenal cancer drug with an important carrier protein. Once temsirolimus binds to HSA, it changes conformation of HSA which in turn can alter the functionality of this important carrier protein and this altered functionality of HSA can be highlighted in variety of diseases.

Peculiarities of the Third Natural Frequency Vibrations of a Cantilever for the Improvement of Energy Harvesting

PubMed Central

Ostasevicius, Vytautas; Janusas, Giedrius; Milasauskaite, Ieva; Zilys, Mindaugas; Kizauskiene, Laura

2015-01-01

This paper focuses on several aspects extending the dynamical efficiency of a cantilever beam vibrating in the third mode. A few ways of producing this mode stimulation, namely vibro-impact or forced excitation, as well as its application for energy harvesting devices are proposed. The paper presents numerical and experimental analyses of novel structural dynamics effects along with an optimal configuration of the cantilever beam. The peculiarities of a cantilever beam vibrating in the third mode are related to the significant increase of the level of deformations capable of extracting significant additional amounts of energy compared to the conventional harvester vibrating in the first mode. Two types of a piezoelectric vibrating energy harvester (PVEH) prototype are analysed in this paper: the first one without electrode segmentation, while the second is segmented using electrode segmentation at the strain nodes of the third vibration mode to achieve effective operation at the third resonant frequency. The results of this research revealed that the voltage generated by any segment of the segmented PVEH prototype excited at the third resonant frequency demonstrated a 3.4–4.8-fold increase in comparison with the non-segmented prototype. Simultaneously, the efficiency of the energy harvester prototype also increased at lower resonant frequencies from 16% to 90%. The insights presented in the paper may serve for the development and fabrication of advanced piezoelectric energy harvesters which would be able to generate a considerably increased amount of electrical energy independently of the frequency of kinematical excitation. PMID:26029948

Unified approach for calculating the number of confined modes in multilayered waveguiding structures

NASA Astrophysics Data System (ADS)

Ruschin, S.; Griffel, G.; Hardy, A.; Croitoru, N.

1986-01-01

A general formalism is developed in order to find the number of modes and mode cutoff conditions in multilayer waveguiding structures. An explicit expression is presented for the number of confined modes that allows the modes to be counted without having to analyze the specific eigenvalue equation of the structure. The method is illustrated by its application to several structures: the buried layer, the directional coupler, and the three-guide symmetrical arrangement. By a suitable extension of the formalism, the number of well-confined modes is found for a four-layer structure.

Application of attachment modes in the control of large space structures

NASA Technical Reports Server (NTRS)

Craig, Roy R., Jr.

1989-01-01

Various ways are examined to obtain reduced order mathematical models of structures for use in dynamic response analyses and in controller design studies. Attachment modes are deflection shapes of a structure subjected to specified unit load distributions. Attachment modes are frequently employed to supplement free-interface normal modes to improve the modeling of components (structures) employed in component mode synthesis analyses. Deflection shapes of structures subjected to generalized loads of some specified distribution and of unit magnitude can also be considered to be attachment modes. Several papers which were written under this contract are summarized herein.

Structural and functional insight into the carbohydrate receptor binding of F4 fimbriae-producing enterotoxigenic Escherichia coli.

PubMed

Moonens, Kristof; Van den Broeck, Imke; De Kerpel, Maia; Deboeck, Francine; Raymaekers, Hanne; Remaut, Han; De Greve, Henri

2015-03-27

Enterotoxigenic Escherichia coli (ETEC) strains are important causes of intestinal disease in humans and lead to severe production losses in animal farming. A range of fimbrial adhesins in ETEC strains determines host and tissue tropism. ETEC strains expressing F4 fimbriae are associated with neonatal and post-weaning diarrhea in piglets. Three naturally occurring variants of F4 fimbriae (F4ab, F4ac, and F4ad) exist that differ in the primary sequence of their major adhesive subunit FaeG, and each features a related yet distinct receptor binding profile. Here the x-ray structure of FaeGad bound to lactose provides the first structural insight into the receptor specificity and mode of binding by the poly-adhesive F4 fimbriae. A small D'-D″-α1-α2 subdomain grafted on the immunoglobulin-like core of FaeG hosts the carbohydrate binding site. Two short amino acid stretches Phe(150)-Glu(152) and Val(166)-Glu(170) of FaeGad bind the terminal galactose in the lactosyl unit and provide affinity and specificity to the interaction. A hemagglutination-based assay with E. coli expressing mutant F4ad fimbriae confirmed the elucidated co-complex structure. Interestingly, the crucial D'-α1 loop that borders the FaeGad binding site adopts a different conformation in the two other FaeG variants and hints at a heterogeneous binding pocket among the FaeG serotypes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Eigenvector centrality is a metric of elastomer modulus, heterogeneity, and damage

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

Welch, Jr., Paul Michael; Welch, Cynthia F.

Here, we present an application of eigenvector centrality to encode the connectivity of polymer networks resolved at the micro- and meso-scopic length scales. This method captures the relative importance of different nodes within the network structure and provides a route toward the development of a statistical mechanics model that correlates connectivity with mechanical response. This scheme may be informed by analytical and semi-analytical models for the network structure, or through direct experimental examination. It may be used to predict the reduction in mechanical performance for heterogeneous materials subjected to specific modes of damage. Here, we develop the method and demonstratemore » that it leads to the prediction of established trends in elastomers. We also apply the model to the case of a self-healing polymer network reported in the literature, extracting insight about the fraction of bonds broken and re-formed during strain and recovery.« less

Wide-field LOFAR-LBA power-spectra analyses: Impact of calibration, polarization leakage and ionosphere

NASA Astrophysics Data System (ADS)

Gehlot, Bharat K.; Koopmans, Léon V. E.

2018-05-01

Contamination due to foregrounds, calibration errors and ionospheric effects pose major challenges in detection of the cosmic 21 cm signal in various Epoch of Reionization (EoR) experiments. We present the results of a study of a field centered on 3C196 using LOFAR Low Band observations, where we quantify various wide field and calibration effects such as gain errors, polarized foregrounds, and ionospheric effects. We observe a `pitchfork' structure in the power spectrum of the polarized intensity in delay-baseline space, which leaks into the modes beyond the instrumental horizon. We show that this structure arises due to strong instrumental polarization leakage (~30%) towards Cas A which is far away from primary field of view. We measure a small ionospheric diffractive scale towards CasA resembling pure Kolmogorov turbulence. Our work provides insights in understanding the nature of aforementioned effects and mitigating them in future Cosmic Dawn observations.

Mathematical modeling of spinning elastic bodies for modal analysis.

NASA Technical Reports Server (NTRS)

Likins, P. W.; Barbera, F. J.; Baddeley, V.

1973-01-01

The problem of modal analysis of an elastic appendage on a rotating base is examined to establish the relative advantages of various mathematical models of elastic structures and to extract general inferences concerning the magnitude and character of the influence of spin on the natural frequencies and mode shapes of rotating structures. In realization of the first objective, it is concluded that except for a small class of very special cases the elastic continuum model is devoid of useful results, while for constant nominal spin rate the distributed-mass finite-element model is quite generally tractable, since in the latter case the governing equations are always linear, constant-coefficient, ordinary differential equations. Although with both of these alternatives the details of the formulation generally obscure the essence of the problem and permit very little engineering insight to be gained without extensive computation, this difficulty is not encountered when dealing with simple concentrated mass models.

Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors.

PubMed

Oyallon, Bruno; Brachet-Botineau, Marie; Logé, Cédric; Bonnet, Pascal; Souab, Mohamed; Robert, Thomas; Ruchaud, Sandrine; Bach, Stéphane; Berthelot, Pascal; Gouilleux, Fabrice; Viaud-Massuard, Marie-Claude; Denevault-Sabourin, Caroline

2018-05-11

We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC 50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel anticancer targeted therapies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco

2016-09-13

The fast and constant development of drug resistant bacteria represents a serious medical emergency. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by OXA-23, a class D β-lactamase, combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture of the molecular steps leading to the formation of the Meropenem-OXA-23 covalent adduct, the subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements, validating the expected reaction path.

Eigenvector centrality is a metric of elastomer modulus, heterogeneity, and damage

DOE PAGES

Welch, Jr., Paul Michael; Welch, Cynthia F.

2017-04-27

Here, we present an application of eigenvector centrality to encode the connectivity of polymer networks resolved at the micro- and meso-scopic length scales. This method captures the relative importance of different nodes within the network structure and provides a route toward the development of a statistical mechanics model that correlates connectivity with mechanical response. This scheme may be informed by analytical and semi-analytical models for the network structure, or through direct experimental examination. It may be used to predict the reduction in mechanical performance for heterogeneous materials subjected to specific modes of damage. Here, we develop the method and demonstratemore » that it leads to the prediction of established trends in elastomers. We also apply the model to the case of a self-healing polymer network reported in the literature, extracting insight about the fraction of bonds broken and re-formed during strain and recovery.« less

Molecular simulations bring new insights into flavonoid/quercetinase interaction modes.

PubMed

Fiorucci, Sébastien; Golebiowski, Jérôme; Cabrol-Bass, Daniel; Antonczak, Serge

2007-06-01

Molecular dynamics simulations, using the AMBER force field, were performed to study Quercetin 2,3-Dioxygenase enzyme (Quercetinase or 2,3QD). We have analyzed the structural modifications of the active site and of the linker region between the native enzyme and the enzyme-substrate complex. New structural informations, such as an allosteric effect in the presence of the substrate, as well as description of the enzyme-substrate interactions and values of binding free energies were brought out. All these results confirm the idea that the linker encloses the substrate in the active site and also enlighten the recognition role of the substrate B-ring by the enzyme. Moreover, a specific interaction scheme has been proposed to explain the relative degradation rate of various flavonoid compounds under the oxygenolysis reaction catalyzed by the Quercetin 2,3-Dioxygenase enzyme. 2007 Wiley-Liss, Inc.

Structural insight into the mechanism of synergistic autoinhibition of SAD kinases

PubMed Central

Wu, Jing-Xiang; Cheng, Yun-Sheng; Wang, Jue; Chen, Lei; Ding, Mei; Wu, Jia-Wei

2015-01-01

The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an ‘αC-out' inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases. PMID:26626945

Structural insight into the mechanism of synergistic autoinhibition of SAD kinases.

PubMed

Wu, Jing-Xiang; Cheng, Yun-Sheng; Wang, Jue; Chen, Lei; Ding, Mei; Wu, Jia-Wei

2015-12-02

The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an 'αC-out' inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases.

Ubiquitin Ligases: Structure, Function, and Regulation.

PubMed

Zheng, Ning; Shabek, Nitzan

2017-06-20

Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins. Early investigations of E3s of the RING (really interesting new gene) and HECT (homologous to the E6AP carboxyl terminus) types shed light on their enzymatic activities, general architectures, and substrate degron-binding modes. Recent studies have provided deeper mechanistic insights into their catalysis, activation, and regulation. In this review, we summarize the current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms. Our increased understanding of ubiquitin ligase function and regulation has provided the rationale for developing E3-targeting therapeutics for the treatment of human diseases.

Binding modes of dihydroquinoxalinones in a homology model of bradykinin receptor 1.

PubMed

Ha, Sookhee N; Hey, Pat J; Ransom, Rick W; Harrell, C Meacham; Murphy, Kathryn L; Chang, Ray; Chen, Tsing-Bau; Su, Dai-Shi; Markowitz, M Kristine; Bock, Mark G; Freidinger, Roger M; Hess, Fred J

2005-05-27

We report the first homology model of human bradykinin receptor B1 generated from the crystal structure of bovine rhodopsin as a template. Using an automated docking procedure, two B1 receptor antagonists of the dihydroquinoxalinone structural class were docked into the receptor model. Site-directed mutagenesis data of the amino acid residues in TM1, TM3, TM6, and TM7 were incorporated to place the compounds in the binding site of the homology model of the human B1 bradykinin receptor. The best pose in agreement with the mutation data was selected for detailed study of the receptor-antagonist interaction. To test the model, the calculated antagonist-receptor binding energy was correlated with the experimentally measured binding affinity (K(i)) for nine dihydroquinoxalinone analogs. The model was used to gain insight into the molecular mechanism for receptor function and to optimize the dihydroquinoxalinone analogs.

Ideas for Policymakers: Enhancing the Impact of Think Tanks. Policy Insight, Volume 1, Issue 2

ERIC Educational Resources Information Center

Montoya, Silvia; Swanger, Rachel M.

2007-01-01

As think tanks have become more numerous, visible, and seemingly influential, scholars have begun to pay more attention to them--analyzing their characteristics, their modes of operation, and their roles in policymaking. This "Policy Insight" builds on this work and examines the role of think tanks in civil society, with an emphasis on…

Analysis of optimal phenotypic space using elementary modes as applied to Corynebacterium glutamicum

PubMed Central

Gayen, Kalyan; Venkatesh, KV

2006-01-01

Background Quantification of the metabolic network of an organism offers insights into possible ways of developing mutant strain for better productivity of an extracellular metabolite. The first step in this quantification is the enumeration of stoichiometries of all reactions occurring in a metabolic network. The structural details of the network in combination with experimentally observed accumulation rates of external metabolites can yield flux distribution at steady state. One such methodology for quantification is the use of elementary modes, which are minimal set of enzymes connecting external metabolites. Here, we have used a linear objective function subject to elementary modes as constraint to determine the fluxes in the metabolic network of Corynebacterium glutamicum. The feasible phenotypic space was evaluated at various combinations of oxygen and ammonia uptake rates. Results Quantification of the fluxes of the elementary modes in the metabolism of C. glutamicum was formulated as linear programming. The analysis demonstrated that the solution was dependent on the criteria of objective function when less than four accumulation rates of the external metabolites were considered. The analysis yielded feasible ranges of fluxes of elementary modes that satisfy the experimental accumulation rates. In C. glutamicum, the elementary modes relating to biomass synthesis through glycolysis and TCA cycle were predominantly operational in the initial growth phase. At a later time, the elementary modes contributing to lysine synthesis became active. The oxygen and ammonia uptake rates were shown to be bounded in the phenotypic space due to the stoichiometric constraint of the elementary modes. Conclusion We have demonstrated the use of elementary modes and the linear programming to quantify a metabolic network. We have used the methodology to quantify the network of C. glutamicum, which evaluates the set of operational elementary modes at different phases of fermentation. The methodology was also used to determine the feasible solution space for a given set of substrate uptake rates under specific optimization criteria. Such an approach can be used to determine the optimality of the accumulation rates of any metabolite in a given network. PMID:17038164

Perceptual Decoding Processes for Language in a Visual Mode and for Language in an Auditory Mode.

ERIC Educational Resources Information Center

Myerson, Rosemarie Farkas

The purpose of this paper is to gain insight into the nature of the reading process through an understanding of the general nature of sensory processing mechanisms which reorganize and restructure input signals for central recognition, and an understanding of how the grammar of the language functions in defining the set of possible sentences in…

Structural, kinetic, and thermodynamic studies of specificity designed HIV-1 protease.

PubMed

Alvizo, Oscar; Mittal, Seema; Mayo, Stephen L; Schiffer, Celia A

2012-07-01

HIV-1 protease recognizes and cleaves more than 12 different substrates leading to viral maturation. While these substrates share no conserved motif, they are specifically selected for and cleaved by protease during viral life cycle. Drug resistant mutations evolve within the protease that compromise inhibitor binding but allow the continued recognition of all these substrates. While the substrate envelope defines a general shape for substrate recognition, successfully predicting the determinants of substrate binding specificity would provide additional insights into the mechanism of altered molecular recognition in resistant proteases. We designed a variant of HIV protease with altered specificity using positive computational design methods and validated the design using X-ray crystallography and enzyme biochemistry. The engineered variant, Pr3 (A28S/D30F/G48R), was designed to preferentially bind to one out of three of HIV protease's natural substrates; RT-RH over p2-NC and CA-p2. In kinetic assays, RT-RH binding specificity for Pr3 increased threefold compared to the wild-type (WT), which was further confirmed by isothermal titration calorimetry. Crystal structures of WT protease and the designed variant in complex with RT-RH, CA-p2, and p2-NC were determined. Structural analysis of the designed complexes revealed that one of the engineered substitutions (G48R) potentially stabilized heterogeneous flap conformations, thereby facilitating alternate modes of substrate binding. Our results demonstrate that while substrate specificity could be engineered in HIV protease, the structural pliability of protease restricted the propagation of interactions as predicted. These results offer new insights into the plasticity and structural determinants of substrate binding specificity of the HIV-1 protease. Copyright © 2012 The Protein Society.

Microfocus diffraction from different regions of a protein crystal: structural variations and unit-cell polymorphism

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

Thompson, Michael C.; Cascio, Duilio; Yeates, Todd O.

Real macromolecular crystals can be non-ideal in a myriad of ways. This often creates challenges for structure determination, while also offering opportunities for greater insight into the crystalline state and the dynamic behavior of macromolecules. To evaluate whether different parts of a single crystal of a dynamic protein, EutL, might be informative about crystal and protein polymorphism, a microfocus X-ray synchrotron beam was used to collect a series of 18 separate data sets from non-overlapping regions of the same crystal specimen. A principal component analysis (PCA) approach was employed to compare the structure factors and unit cells across the datamore » sets, and it was found that the 18 data sets separated into two distinct groups, with largeRvalues (in the 40% range) and significant unit-cell variations between the members of the two groups. This categorization mapped the different data-set types to distinct regions of the crystal specimen. Atomic models of EutL were then refined against two different data sets obtained by separately merging data from the two distinct groups. A comparison of the two resulting models revealed minor but discernable differences in certain segments of the protein structure, and regions of higher deviation were found to correlate with regions where larger dynamic motions were predicted to occur by normal-mode molecular-dynamics simulations. The findings emphasize that large spatially dependent variations may be present across individual macromolecular crystals. This information can be uncovered by simultaneous analysis of multiple partial data sets and can be exploited to reveal new insights about protein dynamics, while also improving the accuracy of the structure-factor data ultimately obtained in X-ray diffraction experiments.« less

Structural and biochemical insights into the substrate-binding mechanism of a novel glycoside hydrolase family 134 β-mannanase.

PubMed

You, Xin; Qin, Zhen; Li, Yan-Xiao; Yan, Qiao-Juan; Li, Bin; Jiang, Zheng-Qiang

2018-06-01

Mannan is one of the major constituent groups of hemicellulose, which is a renewable resource from higher plants. β-Mannanases are enzymes capable of degrading lignocellulosic biomass. Here, an endo-β-mannanase from Rhizopus microsporus (RmMan134A) was cloned and expressed. The recombinant RmMan134A showed maximal activity at pH 5.0 and 50 °C, and exhibited high specific activity towards locust bean gum (2337 U/mg). To gain insight into the substrate-binding mechanism of RmMan134A, four complex structures (RmMan134A-M3, RmMan134A-M4, RmMan134A-M5 and RmMan134A-M6) were further solved. These structures showed that there were at least seven subsites (-3 to +4) in the catalytic groove of RmMan134A. Mannose in the -1 subsite hydrogen bonded with His113 and Tyr131, revealing a unique conformation. Lys48 and Val159 formed steric hindrance, which impedes to bond with galactose branches. In addition, the various binding modes of RmMan134A-M5 indicated that subsites -2 to +2 are indispensable during the hydrolytic process. The structure of RmMan134A-M4 showed that mannotetrose only binds at subsites +1 to +4, and RmMan134A could therefore not hydrolyze mannan oligosaccharides with degree of polymerization ≤4. Through rational design, the specific activity and optimal conditions of RmMan134A were significantly improved. The purpose of this paper is to investigate the structure and function of fungal GH family 134 β-1,4-mannanases, and substrate-binding mechanism of GH family 134 members. Copyright © 2018 Elsevier B.V. All rights reserved.

Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs.

PubMed

Lee, Sang Jae; Choi, Jang-Sik; Han, Byeong-Gu; Kim, Hyoun Sook; Song, Ho-Juhn; Lee, Jaekyoo; Nam, Seungyoon; Goh, Sung-Ho; Kim, Jung-Ho; Koh, Jong Sung; Lee, Byung Il

2016-10-01

Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half-maximal inhibitory concentrations (IC 50 ) of approximately 0.7-33 nm, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499. The atomic coordinates and structure factors for human SYK are in the Protein Data Bank under accession codes 4XG2 (inhibitor-free form), 4XG3 (G206), 4XG4 (G207), 5GHV (O178), 4XG6 (O194), 4XG7 (O259), 4XG8 (O272), and 4XG9 (O282). © 2016 Federation of European Biochemical Societies.

An SMS (single mode - multi mode - single mode) fiber structure for vibration sensing

NASA Astrophysics Data System (ADS)

Waluyo, T. B.; Bayuwati, D.

2017-04-01

We describe an SMS (single mode - multi mode - single mode) fiber structure to be used in a vibration sensing system. The fiber structure was fabricated by splicing a section (about 300 mm in length) of a step index multi mode fiber between two single mode fibers obtained from a communication grade fiber patchcord. Interference between higher order modes occurs while light from a narrow band light source travels along the multi mode fiber. When the multi mode fiber vibrates, the refractive index profile is changed because of the photo-elastics effect and the amplitude of the interference pattern is changed accordingly. To simulate a vibrating structure we used a loudspeaker to vibrate a wooden table. By using a digital oscilloscope, we recorded and analysed the vibrating signals obtained from the SMS fiber structure as well as from a GS-32CT geophone for referencing. We observed that this SMS fiber structure was potential to be used in a vibration sensing system with a measurement range from 30 to 180 Hz with inherent optical fiber sensor advantages such as light weight, immune to electromagnetic interference, and no electricity in the sensing part.

Sensing site-specific structural characteristics and chirality using vibrational circular dichroism of isotope labeled peptides.

PubMed

Keiderling, Timothy A

2017-12-01

Isotope labeling has a long history in chemistry as a tool for probing structure, offering enhanced sensitivity, or enabling site selection with a wide range of spectroscopic tools. Chirality sensitive methods such as electronic circular dichroism are global structural tools and have intrinsically low resolution. Consequently, they are generally insensitive to modifications to enhance site selectivity. The use of isotope labeling to modify vibrational spectra with unique resolvable frequency shifts can provide useful site-specific sensitivity, and these methods have been recently more widely expanded in biopolymer studies. While the spectral shifts resulting from changes in isotopic mass can provide resolution of modes from specific parts of the molecule and can allow detection of local change in structure with perturbation, these shifts alone do not directly indicate structure or chirality. With vibrational circular dichroism (VCD), the shifted bands and their resultant sign patterns can be used to indicate local conformations in labeled biopolymers, particularly if multiple labels are used and if their coupling is theoretically modeled. This mini-review discusses selected examples of the use of labeling specific amides in peptides to develop local structural insight with VCD spectra. © 2017 Wiley Periodicals, Inc.

Solution structure of the Legionella pneumophila Mip-rapamycin complex.

PubMed

Ceymann, Andreas; Horstmann, Martin; Ehses, Philipp; Schweimer, Kristian; Paschke, Anne-Katrin; Steinert, Michael; Faber, Cornelius

2008-03-17

Legionella pneumphila is the causative agent of Legionnaires' disease. A major virulence factor of the pathogen is the homodimeric surface protein Mip. It shows peptidyl-prolyl cis/trans isomerase activty and is a receptor of FK506 and rapamycin, which both inhibit its enzymatic function. Insight into the binding process may be used for the design of novel Mip inhibitors as potential drugs against Legionnaires' disease. We have solved the solution structure of free Mip77-213 and the Mip77-213-rapamycin complex by NMR spectroscopy. Mip77-213 showed the typical FKBP-fold and only minor rearrangements upon binding of rapamycin. Apart from the configuration of a flexible hairpin loop, which is partly stabilized upon binding, the solution structure confirms the crystal structure. Comparisons to the structures of free FKBP12 and the FKBP12-rapamycin complex suggested an identical binding mode for both proteins. The structural similarity of the Mip-rapamycin and FKBP12-rapamycin complexes suggests that FKBP12 ligands may be promising starting points for the design of novel Mip inhibitors. The search for a novel drug against Legionnaires' disease may therefore benefit from the large variety of known FKBP12 inhibitors.

Solution structure of the Legionella pneumophila Mip-rapamycin complex

PubMed Central

Ceymann, Andreas; Horstmann, Martin; Ehses, Philipp; Schweimer, Kristian; Paschke, Anne-Katrin; Steinert, Michael; Faber, Cornelius

2008-01-01

Background Legionella pneumphila is the causative agent of Legionnaires' disease. A major virulence factor of the pathogen is the homodimeric surface protein Mip. It shows peptidyl-prolyl cis/trans isomerase activty and is a receptor of FK506 and rapamycin, which both inhibit its enzymatic function. Insight into the binding process may be used for the design of novel Mip inhibitors as potential drugs against Legionnaires' disease. Results We have solved the solution structure of free Mip77–213 and the Mip77–213-rapamycin complex by NMR spectroscopy. Mip77–213 showed the typical FKBP-fold and only minor rearrangements upon binding of rapamycin. Apart from the configuration of a flexible hairpin loop, which is partly stabilized upon binding, the solution structure confirms the crystal structure. Comparisons to the structures of free FKBP12 and the FKBP12-rapamycin complex suggested an identical binding mode for both proteins. Conclusion The structural similarity of the Mip-rapamycin and FKBP12-rapamycin complexes suggests that FKBP12 ligands may be promising starting points for the design of novel Mip inhibitors. The search for a novel drug against Legionnaires' disease may therefore benefit from the large variety of known FKBP12 inhibitors. PMID:18366641

Modes of therapeutic action.

PubMed

Jones, E E

1997-12-01

The dialectic in psychoanalysis between theories about the mutative effects of interpretation and psychological knowledge and those concerning the effects of interpersonal interaction constitutes an important tension for approaches to psychoanalytic technique. This essay briefly summarises the thinking around these alternative conceptualisations of therapeutic action, and introduces a new empirically derived model, that of 'repetitive interaction structure', which attempts to bridge therapeutic action by insight and by relationship. Interaction structure is a way of formulating those aspects of the analytic process that have come to be termed intersubjectivity, transference-countertransference enactments and role responsiveness. The concept operationalises important aspects of interpersonal interaction, and can help specify the two-person patterns that emerge in an analysis. Patient and analyst interact in repetitive ways; these patterns of interaction, which are slow to change, probably reflect the psychological structure of both patient and analyst, whether psychic structure is conceptualised in terms of object-representations or compromise formations and impulse-defence configurations. Therapeutic action is located in the experience, recognition and understanding by patient and analyst of these repetitive interactions. Interaction structures stress the importance of the intrapsychic as a basis for what becomes manifest in the interactive field. Clinical illustrations from a psychoanalysis are provided, and research on repetitive interaction structures is described.

Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions

NASA Astrophysics Data System (ADS)

Gur, M.; Zomot, E.; Bahar, I.

2013-09-01

The Anton supercomputing technology recently developed for efficient molecular dynamics simulations permits us to examine micro- to milli-second events at full atomic resolution for proteins in explicit water and lipid bilayer. It also permits us to investigate to what extent the collective motions predicted by network models (that have found broad use in molecular biophysics) agree with those exhibited by full-atomic long simulations. The present study focuses on Anton trajectories generated for two systems: the bovine pancreatic trypsin inhibitor, and an archaeal aspartate transporter, GltPh. The former, a thoroughly studied system, helps benchmark the method of comparative analysis, and the latter provides new insights into the mechanism of function of glutamate transporters. The principal modes of motion derived from both simulations closely overlap with those predicted for each system by the anisotropic network model (ANM). Notably, the ANM modes define the collective mechanisms, or the pathways on conformational energy landscape, that underlie the passage between the crystal structure and substates visited in simulations. In particular, the lowest frequency ANM modes facilitate the conversion between the most probable substates, lending support to the view that easy access to functional substates is a robust determinant of evolutionarily selected native contact topology.

Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin

PubMed Central

Bae, Chanhyung; Anselmi, Claudio; Kalia, Jeet; Jara-Oseguera, Andres; Schwieters, Charles D; Krepkiy, Dmitriy; Won Lee, Chul; Kim, Eun-Hee; Kim, Jae Il; Faraldo-Gómez, José D; Swartz, Kenton J

2016-01-01

Venom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, and investigate the interactions of DkTx with the channel and membranes. We find that DkTx binds to the outer edge of the external pore of TRPV1 in a counterclockwise configuration, using a limited protein-protein interface and inserting hydrophobic residues into the bilayer. We also show that DkTx partitions naturally into membranes, with the two lobes exhibiting opposing energetics for membrane partitioning and channel activation. Finally, we find that the toxin disrupts a cluster of hydrophobic residues behind the selectivity filter that are critical for channel activation. Collectively, our findings reveal a novel mode of toxin-channel recognition that has important implications for the mechanism of thermosensation. DOI: http://dx.doi.org/10.7554/eLife.11273.001 PMID:26880553

Insights into molecular plasticity in protein complexes from Trm9-Trm112 tRNA modifying enzyme crystal structure

PubMed Central

Létoquart, Juliette; van Tran, Nhan; Caroline, Vonny; Aleksandrov, Alexey; Lazar, Noureddine; van Tilbeurgh, Herman; Liger, Dominique; Graille, Marc

2015-01-01

Most of the factors involved in translation (tRNA, rRNA and proteins) are subject to post-transcriptional and post-translational modifications, which participate in the fine-tuning and tight control of ribosome and protein synthesis processes. In eukaryotes, Trm112 acts as an obligate activating platform for at least four methyltransferases (MTase) involved in the modification of 18S rRNA (Bud23), tRNA (Trm9 and Trm11) and translation termination factor eRF1 (Mtq2). Trm112 is then at a nexus between ribosome synthesis and function. Here, we present a structure-function analysis of the Trm9-Trm112 complex, which is involved in the 5-methoxycarbonylmethyluridine (mcm5U) modification of the tRNA anticodon wobble position and hence promotes translational fidelity. We also compare the known crystal structures of various Trm112-MTase complexes, highlighting the structural plasticity allowing Trm112 to interact through a very similar mode with its MTase partners, although those share less than 20% sequence identity. PMID:26438534

Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase.

PubMed

Kim, Hyun Tae; Na, Byeong Kwan; Chung, Jiwoung; Kim, Sulhee; Kwon, Sool Ki; Cha, Hyunju; Son, Jonghyeon; Cho, Joong Myung; Hwang, Kwang Yeon

2018-04-19

Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different. Conformational changes via π-π interactions between the loop above the flavin and substrate or non-substrate effectors lead to disorder of the C-terminal α helix in scKMO and shifts of domain III in pfKMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in scKMO and as a non-substrate effector in pfKMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors. Copyright © 2018 Elsevier Ltd. All rights reserved.

Manipulation of Optoelectronic Properties and Band Structure Engineering of Ultrathin Te Nanowires by Chemical Adsorption.

PubMed

Roy, Ahin; Amin, Kazi Rafsanjani; Tripathi, Shalini; Biswas, Sangram; Singh, Abhishek K; Bid, Aveek; Ravishankar, N

2017-06-14

Band structure engineering is a powerful technique both for the design of new semiconductor materials and for imparting new functionalities to existing ones. In this article, we present a novel and versatile technique to achieve this by surface adsorption on low dimensional systems. As a specific example, we demonstrate, through detailed experiments and ab initio simulations, the controlled modification of band structure in ultrathin Te nanowires due to NO 2 adsorption. Measurements of the temperature dependence of resistivity of single ultrathin Te nanowire field-effect transistor (FET) devices exposed to increasing amounts of NO 2 reveal a gradual transition from a semiconducting to a metallic state. Gradual quenching of vibrational Raman modes of Te with increasing concentration of NO 2 supports the appearance of a metallic state in NO 2 adsorbed Te. Ab initio simulations attribute these observations to the appearance of midgap states in NO 2 adsorbed Te nanowires. Our results provide fundamental insights into the effects of ambient on the electronic structures of low-dimensional materials and can be exploited for designing novel chemical sensors.

Structural Basis for Telomerase RNA Recognition and RNP Assembly by the Holoenzyme La Family Protein p65

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

Singh, Mahavir; Wang, Zhonghua; Koo, Bon-Kyung

2012-07-01

Telomerase is a ribonucleoprotein complex essential for maintenance of telomere DNA at linear chromosome ends. The catalytic core of Tetrahymena telomerase comprises a ternary complex of telomerase RNA (TER), telomerase reverse transcriptase (TERT), and the essential La family protein p65. NMR and crystal structures of p65 C-terminal domain and its complex with stem IV of TER reveal that RNA recognition is achieved by a combination of single- and double-stranded RNA binding, which induces a 105{sup o} bend in TER. The domain is a cryptic, atypical RNA recognition motif with a disordered C-terminal extension that forms an {alpha} helix in themore » complex necessary for hierarchical assembly of TERT with p65-TER. This work provides the first structural insight into biogenesis and assembly of TER with a telomerase-specific protein. Additionally, our studies define a structurally homologous domain (xRRM) in genuine La and LARP7 proteins and suggest a general mode of RNA binding for biogenesis of their diverse RNA targets.« less

Capturing Structural Snapshots during Photochemical Reactions with Ultrafast Raman Spectroscopy: From Materials Transformation to Biosensor Responses.

PubMed

Fang, Chong; Tang, Longteng; Oscar, Breland G; Chen, Cheng

2018-06-21

Chemistry studies the composition, structure, properties, and transformation of matter. A mechanistic understanding of the pertinent processes is required to translate fundamental knowledge into practical applications. The current development of ultrafast Raman as a powerful time-resolved vibrational technique, particularly femtosecond stimulated Raman spectroscopy (FSRS), has shed light on the structure-energy-function relationships of various photosensitive systems. This Perspective reviews recent work incorporating optical innovations, including the broad-band up-converted multicolor array (BUMA) into a tunable FSRS setup, and demonstrates its resolving power to watch metal speciation and photolysis, leading to high-quality thin films, and fluorescence modulation of chimeric protein biosensors for calcium ion imaging. We discuss advantages of performing FSRS in the mixed time-frequency domain and present strategies to delineate mechanisms by tracking low-frequency modes and systematically modifying chemical structures with specific functional groups. These unique insights at the chemical-bond level have started to enable the rational design and precise control of functional molecular machines in optical, materials, energy, and life sciences.

Genetic Population Structure in the Antarctic Benthos: Insights from the Widespread Amphipod, Orchomenella franklini

PubMed Central

Baird, Helena Phoenix; Miller, Karen Joy; Stark, Jonathan Sean

2012-01-01

Currently there is very limited understanding of genetic population structure in the Antarctic benthos. We conducted one of the first studies of microsatellite variation in an Antarctic benthic invertebrate, using the ubiquitous amphipod Orchomenella franklini (Walker, 1903). Seven microsatellite loci were used to assess genetic structure on three spatial scales: sites (100 s of metres), locations (1–10 kilometres) and regions (1000 s of kilometres) sampled in East Antarctica at Casey and Davis stations. Considerable genetic diversity was revealed, which varied between the two regions and also between polluted and unpolluted sites. Genetic differentiation among all populations was highly significant (F ST = 0.086, R ST = 0.139, p<0.001) consistent with the brooding mode of development in O. franklini. Hierarchical AMOVA revealed that the majority of the genetic subdivision occurred across the largest geographical scale, with Nem≈1 suggesting insufficient gene flow to prevent independent evolution of the two regions, i.e., Casey and Davis are effectively isolated. Isolation by distance was detected at smaller scales and indicates that gene flow in O. franklini occurs primarily through stepping-stone dispersal. Three of the microsatellite loci showed signs of selection, providing evidence that localised adaptation may occur within the Antarctic benthos. These results provide insights into processes of speciation in Antarctic brooders, and will help inform the design of spatial management initiatives recently endorsed for the Antarctic benthos. PMID:22479613

Three-dimensional structure of the NLRP7 pyrin domain: insight into pyrin-pyrin-mediated effector domain signaling in innate immunity.

PubMed

Pinheiro, Anderson S; Proell, Martina; Eibl, Clarissa; Page, Rebecca; Schwarzenbacher, Robert; Peti, Wolfgang

2010-08-27

The innate immune system provides an initial line of defense against infection. Nucleotide-binding domain- and leucine-rich repeat-containing protein (NLR or (NOD-like)) receptors play a critical role in the innate immune response by surveying the cytoplasm for traces of intracellular invaders and endogenous stress signals. NLRs themselves are multi-domain proteins. Their N-terminal effector domains (typically a pyrin or caspase activation and recruitment domain) are responsible for driving downstream signaling and initiating the formation of inflammasomes, multi-component complexes necessary for cytokine activation. However, the currently available structures of NLR effector domains have not yet revealed the mechanism of their differential modes of interaction. Here, we report the structure and dynamics of the N-terminal pyrin domain of NLRP7 (NLRP7 PYD) obtained by NMR spectroscopy. The NLRP7 PYD adopts a six-alpha-helix bundle death domain fold. A comparison of conformational and dynamics features of the NLRP7 PYD with other PYDs showed distinct differences for helix alpha3 and loop alpha2-alpha3, which, in NLRP7, is stabilized by a strong hydrophobic cluster. Moreover, the NLRP7 and NLRP1 PYDs have different electrostatic surfaces. This is significant, because death domain signaling is driven by electrostatic contacts and stabilized by hydrophobic interactions. Thus, these results provide new insights into NLRP signaling and provide a first molecular understanding of inflammasome formation.

Clonality, genetic diversity and support for the diversifying selection hypothesis in natural populations of a flower-living yeast.

PubMed

Herrera, C M; Pozo, M I; Bazaga, P

2011-11-01

Vast amounts of effort have been devoted to investigate patterns of genetic diversity and structuring in plants and animals, but similar information is scarce for organisms of other kingdoms. The study of the genetic structure of natural populations of wild yeasts can provide insights into the ecological and genetic correlates of clonality, and into the generality of recent hypotheses postulating that microbial populations lack the potential for genetic divergence and allopatric speciation. Ninety-one isolates of the flower-living yeast Metschnikowia gruessii from southeastern Spain were DNA fingerprinted using amplified fragment length polymorphism (AFLP) markers. Genetic diversity and structuring was investigated with band-based methods and model- and nonmodel-based clustering. Linkage disequilibrium tests were used to assess reproduction mode. Microsite-dependent, diversifying selection was tested by comparing genetic characteristics of isolates from bumble bee vectors and different floral microsites. AFLP polymorphism (91%) and genotypic diversity were very high. Genetic diversity was spatially structured, as shown by amova (Φ(st)  = 0.155) and clustering. The null hypothesis of random mating was rejected, clonality seeming the prevailing reproductive mode in the populations studied. Genetic diversity of isolates declined from bumble bee mouthparts to floral microsites, and frequency of five AFLP markers varied significantly across floral microsites, thus supporting the hypothesis of diversifying selection on clonal lineages. Wild populations of clonal fungal microbes can exhibit levels of genetic diversity and spatial structuring that are not singularly different from those shown by sexually reproducing plants or animals. Microsite-dependent, divergent selection can maintain high local and regional genetic diversity in microbial populations despite extensive clonality. © 2011 Blackwell Publishing Ltd.

Vibration-based health monitoring and model refinement of civil engineering structures

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

Farrar, C.R.; Doebling, S.W.

1997-10-01

Damage or fault detection, as determined by changes in the dynamic properties of structures, is a subject that has received considerable attention in the technical literature beginning approximately 30 years ago. The basic idea is that changes in the structure`s properties, primarily stiffness, will alter the dynamic properties of the structure such as resonant frequencies and mode shapes, and properties derived from these quantities such as modal-based flexibility. Recently, this technology has been investigated for applications to health monitoring of large civil engineering structures. This presentation will discuss such a study undertaken by engineers from New Mexico Sate University, Sandiamore » National Laboratory and Los Alamos National Laboratory. Experimental modal analyses were performed in an undamaged interstate highway bridge and immediately after four successively more severe damage cases were inflicted in the main girder of the structure. Results of these tests provide insight into the abilities of modal-based damage ID methods to identify damage and the current limitations of this technology. Closely related topics that will be discussed are the use of modal properties to validate computer models of the structure, the use of these computer models in the damage detection process, and the general lack of experimental investigation of large civil engineering structures.« less

Structural insight into the specificity of the B3 DNA-binding domains provided by the co-crystal structure of the C-terminal fragment of BfiI restriction enzyme

PubMed Central

Golovenko, Dmitrij; Manakova, Elena; Zakrys, Linas; Zaremba, Mindaugas; Sasnauskas, Giedrius; Gražulis, Saulius; Siksnys, Virginijus

2014-01-01

The B3 DNA-binding domains (DBDs) of plant transcription factors (TF) and DBDs of EcoRII and BfiI restriction endonucleases (EcoRII-N and BfiI-C) share a common structural fold, classified as the DNA-binding pseudobarrel. The B3 DBDs in the plant TFs recognize a diverse set of target sequences. The only available co-crystal structure of the B3-like DBD is that of EcoRII-N (recognition sequence 5′-CCTGG-3′). In order to understand the structural and molecular mechanisms of specificity of B3 DBDs, we have solved the crystal structure of BfiI-C (recognition sequence 5′-ACTGGG-3′) complexed with 12-bp cognate oligoduplex. Structural comparison of BfiI-C–DNA and EcoRII-N–DNA complexes reveals a conserved DNA-binding mode and a conserved pattern of interactions with the phosphodiester backbone. The determinants of the target specificity are located in the loops that emanate from the conserved structural core. The BfiI-C–DNA structure presented here expands a range of templates for modeling of the DNA-bound complexes of the B3 family of plant TFs. PMID:24423868

Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C.

PubMed

Chattopadhyay, Debasish; Swingle, Mark R; Salter, Edward A; Wood, Eric; D'Arcy, Brandon; Zivanov, Catherine; Abney, Kevin; Musiyenko, Alla; Rusin, Scott F; Kettenbach, Arminja; Yet, Larry; Schroeder, Chad E; Golden, Jennifer E; Dunham, Wade H; Gingras, Anne-Claude; Banerjee, Surajit; Forbes, David; Wierzbicki, Andrzej; Honkanen, Richard E

2016-06-01

Cantharidin is a natural toxin and an active constituent in a traditional Chinese medicine used to treat tumors. Cantharidin acts as a semi-selective inhibitor of PPP-family ser/thr protein phosphatases. Despite sharing a common catalytic mechanism and marked structural similarity with PP1C, PP2AC and PP5C, human PP4C was found to be insensitive to the inhibitory activity of cantharidin. To explore the molecular basis for this selectivity, we synthesized and tested novel C5/C6-derivatives designed from quantum-based modeling of the interactions revealed in the co-crystal structures of PP5C in complex with cantharidin. Structure-activity relationship studies and analysis of high-resolution (1.25Å) PP5C-inhibitor co-crystal structures reveal close contacts between the inhibitor bridgehead oxygen and both a catalytic metal ion and a non-catalytic phenylalanine residue, the latter of which is substituted by tryptophan in PP4C. Quantum chemistry calculations predicted that steric clashes with the bulkier tryptophan side chain in PP4C would force all cantharidin-based inhibitors into an unfavorable binding mode, disrupting the strong coordination of active site metal ions observed in the PP5C co-crystal structures, thereby rendering PP4C insensitive to the inhibitors. This prediction was confirmed by inhibition studies employing native human PP4C. Mutation of PP5C (F446W) and PP1C (F257W), to mimic the PP4C active site, resulted in markedly suppressed sensitivity to cantharidin. These observations provide insight into the structural basis for the natural selectivity of cantharidin and provide an avenue for PP4C deselection. The novel crystal structures also provide insight into interactions that provide increased selectivity of the C5/C6 modifications for PP5C versus other PPP-family phosphatases. Copyright © 2016 Elsevier Inc. All rights reserved.

Tutorial: Asteroseismic Data Analysis with DIAMONDS

NASA Astrophysics Data System (ADS)

Corsaro, Enrico

Since the advent of the space-based photometric missions such as CoRoT and NASA's Kepler, asteroseismology has acquired a central role in our understanding about stellar physics. The Kepler spacecraft, especially, is still releasing excellent photometric observations that contain a large amount of information not yet investigated. For exploiting the full potential of these data, sophisticated and robust analysis tools are now essential, so that further constraining of stellar structure and evolutionary models can be obtained. In addition, extracting detailed asteroseismic properties for many stars can yield new insights on their correlations to fundamental stellar properties and dynamics. After a brief introduction to the Bayesian notion of probability, I describe the code Diamonds for Bayesian parameter estimation and model comparison by means of the nested sampling Monte Carlo (NSMC) algorithm. NSMC constitutes an efficient and powerful method, in replacement to standard Markov chain Monte Carlo, very suitable for high-dimensional and multimodal problems that are typical of detailed asteroseismic analyses, such as the fitting and mode identification of individual oscillation modes in stars (known as peak-bagging). Diamonds is able to provide robust results for statistical inferences involving tens of individual oscillation modes, while at the same time preserving a considerable computational efficiency for identifying the solution. In the tutorial, I will present the fitting of the stellar background signal and the peak-bagging analysis of the oscillation modes in a red-giant star, providing an example to use Bayesian evidence for assessing the peak significance of the fitted oscillation peaks.

Investigating the interfacial dynamics of thin films

NASA Astrophysics Data System (ADS)

Rosenbaum, Aaron W.

This thesis probes the interfacial dynamics and associated phenomena of thin films. Surface specific tools were used to study the self-assembly of alkanethiols, the mono- and bilayer dynamics of SF6, and the surface motion of poly(methyl methacrylate). Non-pertubative helium atom scattering was the principal technique used to investigate these systems. A variety of other complementary tools, including scanning tunneling microscopy, electron diffraction, Auger spectroscopy, atomic force microscopy, and ellipsometry were used in tandem with the neutral atom scattering studies. Controlling the spontaneous assembly of alkanethiols on Au(111) requires a better fundamental understanding of the adsorbate-adsorbate and substrate-adsorbate interactions. Our characterization focused on two key components, the surface structure and adsorbate vibrations. The study indicates that the Au(111) reconstruction plays a larger role than anticipated in the low-density phase of alkanethiol monolayers. A new structure is proposed for the 1-decanethiol monolayer that impacts the low-energy vibrational mode. Varying the alkane chain lengths imparts insight into the assembly process via characterization of a dispersionless phonon mode. Studies of SF6 physisorbed on Au(111) bridge surface research on rare gas adsorbates with complicated dynamical organic thin films. Mono- and bilayer coverages of SF6/Au(111) were studied at cryogenic temperatures. Our experiments probed the surface properties of SF6 yielding insights into substrate and coverage effects. The study discovered a dispersionless Einstein oscillation with multiple harmonic overtones. A second layer of SF6 softened the mode, but did not show any indications of bulk or cooperative interactions. The vibrational properties of SF 6 showed both striking similarities and differences when compared with physisorbed rare gases. Lastly, this thesis will discuss studies of thin film poly(methyl methacrylate) on Si. The non-pertubative and surface specific nature of helium atom scattering allows for a deft study of the relationship between surface motion and the glass transition temperature. An added parameter in this complex organic system is the film thickness. The confinement effects and enhanced surface displacement were examined as a function of the thermal attenuation of both inelastic and elastic helium atom scattering. The Debye-Waller factor for these thin films of PMMA is similar to the low-density alkanethiol self-assembled monolayers discussed earlier.

Generalization of soft phonon modes

NASA Astrophysics Data System (ADS)

Rudin, Sven P.

2018-04-01

Soft phonon modes describe a collective movement of atoms that transform a higher-symmetry crystal structure into a lower-symmetry crystal structure. Such structural transformations occur at finite temperatures, where the phonons (i.e., the low-temperature vibrational modes) and the static perfect crystal structures provide an incomplete picture of the dynamics. Here, principal vibrational modes (PVMs) are introduced as descriptors of the dynamics of a material system with N atoms. The PVMs represent the independent collective movements of the atoms at a given temperature. Molecular dynamics (MD) simulations, here in the form of quantum MD using density functional theory calculations, provide both the data describing the atomic motion and the data used to construct the PVMs. The leading mode, PVM0, represents the 3 N -dimensional direction in which the system moves with greatest amplitude. For structural phase transitions, PVM0 serves as a generalization of soft phonon modes. At low temperatures, PVM0 reproduces the soft phonon mode in systems where one phonon dominates the phase transformation. In general, multiple phonon modes combine to describe a transformation, in which case PVM0 culls these phonon modes. Moreover, while soft phonon modes arise in the higher-symmetry crystal structure, PVM0 can be equally well calculated on either side of the structural phase transition. Two applications demonstrate these properties: first, transitions into and out of bcc titanium, and, second, the two crystal structures proposed for the β phase of uranium, the higher-symmetry structure of which stabilizes with temperature.

Modal gain characteristics of a 2 μm InGaSb/AlGaAsSb passively mode-locked quantum well laser

NASA Astrophysics Data System (ADS)

Li, Xiang; Wang, Hong; Qiao, Zhongliang; Guo, Xin; Ng, Geok Ing; Zhang, Yu; Niu, Zhichuan; Tong, Cunzhu; Liu, Chongyang

2017-12-01

Passive mode locking with a fundamental repetition rate at ˜18.46 GHz is demonstrated in a two-section InGaSb/AlGaAsSb quantum well laser emitting at 2 μm. Modal gain characteristics of the laser are investigated by performing the Hakki-Paoli method to gain better insight into the impact of the absorber bias voltage (Va) on the light output. The lasing action moves to longer wavelengths markedly with increasing negative Va. The light output contains more longitudinal modes in the mode locking regime if the gain bandwidth is larger at a certain Va. Our findings provide guidelines for output characteristics of the mode-locked laser.

Three-dimensional waveform sensitivity kernels

NASA Astrophysics Data System (ADS)

Marquering, Henk; Nolet, Guust; Dahlen, F. A.

1998-03-01

The sensitivity of intermediate-period (~10-100s) seismic waveforms to the lateral heterogeneity of the Earth is computed using an efficient technique based upon surface-wave mode coupling. This formulation yields a general, fully fledged 3-D relationship between data and model without imposing smoothness constraints on the lateral heterogeneity. The calculations are based upon the Born approximation, which yields a linear relation between data and model. The linear relation ensures fast forward calculations and makes the formulation suitable for inversion schemes; however, higher-order effects such as wave-front healing are neglected. By including up to 20 surface-wave modes, we obtain Fréchet, or sensitivity, kernels for waveforms in the time frame that starts at the S arrival and which includes direct and surface-reflected body waves. These 3-D sensitivity kernels provide new insights into seismic-wave propagation, and suggest that there may be stringent limitations on the validity of ray-theoretical interpretations. Even recently developed 2-D formulations, which ignore structure out of the source-receiver plane, differ substantially from our 3-D treatment. We infer that smoothness constraints on heterogeneity, required to justify the use of ray techniques, are unlikely to hold in realistic earth models. This puts the use of ray-theoretical techniques into question for the interpretation of intermediate-period seismic data. The computed 3-D sensitivity kernels display a number of phenomena that are counter-intuitive from a ray-geometrical point of view: (1) body waves exhibit significant sensitivity to structure up to 500km away from the source-receiver minor arc; (2) significant near-surface sensitivity above the two turning points of the SS wave is observed; (3) the later part of the SS wave packet is most sensitive to structure away from the source-receiver path; (4) the sensitivity of the higher-frequency part of the fundamental surface-wave mode is wider than for its faster, lower-frequency part; (5) delayed body waves may considerably influence fundamental Rayleigh and Love waveforms. The strong sensitivity of waveforms to crustal structure due to fundamental-mode-to-body-wave scattering precludes the use of phase-velocity filters to model body-wave arrivals. Results from the 3-D formulation suggest that the use of 2-D and 1-D techniques for the interpretation of intermediate-period waveforms should seriously be reconsidered.

Synthetic oligonucleotide separations by mixed-mode reversed-phase/weak anion-exchange liquid chromatography.

PubMed

Zimmermann, Aleksandra; Greco, Roberto; Walker, Isabel; Horak, Jeannie; Cavazzini, Alberto; Lämmerhofer, Michael

2014-08-08

Synthetic oligonucleotides gain increasing importance in new therapeutic concepts and as probes in biological sciences. If pharmaceutical-grade purities are required, chromatographic purification using ion-pair reversed-phase chromatography is commonly carried out. However, separation selectivity for structurally closely related impurities is often insufficient, especially at high sample loads. In this study, a "mixed-mode" reversed-phase/weak anion exchanger stationary phase has been investigated as an alternative tool for chromatographic separation of synthetic oligonucleotides with minor sequence variations. The employed mixed-mode phase shows great flexibility in method development. It has been run in various gradient elution modes, viz. one, two or three parameter (mixed) gradients (altering buffer pH, buffer concentration, and organic modifier) to find optimal elution conditions and gain further insight into retention mechanisms. Compared to ion-pair reversed-phase and mere anion-exchange separation, enhanced selectivities were observed with the mixed-mode phase for 20-23 nucleotide (nt) long oligonucleotides with similar sequences. Oligonucleotides differing by 1, 2 or 3 nucleotides in length could be readily resolved and separation factors for single nucleotide replacements declined in the order Cytosine (C)/Guanine (G)>Adenine (A)/Guanine∼Guanine/Thymine (T)>Adenine/Cytosine∼Cytosine/Thymine>Adenine/Thymine. Selectivities were larger when the modification was at the 3' terminal-end, declined when it was in the middle of the sequence and was smallest when it was located at the 5' terminus. Due to the lower surface area of the 200Å pore size mixed-mode stationary phase compared to the corresponding 100Å material, lower retention times with equal selectivities under milder elution conditions were achievable. Considering high sample loading capacities of the mixed-mode anion-exchanger phase, it should have great potential for chromatographic oligonucleotide separation and purification. Copyright © 2014 Elsevier B.V. All rights reserved.

Communication: Equivalence between symmetric and antisymmetric stretching modes of NH 3 in promoting H + NH 3 → H 2 + NH 2 reaction

DOE PAGES

Song, Hongwei; Yang, Minghui; Guo, Hua

2016-10-07

Vibrational excitations of reactants sometimes promote reactions more effectively than the same amount of translational energy. Such mode specificity provides insights into the transition-state modulation of reactivity and might be used to control chemical reactions. We report here a state-ofthe- art full-dimensional quantum dynamical study of the hydrogen abstraction reaction H + NH 3 → H 2 + NH 2 on an accurate ab initio based global potential energy surface. This reaction serves as an ideal candidate to study the relative efficacies of symmetric and degenerate antisymmetric stretching modes. Strong mode specificity, particularly for the NH 3 stretching modes, ismore » demonstrated. In conclusion, it is further shown that nearly identical efficacies of the symmetric and antisymmetric stretching modes of NH 3 in promoting the reaction can be understood in terms of local-mode stretching vibrations of the reactant molecule.« less

Communication: Equivalence between symmetric and antisymmetric stretching modes of NH3 in promoting H + NH3 → H2 + NH2 reaction

NASA Astrophysics Data System (ADS)

Song, Hongwei; Yang, Minghui; Guo, Hua

2016-10-01

Vibrational excitations of reactants sometimes promote reactions more effectively than the same amount of translational energy. Such mode specificity provides insights into the transition-state modulation of reactivity and might be used to control chemical reactions. We report here a state-of-the-art full-dimensional quantum dynamical study of the hydrogen abstraction reaction H + NH3 → H2 + NH2 on an accurate ab initio based global potential energy surface. This reaction serves as an ideal candidate to study the relative efficacies of symmetric and degenerate antisymmetric stretching modes. Strong mode specificity, particularly for the NH3 stretching modes, is demonstrated. It is further shown that nearly identical efficacies of the symmetric and antisymmetric stretching modes of NH3 in promoting the reaction can be understood in terms of local-mode stretching vibrations of the reactant molecule.

A vibrational spectroscopic study of the phosphate mineral lulzacite Sr2Fe2+(Fe2+,Mg)2Al4(PO4)4(OH)10

NASA Astrophysics Data System (ADS)

Frost, Ray L.; López, Andrés; Belotti, Fernanda M.; Xi, Yunfei; Scholz, Ricardo

2014-06-01

The mineral lulzacite from Saint-Aubin des Chateaux mine, France, with theoretical formula Sr2Fe2+(Fe2+,Mg)2Al4(PO4)4(OH)10 has been studied using a combination of electron microscopy with EDX and vibrational spectroscopic techniques. Chemical analysis shows a Sr, Fe, Al phosphate with minor amounts of Ga, Ba and Mg. Raman spectroscopy identifies an intense band at 990 cm-1 with an additional band at 1011 cm-1. These bands are attributed to the PO43-ν1 symmetric stretching mode. The ν3 antisymmetric stretching modes are observed by a large number of Raman bands. The Raman bands at 1034, 1051, 1058, 1069 and 1084 together with the Raman bands at 1098, 1116, 1133, 1155 and 1174 cm-1 are assigned to the ν3 antisymmetric stretching vibrations of PO43- and the HOPO32- units. The observation of these multiple Raman bands in the symmetric and antisymmetric stretching region gives credence to the concept that both phosphate and hydrogen phosphate units exist in the structure of lulzacite. The series of Raman bands at 567, 582, 601, 644, 661, 673 and 687 cm-1 are assigned to the PO43-ν2 bending modes. The series of Raman bands at 437, 468, 478, 491, 503 cm-1 are attributed to the PO43- and HOPO32-ν4 bending modes. No Raman bands of lulzacite which could be attributed to the hydroxyl stretching unit were observed. Infrared bands at 3511 and 3359 cm-1 are ascribed to the OH stretching vibration of the OH units. Very broad bands at 3022 and 3299 cm-1 are attributed to the OH stretching vibrations of water. Vibrational spectroscopy offers insights into the molecular structure of the phosphate mineral lulzacite.

Proton radiography for inline treatment planning and positioning verification of small animals.

PubMed

Müller, Johannes; Neubert, Christian; von Neubeck, Cläre; Baumann, Michael; Krause, Mechthild; Enghardt, Wolfgang; Bütof, Rebecca; Dietrich, Antje; Lühr, Armin

2017-11-01

As proton therapy becomes increasingly well established, there is a need for high-quality clinically relevant in vivo data to gain better insight into the radiobiological effects of proton irradiation on both healthy and tumor tissue. This requires the development of easily applicable setups that allow for efficient, fractionated, image-guided proton irradiation of small animals, the most widely used pre-clinical model. Here, a method is proposed to perform dual-energy proton radiography for inline positioning verification and treatment planning. Dual-energy proton radiography exploits the differential enhancement of object features in two successively measured two-dimensional (2D) dose distributions at two different proton energies. The two raw images show structures that are dominated by energy absorption (absorption mode) or scattering (scattering mode) of protons in the object, respectively. Data post-processing allowed for the separation of both signal contributions in the respective images. The images were evaluated regarding recognizable object details and feasibility of rigid registration to acquired planar X-ray scans. Robust, automated rigid registration of proton radiography and planar X-ray images in scattering mode could be reliably achieved with the animal bedding unit used as registration landmark. Distinguishable external and internal features of the imaged mouse included the outer body contour, the skull with substructures, the lung, abdominal structures and the hind legs. Image analysis based on the combined information of both imaging modes allowed image enhancement and calculation of 2D water-equivalent path length (WEPL) maps of the object along the beam direction. Fractionated irradiation of exposed target volumes (e.g., subcutaneous tumor model or brain) can be realized with the suggested method being used for daily positioning and range determination. Robust registration of X-ray and proton radiography images allows for the irradiation of tumor entities that require conventional computed tomography (CT)-based planning, such as orthotopic lung or brain tumors, similar to conventional patient treatment.

New Insights on Insect's Silent Flight. Part I: Vortex Dynamics and Wing Morphing

NASA Astrophysics Data System (ADS)

Ren, Yan; Liu, Geng; Dong, Haibo; Geng, Biao; Zheng, Xudong; Xue, Qian

2016-11-01

Insects are capable of conducting silent flights. This is attributed to its specially designed wing material properties for the control of vibration and surface morphing during the flapping flight. In current work, we focus on the roles of dynamic wing morphing on the unsteady vortex dynamics of a cicada in steady flight. A 3D image-based surface reconstruction method is used to obtain kinematical and morphological data of cicada wings from high-quality high-speed videos. The observed morphing wing kinematics is highly complex and a singular value decomposition method is used to decompose the wing motion to several dominant modes with distinct motion features. A high-fidelity immersed-boundary-based flow solver is then used to study the vortex dynamics in details. The results show that vortical structures closely relate to the morphing mode, which plays key role in the development and attachment of leading-edge vortex (LEV), thus helps the silent flapping of the cicada wings. This work is supported by AFOSR FA9550-12-1-0071 and NSF CBET-1313217.

Axisymmetric Density Waves in Saturn's Rings

NASA Astrophysics Data System (ADS)

Hedman, Matthew; Nicholson, Philip

2018-04-01

Density waves in Saturn's rings are typically tightly wrapped spiral patterns generated by resonances with either Saturn's moons or structures inside the planet. However, between the Barnard and Bessel Gaps in the Cassini Division (i.e. between 120,240 and 120,300 km), there are density variations that appear to form an axisymmetric density wave, which consists of concentric regions of varying density that propagate radially through the rings. Such a wave requires some process that forces ring particles at all longitudes to pass through pericenter at the same time, and so cannot be generated by satellite resonances. Instead this particular wave appears to be excited by interference between a nearby satellite resonance and normal mode oscillations on the inner edge of the Barnard Gap. Similar axisymmetric waves may exist within the Dawes ringlet and the outermost part of the B ring, which are also just interior to resonantly confined edges that exhibit a large number of normal modes. These waves may therefore provide new insights into how resonant perturbations near an edge can propagate through a disk of material.

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

Song, Hongwei; Yang, Minghui; Guo, Hua

Vibrational excitations of reactants sometimes promote reactions more effectively than the same amount of translational energy. Such mode specificity provides insights into the transition-state modulation of reactivity and might be used to control chemical reactions. We report here a state-ofthe- art full-dimensional quantum dynamical study of the hydrogen abstraction reaction H + NH 3 → H 2 + NH 2 on an accurate ab initio based global potential energy surface. This reaction serves as an ideal candidate to study the relative efficacies of symmetric and degenerate antisymmetric stretching modes. Strong mode specificity, particularly for the NH 3 stretching modes, ismore » demonstrated. In conclusion, it is further shown that nearly identical efficacies of the symmetric and antisymmetric stretching modes of NH 3 in promoting the reaction can be understood in terms of local-mode stretching vibrations of the reactant molecule.« less

Structural covariance networks across healthy young adults and their consistency.

PubMed

Guo, Xiaojuan; Wang, Yan; Guo, Taomei; Chen, Kewei; Zhang, Jiacai; Li, Ke; Jin, Zhen; Yao, Li

2015-08-01

To investigate structural covariance networks (SCNs) as measured by regional gray matter volumes with structural magnetic resonance imaging (MRI) from healthy young adults, and to examine their consistency and stability. Two independent cohorts were included in this study: Group 1 (82 healthy subjects aged 18-28 years) and Group 2 (109 healthy subjects aged 20-28 years). Structural MRI data were acquired at 3.0T and 1.5T using a magnetization prepared rapid-acquisition gradient echo sequence for these two groups, respectively. We applied independent component analysis (ICA) to construct SCNs and further applied the spatial overlap ratio and correlation coefficient to evaluate the spatial consistency of the SCNs between these two datasets. Seven and six independent components were identified for Group 1 and Group 2, respectively. Moreover, six SCNs including the posterior default mode network, the visual and auditory networks consistently existed across the two datasets. The overlap ratios and correlation coefficients of the visual network reached the maximums of 72% and 0.71. This study demonstrates the existence of consistent SCNs corresponding to general functional networks. These structural covariance findings may provide insight into the underlying organizational principles of brain anatomy. © 2014 Wiley Periodicals, Inc.

Generalization of soft phonon modes

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

Rudin, Sven P.

Soft phonon modes describe a collective movement of atoms that transform a higher-symmetry crystal structure into a lower-symmetry crystal structure. Such structural transformations occur at finite temperatures, where the phonons (i.e., the low-temperature vibrational modes) and the static perfect crystal structures provide an incomplete picture of the dynamics. In this paper, principal vibrational modes (PVMs) are introduced as descriptors of the dynamics of a material system withmore » $N$ atoms. The PVMs represent the independent collective movements of the atoms at a given temperature. Molecular dynamics (MD) simulations, here in the form of quantum MD using density functional theory calculations, provide both the data describing the atomic motion and the data used to construct the PVMs. The leading mode, $${\\mathrm{PVM}}_{0}$$, represents the $3N$-dimensional direction in which the system moves with greatest amplitude. For structural phase transitions, $${\\mathrm{PVM}}_{0}$$ serves as a generalization of soft phonon modes. At low temperatures, $${\\mathrm{PVM}}_{0}$$ reproduces the soft phonon mode in systems where one phonon dominates the phase transformation. In general, multiple phonon modes combine to describe a transformation, in which case $${\\mathrm{PVM}}_{0}$$ culls these phonon modes. Moreover, while soft phonon modes arise in the higher-symmetry crystal structure, $${\\mathrm{PVM}}_{0}$$ can be equally well calculated on either side of the structural phase transition. Finally, two applications demonstrate these properties: first, transitions into and out of bcc titanium, and, second, the two crystal structures proposed for the $${\\beta}$$ phase of uranium, the higher-symmetry structure of which stabilizes with temperature.« less

Generalization of soft phonon modes

DOE PAGES

Rudin, Sven P.

2018-04-27

Soft phonon modes describe a collective movement of atoms that transform a higher-symmetry crystal structure into a lower-symmetry crystal structure. Such structural transformations occur at finite temperatures, where the phonons (i.e., the low-temperature vibrational modes) and the static perfect crystal structures provide an incomplete picture of the dynamics. In this paper, principal vibrational modes (PVMs) are introduced as descriptors of the dynamics of a material system withmore » $N$ atoms. The PVMs represent the independent collective movements of the atoms at a given temperature. Molecular dynamics (MD) simulations, here in the form of quantum MD using density functional theory calculations, provide both the data describing the atomic motion and the data used to construct the PVMs. The leading mode, $${\\mathrm{PVM}}_{0}$$, represents the $3N$-dimensional direction in which the system moves with greatest amplitude. For structural phase transitions, $${\\mathrm{PVM}}_{0}$$ serves as a generalization of soft phonon modes. At low temperatures, $${\\mathrm{PVM}}_{0}$$ reproduces the soft phonon mode in systems where one phonon dominates the phase transformation. In general, multiple phonon modes combine to describe a transformation, in which case $${\\mathrm{PVM}}_{0}$$ culls these phonon modes. Moreover, while soft phonon modes arise in the higher-symmetry crystal structure, $${\\mathrm{PVM}}_{0}$$ can be equally well calculated on either side of the structural phase transition. Finally, two applications demonstrate these properties: first, transitions into and out of bcc titanium, and, second, the two crystal structures proposed for the $${\\beta}$$ phase of uranium, the higher-symmetry structure of which stabilizes with temperature.« less

Pyrenyl-linker-glucono gelators. Correlations of gel properties with gelator structures and characterization of solvent effects.

PubMed

Yan, Ni; Xu, Zhiyan; Diehn, Kevin K; Raghavan, Srinivasa R; Fang, Yu; Weiss, Richard G

2013-01-15

A series of glucono-appended 1-pyrenesulfonyl derivatives containing α,ω-diaminoalkane spacers (Pn, where n, the number of methylene units separating the amino groups, is 2, 3, 4, 6, 7, and 8) have been prepared. Careful analyses of correlations between the structures of these molecules and their gels have provided important insights into the factors responsible for one-dimensional aggregation of small molecules containing both lipophilic and hydrophilic parts. The gelation behavior has been examined in 30 liquids of diverse structure and polarity, and the properties of their gels and the gelation mechanisms have been investigated using a variety of techniques. Possible reasons are discussed regarding why the Pn are better gelators than the corresponding naphthyl analogues (Nn) which had been investigated previously. P2 and P3 are ambidextrous gelators (i.e., they gelate both water and some organic liquids), and P4-P8 gelate some organic liquids which are protic and aprotic, but not water. In at least one of the liquids examined, P3, P4, P6, P7, and P8 form gels at less than 1 w/v % concentrations, and some of the gels in 1-decanol are thixotropic. Analyses of the gelation abilities using Hansen solubility parameters yield both qualitative and quantitative insights into the role of liquid-gelator interactions. For example, the critical gelation concentrations increase generally with increasing polar and hydrogen bonding interactions between the gelators and their liquid components. As revealed by FT-IR, (1)H NMR, UV-vis, and fluorescence spectra, hydrogen-bonding between glucono units and π-π stacking between pyrenyl groups are important in the formation and maintenance of the gel networks. The results from this study, especially those relating the aggregation modes and liquid properties, offer insights for the design of new surfactant-containing low-molecular-mass gelators with predefined gelating abilities.

Influence of modes of metal transfer on grain structure and direction of grain growth in low nickel austenitic stainless steel weld metals

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

Mukherjee, Manidipto; Saha, Saptarshi; Pal, Tapan Kumar, E-mail: tkpal.ju@gmail.com

2015-04-15

The present study elaborately discussed the effect of different modes of metal transfer (i.e., short circuit mode, spray mode and pulse mode) on grain structure and direction of grain growth in low nickel austenitic stainless steel weld metals. Electron backscattered diffraction (EBSD) analysis was used to study the grain growth direction and grain structure in weld metals. The changes in grain structure and grain growth direction were found to be essentially varied with the weld pool shape and acting forces induced by modes of metal transfer at a constant welding speed. Short circuit mode of metal transfer owing to highermore » Marangoni force (M{sub a}) and low electromagnetic force (R{sub m}) promotes the lower weld pool volume (Γ) and higher weld pool maximum radius (r{sub m}). Short circuit mode also shows curved and tapered columnar grain structures and the grain growth preferentially occurred in <001> direction. In contrast, spray mode of metal transfer increases the Γ and reduces the r{sub m} values due to very high R{sub m} and typically reveals straight and broad columnar grain structures with preferential growth direction in <111>. In the pulse mode of metal transfer relatively high M{sub a} and R{sub m} simultaneously increase the weld pool width and the primary penetration which might encourage relatively complex grain growth directions in the weld pool and cause a shift of major intensity from <001> to <111> direction. It can also be concluded that the fusion zone grain structure and direction of grain growth are solely dependent on modes of metal transfer and remain constant for a particular mode of metal transfer irrespective of filler wire used. - Highlights: • Welded joints of LNiASS were prepared by varying modes of metal transfer. • Weld pool shape, grain structure and grain growth direction were studied. • Short circuit mode shows curved and tapered grain growth in <001> direction. • Spray mode shows straight and broad columnar grain growth in <111> direction. • Pulse mode shows complex grain growth with a shift in growth direction.« less

New insights into the interaction between pyrrolyl diketoacids and HIV-1 integrase active site and comparison with RNase H.

PubMed

Corona, Angela; di Leva, Francesco Saverio; Rigogliuso, Giuseppe; Pescatori, Luca; Madia, Valentina Noemi; Subra, Frederic; Delelis, Olivier; Esposito, Francesca; Cadeddu, Marta; Costi, Roberta; Cosconati, Sandro; Novellino, Ettore; di Santo, Roberto; Tramontano, Enzo

2016-10-01

HIV-1 integrase (IN) inhibitors are one of the most recent innovations in the treatment of HIV infection. The selection of drug resistance viral strains is however a still open issue requiring constant efforts to identify new anti-HIV-1 drugs. Pyrrolyl diketo acid (DKA) derivatives inhibit HIV-1 replication by interacting with the Mg 2+ cofactors within the HIV-1 IN active site or within the HIV-1 reverse-transcriptase associated ribonuclease H (RNase H) active site. While the interaction mode of pyrrolyl DKAs with the RNase H active site has been recently reported and substantiated by mutagenesis experiments, their interaction within the IN active site still lacks a detailed understanding. In this study, we investigated the binding mode of four pyrrolyl DKAs to the HIV-1 IN active site by molecular modeling coupled with site-directed mutagenesis studies showing that the DKA pyrrolyl scaffold primarily interacts with the IN amino residues P145, Q146 and Q148. Importantly, the tested DKAs demonstrated good effectiveness against HIV-1 Raltegravir resistant Y143A and N155H INs, thus showing an interaction pattern with relevant differences if compared with the first generation IN inhibitors. These data provide precious insights for the design of new HIV inhibitors active on clinically selected Raltegravir resistant variants. Furthermore, this study provides new structural information to modulate IN and RNase H inhibitory activities for development of dual-acting anti-HIV agents. Copyright © 2016 Elsevier B.V. All rights reserved.

It is all about location: how to pinpoint microorganisms and their functions in multispecies biofilms.

PubMed

Costa, Angela M; Mergulhão, Filipe J; Briandet, Romain; Azevedo, Nuno F

2017-09-01

Multispecies biofilms represent the dominant mode of life for the vast majority of microorganisms. Bacterial spatial localization in such biostructures governs ecological interactions between different populations and triggers the overall community functions. Here, we discuss the pros and cons of fluorescence-based techniques used to decipher bacterial species patterns in biofilms at single cell level, including fluorescence in situ hybridization and the use of genetically modified bacteria that express fluorescent proteins, reporting the significant improvements of those techniques. The development of tools for spatial and temporal study of multispecies biofilms will allow live imaging and spatial localization of cells in naturally occurring biofilms coupled with metabolic information, increasing insight of microbial community and the relation between its structure and functions.

Neurobiological Basis of Language Learning Difficulties.

PubMed

Krishnan, Saloni; Watkins, Kate E; Bishop, Dorothy V M

2016-09-01

In this paper we highlight why there is a need to examine subcortical learning systems in children with language impairment and dyslexia, rather than focusing solely on cortical areas relevant for language. First, behavioural studies find that children with these neurodevelopmental disorders perform less well than peers on procedural learning tasks that depend on corticostriatal learning circuits. Second, fMRI studies in neurotypical adults implicate corticostriatal and hippocampal systems in language learning. Finally, structural and functional abnormalities are seen in the striatum in children with language disorders. Studying corticostriatal networks in developmental language disorders could offer us insights into their neurobiological basis and elucidate possible modes of compensation for intervention. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

New insights on SOI Tunnel FETs with low-temperature process flow for CoolCube™ integration

NASA Astrophysics Data System (ADS)

Diaz Llorente, C.; Le Royer, C.; Batude, P.; Fenouillet-Beranger, C.; Martinie, S.; Lu, C.-M. V.; Allain, F.; Colinge, J.-P.; Cristoloveanu, S.; Ghibaudo, G.; Vinet, M.

2018-06-01

This paper reports the fabrication and electrical characterization of planar SOI Tunnel FETs (TFETs) made using a Low-Temperature (LT) process designed for 3D sequential integration. These proof-of-concept TFETs feature junctions obtained by Solid Phase Epitaxy Regrowth (SPER). Their electrical behavior is analyzed and compared to reference samples (regular process using High-Temperature junction formation, HT). Dual ID-VDS measurements verify that the TFET structures present Band-to-Band tunnelling (BTBT) carrier injection and not Schottky Barrier tunnelling. P-mode operating LT TFETs deliver an ON state current similar to that of the HT reference, opening the door towards optimized devices operating with very low threshold voltage VTH and low supply voltage VDD.

Sensitivity of coronal loop sausage mode frequencies and decay rates to radial and longitudinal density inhomogeneities: a spectral approach

NASA Astrophysics Data System (ADS)

Cally, Paul S.; Xiong, Ming

2018-01-01

Fast sausage modes in solar magnetic coronal loops are only fully contained in unrealistically short dense loops. Otherwise they are leaky, losing energy to their surrounds as outgoing waves. This causes any oscillation to decay exponentially in time. Simultaneous observations of both period and decay rate therefore reveal the eigenfrequency of the observed mode, and potentially insight into the tubes’ nonuniform internal structure. In this article, a global spectral description of the oscillations is presented that results in an implicit matrix eigenvalue equation where the eigenvalues are associated predominantly with the diagonal terms of the matrix. The off-diagonal terms vanish identically if the tube is uniform. A linearized perturbation approach, applied with respect to a uniform reference model, is developed that makes the eigenvalues explicit. The implicit eigenvalue problem is easily solved numerically though, and it is shown that knowledge of the real and imaginary parts of the eigenfrequency is sufficient to determine the width and density contrast of a boundary layer over which the tubes’ enhanced internal densities drop to ambient values. Linearized density kernels are developed that show sensitivity only to the extreme outside of the loops for radial fundamental modes, especially for small density enhancements, with no sensitivity to the core. Higher radial harmonics do show some internal sensitivity, but these will be more difficult to observe. Only kink modes are sensitive to the tube centres. Variation in internal and external Alfvén speed along the loop is shown to have little effect on the fundamental dimensionless eigenfrequency, though the associated eigenfunction becomes more compact at the loop apex as stratification increases, or may even displace from the apex.

Influence of anisotropic dipolar interaction on the spin dynamics of Ni80Fe20 nanodot arrays arranged in honeycomb and octagonal lattices

NASA Astrophysics Data System (ADS)

Mondal, Sucheta; Barman, Saswati; Choudhury, Samiran; Otani, Yoshichika; Barman, Anjan

2018-07-01

Ultrafast spin dynamics in ferromagnetic nanodot arrays with dot diameter 100 nm and thickness 20 nm arranged in honeycomb and octagonal lattice symmetries are studied to explore the tunability of the collective magnetization dynamics. By varying the inter-dot separation between 30 nm and 300 nm drastic variation in the precessional dynamics from strongly collective to completely isolated regime has been observed by using all-optical time-resolved magneto-optical Kerr microscope. Micromagnetic simulation is exploited to gain insights about the resonant mode profiles and magnetic coupling between the nanodots. A significant spectral and spatial variation in the resonant mode with increasing dipolar interaction is demonstrated with increasing inter-dot separation. The spins driven by effective field inside single nanodots are prone to precess independently, generating two self-standing centre and edge modes in the array that are influenced by the relative orientation between the inter-dot coupling direction and bias magnetic field. The anisotropic behavior of dipolar field is rigorously investigated here. Splitting of the centre mode in case of octagonal lattice is experimentally observed here as a consequence of the anisotropic dipolar field between the nanodot pairs coupled horizontally and vertically, which is not found in the honeycomb lattice. In addition, proper understanding of the modification of dynamic mode profile by neighboring dipolar interaction built up here, is imperative for further control of the dynamic dipolar interaction and the corresponding collective excitation in magnonic crystals. The usage of nanodot lattices with complex basis structures can be advantageous for the designing of high density magnetic recording media, spin-wave filter and logic devices.

Characteristic vibration patterns of odor compounds from bread-baking volatiles upon protein binding: density functional and ONIOM study and principal component analysis.

PubMed

Treesuwan, Witcha; Hirao, Hajime; Morokuma, Keiji; Hannongbua, Supa

2012-05-01

As the mechanism underlying the sense of smell is unclear, different models have been used to rationalize structure-odor relationships. To gain insight into odorant molecules from bread baking, binding energies and vibration spectra in the gas phase and in the protein environment [7-transmembrane helices (7TMHs) of rhodopsin] were calculated using density functional theory [B3LYP/6-311++G(d,p)] and ONIOM [B3LYP/6-311++G(d,p):PM3] methods. It was found that acetaldehyde ("acid" category) binds strongly in the large cavity inside the receptor, whereas 2-ethyl-3-methylpyrazine ("roasted") binds weakly. Lys296, Tyr268, Thr118 and Ala117 were identified as key residues in the binding site. More emphasis was placed on how vibrational frequencies are shifted and intensities modified in the receptor protein environment. Principal component analysis (PCA) suggested that the frequency shifts of C-C stretching, CH(3) umbrella, C = O stretching and CH(3) stretching modes have a significant effect on odor quality. In fact, the frequency shifts of the C-C stretching and C = O stretching modes, as well as CH(3) umbrella and CH(3) symmetric stretching modes, exhibit different behaviors in the PCA loadings plot. A large frequency shift in the CH(3) symmetric stretching mode is associated with the sweet-roasted odor category and separates this from the acid odor category. A large frequency shift of the C-C stretching mode describes the roasted and oily-popcorn odor categories, and separates these from the buttery and acid odor categories.

Data-resolution matrix and model-resolution matrix for Rayleigh-wave inversion using a damped least-squares method

USGS Publications Warehouse

Xia, J.; Miller, R.D.; Xu, Y.

2008-01-01

Inversion of multimode surface-wave data is of increasing interest in the near-surface geophysics community. For a given near-surface geophysical problem, it is essential to understand how well the data, calculated according to a layered-earth model, might match the observed data. A data-resolution matrix is a function of the data kernel (determined by a geophysical model and a priori information applied to the problem), not the data. A data-resolution matrix of high-frequency (>2 Hz) Rayleigh-wave phase velocities, therefore, offers a quantitative tool for designing field surveys and predicting the match between calculated and observed data. We employed a data-resolution matrix to select data that would be well predicted and we find that there are advantages of incorporating higher modes in inversion. The resulting discussion using the data-resolution matrix provides insight into the process of inverting Rayleigh-wave phase velocities with higher-mode data to estimate S-wave velocity structure. Discussion also suggested that each near-surface geophysical target can only be resolved using Rayleigh-wave phase velocities within specific frequency ranges, and higher-mode data are normally more accurately predicted than fundamental-mode data because of restrictions on the data kernel for the inversion system. We used synthetic and real-world examples to demonstrate that selected data with the data-resolution matrix can provide better inversion results and to explain with the data-resolution matrix why incorporating higher-mode data in inversion can provide better results. We also calculated model-resolution matrices in these examples to show the potential of increasing model resolution with selected surface-wave data. ?? Birkhaueser 2008.

Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist

NASA Astrophysics Data System (ADS)

Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

2016-08-01

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

H2CN+ and H2CNH+: New insight into the structure and dynamics from mass-selected threshold photoelectron spectra

NASA Astrophysics Data System (ADS)

Holzmeier, Fabian; Lang, Melanie; Hader, Kilian; Hemberger, Patrick; Fischer, Ingo

2013-06-01

In this paper, we reinvestigate the photoionization of nitrogen containing reactive intermediates of the composition H2CN and H2CNH, molecules of importance in astrochemistry and biofuel combustion. In particular, H2CN is also of considerable interest to theory, because of its complicated potential energy surface. The species were generated by flash pyrolysis, ionized with vacuum ultraviolet synchrotron radiation, and studied by mass-selected threshold photoelectron (TPE) spectroscopy. In the mass-selected TPE-spectrum of m/z = 28, contributions of all four isomers of H2CN were identified. The excitation energy to the triplet cation of the methylene amidogen radical H2CN was determined to be 12.32 eV. Considerable activity in the C-N mode of the cation is visible. Furthermore, we derived values for excitation into the triplet cations of 11.72 eV for cis-HCNH, 12.65 eV for trans-HCNH, and 11.21 eV for H2NC. The latter values are probably accurate to within one vibrational quantum. The spectrum features an additional peak at 10.43 eV that corresponds to excitation into the C2v-symmetric H2CN+. As this structure constitutes a saddle point, the peak is assigned to an activated complex on the singlet potential energy surface of the cation, corresponding to a hydrogen atom migration. For methanimine, H2CNH, the adiabatic ionization energy IEad was determined to be 9.99 eV and the vibrational structure of the spectrum was analyzed in detail. The uncertainty of earlier values that simply assigned the signal onset to the IEad is thus considerably reduced. The spectrum is dominated by the H-N-C bending mode ν1+ and the rocking mode ν3+. All experimental data were supported by calculations and Franck-Condon simulations.

Elucidation of a side reaction occurring during nitroxide-mediated polymerization of cyclic ketene acetals by tandem mass spectrometric end-group analysis of aliphatic polyesters.

PubMed

Albergaria Pereira, Bruna de Fátima; Tardy, Antoine; Monnier, Valérie; Guillaneuf, Yohann; Gigmes, Didier; Charles, Laurence

2015-12-15

In order to prevent side reactions while developing new polymerization processes, their mechanism has to be understood and one first key insight is the structure of the end-groups in polymeric by-products. The synthetic method scrutinized here is the nitroxide-mediated polymerization (NMP) of a cyclic ketene acetal, a promising alternative process to the production of polyesters. Polymer end-group characterization was performed by mass spectrometry (MS), combining elemental composition information derived from accurate mass data in the MS mode with fragmentation features recorded in the MS/MS mode. Electrospray was used as the ionization method to ensure the integrity of original chain terminations and a quadrupole time-of-flight (QTOF) instrument was employed for high-resolution mass measurements in both MS and tandem mass spectrometry (MS/MS) modes. Occurrence of side reactions in the studied polymerization method, first evidenced by an unusual increase in dispersity with conversion, was confirmed in MS with the detection of two polymeric impurities in addition to the expected species. Fragmentation rules were first established for this new polyester family in order to derive useful structural information from MS/MS data. In addition to a usual NMP by-product, the initiating group of the second polymeric impurities revealed the degradation of the nitroxide moiety. Unambiguous MS/MS identification of end-groups in by-products sampled from the polymerization medium allowed an unusual side reaction to be identified during the NMP preparation of polyesters. On-going optimization of the polymerization method aims at preventing this undesired process. Copyright © 2015 John Wiley & Sons, Ltd.

Mechanistic insights into c-di-GMP–dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa

DOE PAGES

Matsuyama, Bruno Y.; Krasteva, Petya V.; Baraquet, Claudine; ...

2015-12-28

Bacterial biofilm formation during chronic infections confers increased fitness, antibiotic tolerance, and cytotoxicity. In many pathogens, the transition from a planktonic lifestyle to collaborative, sessile biofilms represents a regulated process orchestrated by the intracellular second-messenger c-di-GMP. A main effector for c-di-GMP signaling in the opportunistic pathogen Pseudomonas aeruginosa is the transcription regulator FleQ. FleQ is a bacterial enhancer-binding protein (bEBP) with a central AAA+ ATPase σ 54-interaction domain, flanked by a C-terminal helix-turn-helix DNA-binding motif and a divergent N-terminal receiver domain. Together with a second ATPase, FleN, FleQ regulates the expression of flagellar and exopolysaccharide biosynthesis genes in response tomore » cellular c-di-GMP. Here we report structural and functional data that reveal an unexpected mode of c-di-GMP recognition that is associated with major conformational rearrangements in FleQ. Crystal structures of FleQ’s AAA+ ATPase domain in its apo-state or bound to ADP or ATP-γ-S show conformations reminiscent of the activated ring-shaped assemblies of other bEBPs. As revealed by the structure of c-di-GMP–complexed FleQ, the second messenger interacts with the AAA+ ATPase domain at a site distinct from the ATP binding pocket. c-di-GMP interaction leads to active site obstruction, hexameric ring destabilization, and discrete quaternary structure transitions. Solution and cell-based studies confirm coupling of the ATPase active site and c-di-GMP binding, as well as the functional significance of crystallographic interprotomer interfaces. Taken together, our data offer unprecedented insight into conserved regulatory mechanisms of gene expression under direct c-di-GMP control via FleQ and FleQ-like bEBPs.« less

Mechanistic insights into c-di-GMP–dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa

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

Matsuyama, Bruno Y.; Krasteva, Petya V.; Baraquet, Claudine

Bacterial biofilm formation during chronic infections confers increased fitness, antibiotic tolerance, and cytotoxicity. In many pathogens, the transition from a planktonic lifestyle to collaborative, sessile biofilms represents a regulated process orchestrated by the intracellular second-messenger c-di-GMP. A main effector for c-di-GMP signaling in the opportunistic pathogen Pseudomonas aeruginosa is the transcription regulator FleQ. FleQ is a bacterial enhancer-binding protein (bEBP) with a central AAA+ ATPase σ 54-interaction domain, flanked by a C-terminal helix-turn-helix DNA-binding motif and a divergent N-terminal receiver domain. Together with a second ATPase, FleN, FleQ regulates the expression of flagellar and exopolysaccharide biosynthesis genes in response tomore » cellular c-di-GMP. Here we report structural and functional data that reveal an unexpected mode of c-di-GMP recognition that is associated with major conformational rearrangements in FleQ. Crystal structures of FleQ’s AAA+ ATPase domain in its apo-state or bound to ADP or ATP-γ-S show conformations reminiscent of the activated ring-shaped assemblies of other bEBPs. As revealed by the structure of c-di-GMP–complexed FleQ, the second messenger interacts with the AAA+ ATPase domain at a site distinct from the ATP binding pocket. c-di-GMP interaction leads to active site obstruction, hexameric ring destabilization, and discrete quaternary structure transitions. Solution and cell-based studies confirm coupling of the ATPase active site and c-di-GMP binding, as well as the functional significance of crystallographic interprotomer interfaces. Taken together, our data offer unprecedented insight into conserved regulatory mechanisms of gene expression under direct c-di-GMP control via FleQ and FleQ-like bEBPs.« less

Mechanistic insights into c-di-GMP–dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa

PubMed Central

Matsuyama, Bruno Y.; Krasteva, Petya V.; Baraquet, Claudine; Harwood, Caroline S.; Sondermann, Holger; Navarro, Marcos V. A. S.

2016-01-01

Bacterial biofilm formation during chronic infections confers increased fitness, antibiotic tolerance, and cytotoxicity. In many pathogens, the transition from a planktonic lifestyle to collaborative, sessile biofilms represents a regulated process orchestrated by the intracellular second-messenger c-di-GMP. A main effector for c-di-GMP signaling in the opportunistic pathogen Pseudomonas aeruginosa is the transcription regulator FleQ. FleQ is a bacterial enhancer-binding protein (bEBP) with a central AAA+ ATPase σ54-interaction domain, flanked by a C-terminal helix-turn-helix DNA-binding motif and a divergent N-terminal receiver domain. Together with a second ATPase, FleN, FleQ regulates the expression of flagellar and exopolysaccharide biosynthesis genes in response to cellular c-di-GMP. Here we report structural and functional data that reveal an unexpected mode of c-di-GMP recognition that is associated with major conformational rearrangements in FleQ. Crystal structures of FleQ’s AAA+ ATPase domain in its apo-state or bound to ADP or ATP-γ-S show conformations reminiscent of the activated ring-shaped assemblies of other bEBPs. As revealed by the structure of c-di-GMP–complexed FleQ, the second messenger interacts with the AAA+ ATPase domain at a site distinct from the ATP binding pocket. c-di-GMP interaction leads to active site obstruction, hexameric ring destabilization, and discrete quaternary structure transitions. Solution and cell-based studies confirm coupling of the ATPase active site and c-di-GMP binding, as well as the functional significance of crystallographic interprotomer interfaces. Taken together, our data offer unprecedented insight into conserved regulatory mechanisms of gene expression under direct c-di-GMP control via FleQ and FleQ-like bEBPs. PMID:26712005

Self-force calculations with matched expansions and quasinormal mode sums

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

Casals, Marc; Dolan, Sam; Ottewill, Adrian C.

2009-06-15

Accurate modeling of gravitational wave emission by extreme-mass ratio inspirals is essential for their detection by the LISA mission. A leading perturbative approach involves the calculation of the self-force acting upon the smaller orbital body. In this work, we present the first application of the Poisson-Wiseman-Anderson method of 'matched expansions' to compute the self-force acting on a point particle moving in a curved spacetime. The method employs two expansions for the Green function, which are, respectively, valid in the 'quasilocal' and 'distant past' regimes, and which may be matched together within the normal neighborhood. We perform our calculation in amore » static region of the spherically symmetric Nariai spacetime (dS{sub 2}xS{sup 2}), in which scalar-field perturbations are governed by a radial equation with a Poeschl-Teller potential (frequently used as an approximation to the Schwarzschild radial potential) whose solutions are known in closed form. The key new ingredients in our study are (i) very high order quasilocal expansions and (ii) expansion of the distant past Green function in quasinormal modes. In combination, these tools enable a detailed study of the properties of the scalar-field Green function. We demonstrate that the Green function is singular whenever x and x{sup '} are connected by a null geodesic, and apply asymptotic methods to determine the structure of the Green function near the null wave front. We show that the singular part of the Green function undergoes a transition each time the null wave front passes through a caustic point, following a repeating fourfold sequence {delta}({sigma}), 1/{pi}{sigma}, -{delta}({sigma}), -1/{pi}{sigma}, etc., where {sigma} is Synge's world function. The matched-expansion method provides insight into the nonlocal properties of the self-force. We show that the self-force generated by the segment of the worldline lying outside the normal neighborhood is not negligible. We apply the matched-expansion method to compute the scalar self-force acting on a static particle on the Nariai spacetime, and validate against an alternative method, obtaining agreement to six decimal places. We conclude with a discussion of the implications for wave propagation and self-force calculations. On black hole spacetimes, any expansion of the Green function in quasinormal modes must be augmented by a branch-cut integral. Nevertheless, we expect the Green function in Schwarzschild spacetime to inherit certain key features, such as a fourfold singular structure manifesting itself through the asymptotic behavior of quasinormal modes. In this way, the Nariai spacetime provides a fertile testing ground for developing insight into the nonlocal part of the self-force on black hole spacetimes.« less

Vibrational Spectroscopy of BENZENE-(WATER)_N Clusters with N=6,7

NASA Astrophysics Data System (ADS)

Tabor, Daniel P.; Sibert, Edwin; Kusaka, Ryoji; Walsh, Patrick S.; Zwier, Timothy S.

2015-06-01

The investigation of benzene-water clusters (Bz-(H_2O)_n) provides insight into the relative importance π-hydrogen bond interactions in cluster formation. Taking advantage of the higher resolution of current IR sources, isomer-specific resonant ion-dip infrared (RIDIR) spectra were recorded in the OH stretch region (3000-3750 cm-1). A local mode Hamiltonian for describing the OH stretch vibrations of water clusters is applied to Bz-(H_2O)_6 and Bz-(H_2O)_7 and compared with the RIDIR spectra. These clusters are the smallest water clusters in which three-dimensional H-bonded networks containing three-coordinate water molecules begin to be formed, and are therefore particularly susceptible to re-ordering or re-shaping in response to the presence of a benzene molecule. The spectrum of Bz-(H_2O)_6 is assigned to an inverted book structure while the major conformer of Bz-(H_2O)_7 is assigned to an S_4-derived inserted cubic structure in which the benzene occupies one corner of the cube. The local mode model is used to extract monomer Hamiltonians for individual water molecules, including stretch-bend Fermi resonance and intra-monomer couplings. The monomer Hamiltonians divide into sub-groups based on their local H-bonding architecture (DA, DDA, DAA) and the nature of their interaction with benzene.

KOSMOS: a universal morph server for nucleic acids, proteins and their complexes

PubMed Central

Seo, Sangjae; Kim, Moon Ki

2012-01-01

KOSMOS is the first online morph server to be able to address the structural dynamics of DNA/RNA, proteins and even their complexes, such as ribosomes. The key functions of KOSMOS are the harmonic and anharmonic analyses of macromolecules. In the harmonic analysis, normal mode analysis (NMA) based on an elastic network model (ENM) is performed, yielding vibrational modes and B-factor calculations, which provide insight into the potential biological functions of macromolecules based on their structural features. Anharmonic analysis involving elastic network interpolation (ENI) is used to generate plausible transition pathways between two given conformations by optimizing a topology-oriented cost function that guarantees a smooth transition without steric clashes. The quality of the computed pathways is evaluated based on their various facets, including topology, energy cost and compatibility with the NMA results. There are also two unique features of KOSMOS that distinguish it from other morph servers: (i) the versatility in the coarse-graining methods and (ii) the various connection rules in the ENM. The models enable us to analyze macromolecular dynamics with the maximum degrees of freedom by combining a variety of ENMs from full-atom to coarse-grained, backbone and hybrid models with one connection rule, such as distance-cutoff, number-cutoff or chemical-cutoff. KOSMOS is available at http://bioengineering.skku.ac.kr/kosmos. PMID:22669912

In situ growth, structure, and real-time chemical reactivity of well-defined CeO x-Ru(0001) model surfaces

DOE PAGES

Grinter, David C.; Senanayake, Sanjaya D.; Flege, Jan Ingo

2016-11-15

Ceria is an important material for chemical conversion processes in catalysis. Its intrinsic properties as a reducible oxide can be exploited to achieve catalytic selectivity and activity. However, numerous phenomenological characteristics of ceria remain unknown and its active nature is ever slowly being unraveled. Well defined models of ceria (111) are an important way to systematically study these properties and take advantage of new in situ methods that require pristine materials that allow for the interrogation of the most fundamental traits of this material. The ceria-Ru(0001) model is now the most well studied model surface with numerous aspects of itsmore » preparation, atomic structure and reactivity studied by several groups. The preparation of CeO x structures oriented with a (111) surface termination can be achieved through molecular beam deposition, facilitating the growth of well-defined nanostructures, microparticles, and films on the Ru(0001) surface. The growth mechanism exploits the epitaxial relationship between CeOx and Ru to form a carpet mode of well oriented layers of Osingle bondCesingle bondO. These models can be studied to unravel the atomic structure and the oxidation state (Ce 4+ and Ce 3+), as prepared and under redox conditions (reduction/oxidation) or with reaction using reactants (e.g., H 2, methanol). Here, we present a discussion of these most recent observations pertaining to the growth mode, arrangement of atoms on the surface, characteristic chemical state, and redox chemistry of the CeO x-Ru surface. As a result, with insights from these studies we propose new strategies to further unravel the chemistry of ceria.« less

Transportation Energy Futures: Freight Transportation Modal Shares: Scenarios for a Low-Carbon Future

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

Brogan, J. J.; Aeppli, A. E.; Brown, D. F.

2013-03-01

Freight transportation modes—truck, rail, water, air, and pipeline—each serve a distinct share of the freight transportation market. A variety of factors influence the modes chosen by shippers, carriers, and others involved in freight supply chains. Analytical methods can be used to project future modal shares, and federal policy actions could influence future freight mode choices. This report considers how these topics have been addressed in existing literature and offers insights on federal policy decisions with the potential to prompt mode choices that reduce energy use and greenhouse gas emissions.

Mode conversion in metal-insulator-metal waveguide with a shifted cavity

NASA Astrophysics Data System (ADS)

Wang, Yueke; Yan, Xin

2018-01-01

We propose a method, which is utilized to achieve the plasmonic mode conversion in metal-insulator-metal (MIM) waveguide, theoretically. Our proposed structure is composed of bus waveguides and a shifted cavity. The shifted cavity can choose out a plasmonic mode (a- or s-mode) when it is in Fabry-Perot (FP) resonance. The length of the shifted cavity L is carefully chosen, and our structure can achieve the mode conversion between a- and s-mode in the communication region. Besides, our proposed structure can also achieve plasmonic mode-division multiplexing. All the numerical simulations are carried on by the finite element method to verify our design.

Magnetic alloy nanowire arrays with different lengths: Insights into the crossover angle of magnetization reversal process

NASA Astrophysics Data System (ADS)

Samanifar, S.; Alikhani, M.; Almasi Kashi, M.; Ramazani, A.; Montazer, A. H.

2017-05-01

Nanoscale magnetic alloy wires are being actively investigated, providing fundamental insights into tuning properties in magnetic data storage and processing technologies. However, previous studies give trivial information about the crossover angle of magnetization reversal process in alloy nanowires (NWs). Here, magnetic alloy NW arrays with different compositions, composed of Fe, Co and Ni have been electrochemically deposited into hard-anodic aluminum oxide templates with a pore diameter of approximately 150 nm. Under optimized conditions of alumina barrier layer and deposition bath concentrations, the resulting alloy NWs with aspect ratio and saturation magnetization (Ms) up to 550 and 1900 emu cm-3, respectively, are systematically investigated in terms of composition, crystalline structure and magnetic properties. Using angular dependence of coercivity extracted from hysteresis loops, the reversal processes are evaluated, indicating non-monotonic behavior. The crossover angle (θc) is found to depend on NW length and Ms. At a constant Ms, increasing NW length decreases θc, thereby decreasing the involvement of vortex mode during the magnetization reversal process. On the other hand, decreasing Ms decreases θc in large aspect ratio (>300) alloy NWs. Phenomenologically, it is newly found that increasing Ni content in the composition decreases θc. The angular first-order reversal curve (AFORC) measurements including the irreversibility of magnetization are also investigated to gain a more detailed insight into θc.

The crystal structure of N-acetyl-L-glutamate synthase from Neisseria gonorrhoeae provides insights into mechanisms of catalysis and regulation.

PubMed

Shi, Dashuang; Sagar, Vatsala; Jin, Zhongmin; Yu, Xiaolin; Caldovic, Ljubica; Morizono, Hiroki; Allewell, Norma M; Tuchman, Mendel

2008-03-14

The crystal structures of N-acetylglutamate synthase (NAGS) in the arginine biosynthetic pathway of Neisseria gonorrhoeae complexed with acetyl-CoA and with CoA plus N-acetylglutamate have been determined at 2.5- and 2.6-A resolution, respectively. The monomer consists of two separately folded domains, an amino acid kinase (AAK) domain and an N-acetyltransferase (NAT) domain connected through a 10-A linker. The monomers assemble into a hexameric ring that consists of a trimer of dimers with 32-point symmetry, inner and outer ring diameters of 20 and 100A, respectively, and a height of 110A(.) Each AAK domain interacts with the cognate domains of two adjacent monomers across two 2-fold symmetry axes and with the NAT domain from a second monomer of the adjacent dimer in the ring. The catalytic sites are located within the NAT domains. Three active site residues, Arg316, Arg425, and Ser427, anchor N-acetylglutamate in a position at the active site to form hydrogen bond interactions to the main chain nitrogen atoms of Cys356 and Leu314, and hydrophobic interactions to the side chains of Leu313 and Leu314. The mode of binding of acetyl-CoA and CoA is similar to other NAT family proteins. The AAK domain, although catalytically inactive, appears to bind arginine. This is the first reported crystal structure of any NAGS, and it provides insights into the catalytic function and arginine regulation of NAGS enzymes.

The Crystal Structure of N-Acetyl-L-glutamate Synthase from Neisseria gonorrhoeae Provides Insights into Mechanisms of Catalysis and Regulation

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

Shi, Dashuang; Sagar, Vatsala; Jin, Zhongmin

2010-01-07

The crystal structures of N-acetylglutamate synthase (NAGS) in the arginine biosynthetic pathway of Neisseria gonorrhoeae complexed with acetyl-CoA and with CoA plus N-acetylglutamate have been determined at 2.5- and 2.6-A resolution, respectively. The monomer consists of two separately folded domains, an amino acid kinase (AAK) domain and an N-acetyltransferase (NAT) domain connected through a 10-A linker. The monomers assemble into a hexameric ring that consists of a trimer of dimers with 32-point symmetry, inner and outer ring diameters of 20 and 100A, respectively, and a height of 110A(.) Each AAK domain interacts with the cognate domains of two adjacent monomersmore » across two 2-fold symmetry axes and with the NAT domain from a second monomer of the adjacent dimer in the ring. The catalytic sites are located within the NAT domains. Three active site residues, Arg316, Arg425, and Ser427, anchor N-acetylglutamate in a position at the active site to form hydrogen bond interactions to the main chain nitrogen atoms of Cys356 and Leu314, and hydrophobic interactions to the side chains of Leu313 and Leu314. The mode of binding of acetyl-CoA and CoA is similar to other NAT family proteins. The AAK domain, although catalytically inactive, appears to bind arginine. This is the first reported crystal structure of any NAGS, and it provides insights into the catalytic function and arginine regulation of NAGS enzymes.« less

Release of Native-like Gaseous Proteins from Electrospray Droplets via the Charged Residue Mechanism: Insights from Molecular Dynamics Simulations.

PubMed

McAllister, Robert G; Metwally, Haidy; Sun, Yu; Konermann, Lars

2015-10-07

The mechanism whereby gaseous protein ions are released from charged solvent droplets during electrospray ionization (ESI) remains a matter of debate. Also, it is unclear to what extent electrosprayed proteins retain their solution structure. Molecular dynamics (MD) simulations offer insights into the temporal evolution of protein systems. Surprisingly, there have been no all-atom simulations of the protein ESI process to date. The current work closes this gap by investigating the behavior of protein-containing aqueous nanodroplets that carry excess positive charge. We focus on "native ESI", where proteins initially adopt their biologically active solution structures. ESI proceeds while the protein remains entrapped within the droplet. Protein release into the gas phase occurs upon solvent evaporation to dryness. Droplet shrinkage is accompanied by ejection of charge carriers (Na(+) for the conditions chosen here), keeping the droplet at ∼85% of the Rayleigh limit throughout its life cycle. Any remaining charge carriers bind to the protein as the final solvent molecules evaporate. The outcome of these events is largely independent of the initial protein charge and the mode of charge carrier binding. ESI charge states and collision cross sections of the MD structures agree with experimental data. Our results confirm the Rayleigh/charged residue model (CRM). Field emission of excess Na(+) plays an ancillary role by governing the net charge of the shrinking droplet. Models that envision protein ejection from the droplet are not supported. Most nascent CRM ions retain native-like conformations. For unfolded proteins ESI likely proceeds along routes that are different from the native state mechanism explored here.

Microscopic insight into thermodynamics of conformational changes of SAP-SLAM complex in signal transduction cascade

NASA Astrophysics Data System (ADS)

Samanta, Sudipta; Mukherjee, Sanchita

2017-04-01

The signalling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, associate with SLAM-associated protein (SAP)-related molecules, composed of single SH2 domain architecture. SAP activates Src-family kinase Fyn after SLAM ligation, resulting in a SLAM-SAP-Fyn complex, where, SAP binds the Fyn SH3 domain that does not involve canonical SH3 or SH2 interactions. This demands insight into this SAP mediated signalling cascade. Thermodynamics of the conformational changes are extracted from the histograms of dihedral angles obtained from the all-atom molecular dynamics simulations of this structurally well characterized SAP-SLAM complex. The results incorporate the binding induced thermodynamic changes of individual amino acid as well as the secondary structural elements of the protein and the solvent. Stabilization of the peptide partially comes through a strong hydrogen bonding network with the protein, while hydrophobic interactions also play a significant role where the peptide inserts itself into a hydrophobic cavity of the protein. SLAM binding widens SAP's second binding site for Fyn, which is the next step in the signal transduction cascade. The higher stabilization and less fluctuation of specific residues of SAP in the Fyn binding site, induced by SAP-SLAM complexation, emerge as the key structural elements to trigger the recognition of SAP by the SH3 domain of Fyn. The thermodynamic quantification of the protein due to complexation not only throws deeper understanding in the established mode of SAP-SLAM interaction but also assists in the recognition of the relevant residues of the protein responsible for alterations in its activity.

Conversion of D-ribulose 5-phosphate to D-xylulose 5-phosphate : new insights from structural and biochemical studies on human RPE.

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

Liang, W.; Ouyang, S.; Shaw, N.

2011-02-01

The pentose phosphate pathway (PPP) confers protection against oxidative stress by supplying NADPH necessary for the regeneration of glutathione, which detoxifies H{sub 2}O{sub 2} into H{sub 2}O and O{sub 2}. RPE functions in the PPP, catalyzing the reversible conversion of D-ribulose 5-phosphate to D-xylulose 5-phosphate and is an important enzyme for cellular response against oxidative stress. Here, using structural, biochemical, and functional studies, we show that human D-ribulose 5-phosphate 3-epimerase (hRPE) uses Fe{sup 2+} for catalysis. Structures of the binary complexes of hRPE with D-ribulose 5-phosphate and D-xylulose 5-phosphate provide the first detailed molecular insights into the binding mode ofmore » physiological ligands and reveal an octahedrally coordinated Fe{sup 2+} ion buried deep inside the active site. Human RPE folds into a typical ({beta}/{alpha}){sub 8} triosephosphate isomerase (TIM) barrel with a loop regulating access to the active site. Two aspartic acids are well positioned to carry out the proton transfers in an acid-base type of reaction mechanism. Interestingly, mutating Ser-10 to alanine almost abolished the enzymatic activity, while L12A and M72A mutations resulted in an almost 50% decrease in the activity. The binary complexes of hRPE reported here will aid in the design of small molecules for modulating the activity of the enzyme and altering flux through the PPP.« less

Microscopic insight into thermodynamics of conformational changes of SAP-SLAM complex in signal transduction cascade.

PubMed

Samanta, Sudipta; Mukherjee, Sanchita

2017-04-28

The signalling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, associate with SLAM-associated protein (SAP)-related molecules, composed of single SH2 domain architecture. SAP activates Src-family kinase Fyn after SLAM ligation, resulting in a SLAM-SAP-Fyn complex, where, SAP binds the Fyn SH3 domain that does not involve canonical SH3 or SH2 interactions. This demands insight into this SAP mediated signalling cascade. Thermodynamics of the conformational changes are extracted from the histograms of dihedral angles obtained from the all-atom molecular dynamics simulations of this structurally well characterized SAP-SLAM complex. The results incorporate the binding induced thermodynamic changes of individual amino acid as well as the secondary structural elements of the protein and the solvent. Stabilization of the peptide partially comes through a strong hydrogen bonding network with the protein, while hydrophobic interactions also play a significant role where the peptide inserts itself into a hydrophobic cavity of the protein. SLAM binding widens SAP's second binding site for Fyn, which is the next step in the signal transduction cascade. The higher stabilization and less fluctuation of specific residues of SAP in the Fyn binding site, induced by SAP-SLAM complexation, emerge as the key structural elements to trigger the recognition of SAP by the SH3 domain of Fyn. The thermodynamic quantification of the protein due to complexation not only throws deeper understanding in the established mode of SAP-SLAM interaction but also assists in the recognition of the relevant residues of the protein responsible for alterations in its activity.

Structural and functional insights into the HIV-1 maturation inhibitor binding pocket.

PubMed

Waki, Kayoko; Durell, Stewart R; Soheilian, Ferri; Nagashima, Kunio; Butler, Scott L; Freed, Eric O

2012-01-01

Processing of the Gag precursor protein by the viral protease during particle release triggers virion maturation, an essential step in the virus replication cycle. The first-in-class HIV-1 maturation inhibitor dimethylsuccinyl betulinic acid [PA-457 or bevirimat (BVM)] blocks HIV-1 maturation by inhibiting the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. A structurally distinct molecule, PF-46396, was recently reported to have a similar mode of action to that of BVM. Because of the structural dissimilarity between BVM and PF-46396, we hypothesized that the two compounds might interact differentially with the putative maturation inhibitor-binding pocket in Gag. To test this hypothesis, PF-46396 resistance was selected for in vitro. Resistance mutations were identified in three regions of Gag: around the CA-SP1 cleavage site where BVM resistance maps, at CA amino acid 201, and in the CA major homology region (MHR). The MHR mutants are profoundly PF-46396-dependent in Gag assembly and release and virus replication. The severe defect exhibited by the inhibitor-dependent MHR mutants in the absence of the compound is also corrected by a second-site compensatory change far downstream in SP1, suggesting structural and functional cross-talk between the HIV-1 CA MHR and SP1. When PF-46396 and BVM were both present in infected cells they exhibited mutually antagonistic behavior. Together, these results identify Gag residues that line the maturation inhibitor-binding pocket and suggest that BVM and PF-46396 interact differentially with this putative pocket. These findings provide novel insights into the structure-function relationship between the CA MHR and SP1, two domains of Gag that are critical to both assembly and maturation. The highly conserved nature of the MHR across all orthoretroviridae suggests that these findings will be broadly relevant to retroviral assembly. Finally, the results presented here provide a framework for increased structural understanding of HIV-1 maturation inhibitor activity.

Coupling of small, low-loss hexapole mode with photonic crystal slab waveguide mode.

PubMed

Kim, Guk-Hyun; Lee, Yong-Hee; Shinya, Akihiko; Notomi, Masaya

2004-12-27

Coupling characteristics between the single-cell hexapole mode and the triangular-lattice photonic crystal slab waveguide mode is studied by the finite-difference time-domain method. The single-cell hexapole mode has a high quality factor (Q) of 3.3Chi106 and a small modal volume of 1.18(lambda/n)3. Based on the symmetry, three representative types of coupling geometries (shoulder-couple, butt-couple and side-couple structures) are selected and tested. The coupling efficiency shows strong dependence on the transverse overlap of the cavity mode and the waveguide mode over the region of the waveguide. The shoulder-couple structure shows best coupling characteristics among three tested structures. For example, two shouldercouple waveguides and a hexapole cavity result in a high performance resonant-tunneling-filter with Q of 9.7Chi105 and transmittance of 0.48. In the side-couple structure, the coupling strength is much weaker than that of the shoulder-couple structure because of the poor spatial overlap between the mode profiles. In the direct-couple structure, the energy transfer from the cavity to the waveguide is prohibited because of the symmetry mismatch and no coupling is observed.

Ab initio prediction of superdense tetragonal and monoclinic polymorphs of carbon

DOE PAGES

Li, Zhen -Zhen; Wang, Jian -Tao; Xu, Li -Fang; ...

2016-11-02

The design and synthesis of three-dimensional denser carbons are one of the hot issues in condensed matter physics because of their fascinating properties. Here we identify by ab initio calculations several tetragonal and monoclinic polymorphs of carbon that adopt the t32, t32*, m32, and m32* structures in P4¯2 1c, P4 32 12, P2 1/c, and C2 symmetry, respectively. These carbon polymorphs have large 32-atom unit cells in all-sp 3 bonding networks comprising five- and six-membered rings that are dynamically stable, as verified by a phonon mode analysis. Electronic band structure calculations show that they are insulators with band gaps inmore » the range of 5.19–5.41 eV, close to the calculated band gap of 5.34 eV for diamond. Remarkably, these carbon phases possess an extremely high atom number density exceeding that of diamond. Lastly, the present results establish different types of carbon phases and offer insights into their outstanding structural and electronic properties.« less

Bipartite Structure of the 5s Ribosomal Gene Family in a Drosophila Melanogaster Strain, and Its Evolutionary Implications

PubMed Central

Samson, M. L.; Wegnez, M.

1988-01-01

Knowledge of multigenic family organization should provide insight into their mode of evolution. Accordingly, we characterized the 5S ribosomal gene family in the Drosophila melanogaster strain ry(506). The 5S genes in this strain display a striking HindIII restriction difference compared to the ``standard'' D. melanogaster 5S genes. The sequence of three ry(506) 5S genes was determined. We show that the HindIII restriction site heterogeneity within the ry(506) 5S family most probably results from the same point mutation, suggesting that a single 5S variant was propagated into the 5S cluster of this strain. Furthermore, we demonstrate that the structural organization of the 5S genes in ry(506) is a bipartite structure, i.e., that about 40% of the 5S genes constitute a HindIII(+)/HindIII(-) mixed cluster, while those remaining constitute an homogeneous HindIII(-) cluster. The events which might lead to such an heterogeneous pattern are discussed from an evolutionary point of view. PMID:2835290

Structure and function of the interacting domains of Spire and Fmn-family formins.

PubMed

Vizcarra, Christina L; Kreutz, Barry; Rodal, Avital A; Toms, Angela V; Lu, Jun; Zheng, Wei; Quinlan, Margot E; Eck, Michael J

2011-07-19

Evidence for cooperation between actin nucleators is growing. The WH2-containing nucleator Spire and the formin Cappuccino interact directly, and both are essential for assembly of an actin mesh during Drosophila oogenesis. Their interaction requires the kinase noncatalytic C-lobe domain (KIND) domain of Spire and the C-terminal tail of the formin. Here we describe the crystal structure of the KIND domain of human Spir1 alone and in complex with the tail of Fmn2, a mammalian ortholog of Cappuccino. The KIND domain is structurally similar to the C-lobe of protein kinases. The Fmn2 tail is coordinated in an acidic cleft at the base of the domain that appears to have evolved via deletion of a helix from the canonical kinase fold. Our functional analysis of Cappuccino reveals an unexpected requirement for its tail in actin assembly. In addition, we find that the KIND/tail interaction blocks nucleation by Cappuccino and promotes its displacement from filament barbed ends providing insight into possible modes of cooperation between Spire and Cappuccino.

Energy-absorption capability of composite tubes and beams. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Farley, Gary L.; Jones, Robert M.

1989-01-01

In this study the objective was to develop a method of predicting the energy-absorption capability of composite subfloor beam structures. Before it is possible to develop such an analysis capability, an in-depth understanding of the crushing process of composite materials must be achieved. Many variables affect the crushing process of composite structures, such as the constituent materials' mechanical properties, specimen geometry, and crushing speed. A comprehensive experimental evaluation of tube specimens was conducted to develop insight into how composite structural elements crush and what are the controlling mechanisms. In this study the four characteristic crushing modes, transverse shearing, brittle fracturing, lamina bending, and local buckling were identified and the mechanisms that control the crushing process defined. An in-depth understanding was developed of how material properties affect energy-absorption capability. For example, an increase in fiber and matrix stiffness and failure strain can, depending upon the configuration of the tube, increase energy-absorption capability. An analysis to predict the energy-absorption capability of composite tube specimens was developed and verified. Good agreement between experiment and prediction was obtained.

Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

PubMed Central

2016-01-01

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins. PMID:25781223

Structural insights into Rhino-Deadlock complex for germline piRNA cluster specification.

PubMed

Yu, Bowen; Lin, Yu An; Parhad, Swapnil S; Jin, Zhaohui; Ma, Jinbiao; Theurkauf, William E; Zhang, Zz Zhao; Huang, Ying

2018-06-01

PIWI-interacting RNAs (piRNAs) silence transposons in germ cells to maintain genome stability and animal fertility. Rhino, a rapidly evolving heterochromatin protein 1 (HP1) family protein, binds Deadlock in a species-specific manner and so defines the piRNA-producing loci in the Drosophila genome. Here, we determine the crystal structures of Rhino-Deadlock complex in Drosophila melanogaster and simulans In both species, one Rhino binds the N-terminal helix-hairpin-helix motif of one Deadlock protein through a novel interface formed by the beta-sheet in the Rhino chromoshadow domain. Disrupting the interface leads to infertility and transposon hyperactivation in flies. Our structural and functional experiments indicate that electrostatic repulsion at the interaction interface causes cross-species incompatibility between the sibling species. By determining the molecular architecture of this piRNA-producing machinery, we discover a novel HP1-partner interacting mode that is crucial to piRNA biogenesis and transposon silencing. We thus explain the cross-species incompatibility of two sibling species at the molecular level. © 2018 The Authors.

Analysis of intermediate period correlations of coda from deep earthquakes

NASA Astrophysics Data System (ADS)

Poli, Piero; Campillo, Michel; de Hoop, Maarten

2017-11-01

We aim at assessing quantitatively the nature of the signals that appear in coda wave correlations at periods >20 s. These signals contain transient constituents with arrival times corresponding to deep seismic phases. These (body-wave) constituents can be used for imaging. To evaluate this approach, we calculate the autocorrelations of the vertical component seismograms for the Mw 8.4 sea of Okhotsk earthquake at 400 stations in the Eastern US, using data from 1 h before to 50 h after the earthquake. By using array analysis and modes identification, we discover the dominant role played by high quality factor normal modes in the emergence of strong coherent phases as ScS-like, and P'P'df-like. We then make use of geometrical quantization to derive the constituent rays associated with particular modes, and gain insights about the ballistic reverberation of the rays that contributes to the emergence of body waves. Our study indicates that the signals measured in the spatially averaged autocorrelations have a physical significance, but a direct interpretation of ScS-like and P'P'df-like is not trivial. Indeed, even a single simple measurement of long period late coda in a limited period band could provide valuable information on the deep structure by using the temporal information of its autocorrelation, a procedure that could be also useful for planetary exploration.

Integration of Quartz Crystal Microbalance-Dissipation and Reflection-Mode Localized Surface Plasmon Resonance Sensors for Biomacromolecular Interaction Analysis.

PubMed

Ferhan, Abdul Rahim; Jackman, Joshua A; Cho, Nam-Joon

2016-12-20

The combination of label-free, surface-sensitive measurement techniques based on different physical principles enables detailed characterization of biomacromolecular interactions at solid-liquid interfaces. To date, most combined measurement systems have involved experimental techniques with similar probing volumes, whereas the potential of utilizing techniques with different surface sensitivities remains largely unexplored, especially for data interpretation. Herein, we report a combined measurement approach that integrates a conventional quartz crystal microbalance-dissipation (QCM-D) setup with a reflection-mode localized surface plasmon (LSPR) sensor. Using this platform, we investigate vesicle adsorption on a titanium oxide-coated sensing substrate along with the amphipathic, α-helical (AH) peptide-induced structural transformation of surface-adsorbed lipid vesicles into a supported lipid bilayer (SLB) as a model biomacromolecular interaction. While the QCM-D and LSPR signals both detected mass uptake arising from vesicle adsorption, tracking the AH peptide-induced structural transformation revealed more complex measurement responses based on the different surface sensitivities of the two techniques. In particular, the LSPR signal recorded an increase in optical mass near the sensor surface which indicated SLB formation, whereas the QCM-D signals detected a significant loss in net acoustic mass due to excess lipid and coupled solvent leaving the probing volume. Importantly, these measurement capabilities allowed us to temporally distinguish the process of SLB formation at the sensor surface from the overall structural transformation process. Looking forward, these label-free measurement capabilities to simultaneously probe adsorbates at multiple length scales will provide new insights into complex biomacromolecular interactions.

A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation

PubMed Central

Qin, Feng

2015-01-01

The transient receptor potential (TRP) channels act as key sensors of various chemical and physical stimuli in eukaryotic cells. Despite years of study, the molecular mechanisms of TRP channel activation remain unclear. To elucidate the structural, dynamic, and energetic basis of gating in TRPV1 (a founding member of the TRPV subfamily), we performed coarse-grained modeling and all-atom molecular dynamics (MD) simulation based on the recently solved high resolution structures of the open and closed form of TRPV1. Our coarse-grained normal mode analysis captures two key modes of collective motions involved in the TRPV1 gating transition, featuring a quaternary twist motion of the transmembrane domains (TMDs) relative to the intracellular domains (ICDs). Our transition pathway modeling predicts a sequence of structural movements that propagate from the ICDs to the TMDs via key interface domains (including the membrane proximal domain and the C-terminal domain), leading to sequential opening of the selectivity filter followed by the lower gate in the channel pore (confirmed by modeling conformational changes induced by the activation of ICDs). The above findings of coarse-grained modeling are robust to perturbation by lipids. Finally, our MD simulation of the ICD identifies key residues that contribute differently to the nonpolar energy of the open and closed state, and these residues are predicted to control the temperature sensitivity of TRPV1 gating. These computational predictions offer new insights to the mechanism for heat activation of TRPV1 gating, and will guide our future electrophysiology and mutagenesis studies. PMID:25918362

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

Grinter, David C.; Senanayake, Sanjaya D.; Flege, Jan Ingo

Ceria is an important material for chemical conversion processes in catalysis. Its intrinsic properties as a reducible oxide can be exploited to achieve catalytic selectivity and activity. However, numerous phenomenological characteristics of ceria remain unknown and its active nature is ever slowly being unraveled. Well defined models of ceria (111) are an important way to systematically study these properties and take advantage of new in situ methods that require pristine materials that allow for the interrogation of the most fundamental traits of this material. The ceria-Ru(0001) model is now the most well studied model surface with numerous aspects of itsmore » preparation, atomic structure and reactivity studied by several groups. The preparation of CeO x structures oriented with a (111) surface termination can be achieved through molecular beam deposition, facilitating the growth of well-defined nanostructures, microparticles, and films on the Ru(0001) surface. The growth mechanism exploits the epitaxial relationship between CeOx and Ru to form a carpet mode of well oriented layers of Osingle bondCesingle bondO. These models can be studied to unravel the atomic structure and the oxidation state (Ce 4+ and Ce 3+), as prepared and under redox conditions (reduction/oxidation) or with reaction using reactants (e.g., H 2, methanol). Here, we present a discussion of these most recent observations pertaining to the growth mode, arrangement of atoms on the surface, characteristic chemical state, and redox chemistry of the CeO x-Ru surface. As a result, with insights from these studies we propose new strategies to further unravel the chemistry of ceria.« less

Crystal structure of E. coli ZinT with one zinc-binding mode and complexed with citrate.

PubMed

Chen, Jinli; Wang, Lulu; Shang, Fei; Dong, Yuesheng; Ha, Nam-Chul; Nam, Ki Hyun; Quan, Chunshan; Xu, Yongbin

2018-06-02

The ZnuABC ATP-binding cassette transporter found in gram-negative bacteria has been implicated in ensuring adequate zinc import into Zn(II)-poor environments. ZinT is an essential component of ZnuABC and contributes to metal transport by transferring metals to ZnuA, which delivers them to ZnuB in periplasmic zinc recruitment. Although several structures of E. coli ZinT have been reported, its zinc-binding sites and oligomeric state have not been clearly identified. Here, we report the crystal structure of E. coli ZinT at 1.76 Å resolution. This structure contains one zinc ion in its calycin-like domain, and this ion is coordinated by three highly conserved histidine residues (His167, His176 and His178). Moreover, three oxygen atoms (O 1 , O 6 and O 7 ) from the citrate molecule interact with zinc, giving the zinc ion stable octahedral coordination. Our EcZinT structure shows the fewest zinc ions bound of all reported EcZinT structures. Crystallographic packing and size exclusion chromatography suggest that EcZinT prefers to form monomers in solution. Our results provide insights into the molecular function of ZinT. Copyright © 2018. Published by Elsevier Inc.

Structural formation of huntingtin-like aggregates probed by small-angle neutron scattering

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

Stanley, Christopher B; Perevozchikova, Tatiana; Berthelier-Jung, Valerie M

2011-01-01

In several neurodegenerative disorders, including Huntington s disease (HD), aspects concerning the earliest of protein structures that form along the aggregation pathway have increasingly gained attention since these particular species are likely to be neurotoxic. We used time-resolved small-angle neutron scattering (SANS) to probe in solution these transient structures formed by peptides having the N-terminal sequence context of mutant huntingtin (Htt) exon 1. We obtained snapshots of the formed aggregates as the kinetic reaction ensued to yield quantitative information on their size and mass. At the early stage, small precursor species with an initial radius of gyration (Rg) of 16.1more » 5.9 and average mass of a dimer to trimer were monitored. Structural growth was treated as two modes with a transition from three-dimensional early aggregate formation to two-dimensional fibril growth and association. Our SANS results on the internal structure of the mature fibrils demonstrate loose packing with about 1 peptide per 4.75 -sheet repeat distance, which is shown to be quantitatively consistent with a -helix model. This research provides new insights into the structures forming along the pathway of Htt exon 1 aggregation and should assist in determining the role that precursors play in neuronal toxicity.« less

University Students' Knowledge Structures and Informal Reasoning on the Use of Genetically Modified Foods: Multidimensional Analyses

NASA Astrophysics Data System (ADS)

Wu, Ying-Tien

2013-10-01

This study aims to provide insights into the role of learners' knowledge structures about a socio-scientific issue (SSI) in their informal reasoning on the issue. A total of 42 non-science major university students' knowledge structures and informal reasoning were assessed with multidimensional analyses. With both qualitative and quantitative analyses, this study revealed that those students with more extended and better-organized knowledge structures, as well as those who more frequently used higher-order information processing modes, were more oriented towards achieving a higher-level informal reasoning quality. The regression analyses further showed that the "richness" of the students' knowledge structures explained 25 % of the variation in their rebuttal construction, an important indicator of reasoning quality, indicating the significance of the role of students' sophisticated knowledge structure in SSI reasoning. Besides, this study also provides some initial evidence for the significant role of the "core" concept within one's knowledge structure in one's SSI reasoning. The findings in this study suggest that, in SSI-based instruction, science instructors should try to identify students' core concepts within their prior knowledge regarding the SSI, and then they should try to guide students to construct and structure relevant concepts or ideas regarding the SSI based on their core concepts. Thus, students could obtain extended and well-organized knowledge structures, which would then help them achieve better learning transfer in dealing with SSIs.

CryoEM and Molecular Dynamics of the Circadian KaiB-KaiC Complex Indicates That KaiB Monomers Interact with KaiC and Block ATP Binding Clefts

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

Villarreal, Seth A.; Pattanayek, Rekha; Williams, Dewight R.

The circadian control of cellular processes in cyanobacteria is regulated by a posttranslational oscillator formed by three Kai proteins. During the oscillator cycle, KaiA serves to promote autophosphorylation of KaiC while KaiB counteracts this effect. Here, we present a crystallographic structure of the wild-type Synechococcus elongatus KaiB and a cryo-electron microscopy (cryoEM) structure of a KaiBC complex. The crystal structure shows the expected dimer core structure and significant conformational variations of the KaiB C-terminal region, which is functionally important in maintaining rhythmicity. The KaiBC sample was formed with a C-terminally truncated form of KaiC, KaiC-Δ489, which is persistently phosphorylated. Themore » KaiB–KaiC-Δ489 structure reveals that the KaiC hexamer can bind six monomers of KaiB, which form a continuous ring of density in the KaiBC complex. We performed cryoEM-guided molecular dynamics flexible fitting simulations with crystal structures of KaiB and KaiC to probe the KaiBC protein–protein interface. This analysis indicated a favorable binding mode for the KaiB monomer on the CII end of KaiC, involving two adjacent KaiC subunits and spanning an ATP binding cleft. A KaiC mutation, R468C, which has been shown to affect the affinity of KaiB for KaiC and lengthen the period in a bioluminescence rhythm assay, is found within the middle of the predicted KaiBC interface. The proposed KaiB binding mode blocks access to the ATP binding cleft in the CII ring of KaiC, which provides insight into how KaiB might influence the phosphorylation status of KaiC.« less

Probing the structural dynamics of the CRISPR-Cas9 RNA-guided DNA-cleavage system by coarse-grained modeling.

PubMed

Zheng, Wenjun

2017-02-01

In the adaptive immune systems of many bacteria and archaea, the Cas9 endonuclease forms a complex with specific guide/scaffold RNA to identify and cleave complementary target sequences in foreign DNA. This DNA targeting machinery has been exploited in numerous applications of genome editing and transcription control. However, the molecular mechanism of the Cas9 system is still obscure. Recently, high-resolution structures have been solved for Cas9 in different structural forms (e.g., unbound forms, RNA-bound binary complexes, and RNA-DNA-bound tertiary complexes, corresponding to an inactive state, a pre-target-bound state, and a cleavage-competent or product state), which offered key structural insights to the Cas9 mechanism. To further probe the structural dynamics of Cas9 interacting with RNA and DNA at the amino-acid level of details, we have performed systematic coarse-grained modeling using an elastic network model and related analyses. Our normal mode analysis predicted a few key modes of collective motions that capture the observed conformational changes featuring large domain motions triggered by binding of RNA and DNA. Our flexibility analysis identified specific regions with high or low flexibility that coincide with key functional sites (such as DNA/RNA-binding sites, nuclease cleavage sites, and key hinges). We also identified a small set of hotspot residues that control the energetics of functional motions, which overlap with known functional sites and offer promising targets for future mutagenesis efforts to improve the specificity of Cas9. Finally, we modeled the conformational transitions of Cas9 from the unbound form to the binary complex and then the tertiary complex, and predicted a distinct sequence of domain motions. In sum, our findings have offered rich structural and dynamic details relevant to the Cas9 machinery, and will guide future investigation and engineering of the Cas9 systems. Proteins 2017; 85:342-353. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations

NASA Astrophysics Data System (ADS)

Martins, Luan Carvalho; Torres, Pedro Henrique Monteiro; de Oliveira, Renata Barbosa; Pascutti, Pedro Geraldo; Cino, Elio A.; Ferreira, Rafaela Salgado

2018-05-01

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC50 = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.

Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations

NASA Astrophysics Data System (ADS)

Martins, Luan Carvalho; Torres, Pedro Henrique Monteiro; de Oliveira, Renata Barbosa; Pascutti, Pedro Geraldo; Cino, Elio A.; Ferreira, Rafaela Salgado

2018-03-01

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC50 = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.

Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations.

PubMed

Martins, Luan Carvalho; Torres, Pedro Henrique Monteiro; de Oliveira, Renata Barbosa; Pascutti, Pedro Geraldo; Cino, Elio A; Ferreira, Rafaela Salgado

2018-05-01

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC 50  = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.

Fault-controlled development of shallow hydrothermal systems: Structural and mineralogical insights from the Southern Andes

NASA Astrophysics Data System (ADS)

Roquer, T.; Arancibia, G.; Rowland, J. V.; Iturrieta, P. C.; Morata, D.; Cembrano, J. M.

2017-12-01

Paleofluid-transporting systems can be recognized as meshes of fracture-filled veins in eroded zones of extinct hydrothermal systems. Here we conducted meso-microstructural analysis and mechanical modeling from two exhumed exposures of the faults governing regional tectonics of the Southern Andes: the Liquiñe-Ofqui Fault System (LOFS) and the Andean Transverse Faults (ATF). A total of 107 fractures in both exposures were analyzed. The ATF specific segment shows two tectonic solutions that can be modeled as Andersonian and non-Andersonian tectonic regimes: (1) shear (mode II/III) failure occurs at differential stresses > 28 MPa and fluid pressures < 40-80% lithostatic in the Andersonian regime; and (2) sporadic hybrid extensional + shear (modes I + II/III) failure occurs at differential stresses < 20 MPa and anomalously high fluid pressures > 85-98% lithostatic in the non-Andersonian regime. Additionally, the LOFS exposure cyclically fails in extension (mode I) or extension + shear (modes I + II/III) in the Andersonian regime, at differential stresses < 28 MPa and fluid pressures > 40-80% lithostatic. In areas of spatial interaction between ATF and LOFS, these conditions might favor: (1) the storage of overpressured fluids in hydrothermal systems associated with the ATF faults, and (2) continuous fluid flow through vertical conduits in the LOFS faults. These observations suggest that such intersections are highly probable locations for concentrated hydrothermal activity, which must be taken into consideration for further geothermal exploration. ACKNOWLEDGEMENTS. PhD CONICYT grants, Centro de Excelencia en Geotermia de los Andes (CEGA-FONDAP/CONICYT Project #15090013), FONDECYT Project #1130030 and Project CONICYT REDES #140036.

A Comparative Study of [CaEDTA](2-) and [MgEDTA](2-): Structural and Dynamical Insights from Quantum Mechanical Charge Field Molecular Dynamics.

PubMed

Tirler, Andreas O; Hofer, Thomas S

2015-07-09

Structure and dynamics of [MgEDTA](2-) and [CaEDTA](2-) complexes in aqueous solution have been investigated via quantum mechanical/molecular mechanical (QM/MM) simulations. While for the first a 6-fold octahedral complex has been observed, the presence of an additional coordinating water ligand has been observed in the latter case. Because of rapidly exchanging water molecules, this 7-fold coordination complex was found to form pentagonal bipyramidal as well as capped trigonal prismatic configurations along the simulation interchanging on the picosecond time scale. Also in the case of [MgEDTA](2-) a trigonal prismatic configuration has been observed for a very short time period of approximately 1 ps. This work reports for the first time the presence of trigonal prismatic structures observed in the coordination sphere of [MgEDTA](2-) and [CaEDTA](2-) complexes in aqueous solution. In addition to the detailed characterization of structure and dynamics of the systems, the prediction of the associated infrared spectra indicates that the ion-water vibrational mode found at approximately 250 cm(-1) provides a distinctive measure to experimentally detect the presence of the coordinating water molecule via low-frequency IR setups.

Insights into molecular plasticity in protein complexes from Trm9-Trm112 tRNA modifying enzyme crystal structure.

PubMed

Létoquart, Juliette; van Tran, Nhan; Caroline, Vonny; Aleksandrov, Alexey; Lazar, Noureddine; van Tilbeurgh, Herman; Liger, Dominique; Graille, Marc

2015-12-15

Most of the factors involved in translation (tRNA, rRNA and proteins) are subject to post-transcriptional and post-translational modifications, which participate in the fine-tuning and tight control of ribosome and protein synthesis processes. In eukaryotes, Trm112 acts as an obligate activating platform for at least four methyltransferases (MTase) involved in the modification of 18S rRNA (Bud23), tRNA (Trm9 and Trm11) and translation termination factor eRF1 (Mtq2). Trm112 is then at a nexus between ribosome synthesis and function. Here, we present a structure-function analysis of the Trm9-Trm112 complex, which is involved in the 5-methoxycarbonylmethyluridine (mcm(5)U) modification of the tRNA anticodon wobble position and hence promotes translational fidelity. We also compare the known crystal structures of various Trm112-MTase complexes, highlighting the structural plasticity allowing Trm112 to interact through a very similar mode with its MTase partners, although those share less than 20% sequence identity. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Structural Basis of Interaction between Urokinase-Type Plasminogen Activator and Its Receptor

PubMed Central

Barinka, Cyril; Parry, Graham; Callahan, Jennifer; Shaw, David E.; Kuo, Alice; Bdeir, Khalil; Cines, Douglas B.; Mazar, Andrew; Lubkowski, Jacek

2009-01-01

Summary Recent studies indicate that binding of urokinase-type plasminogen activator (uPA) to its high affinity receptor (uPAR), orchestrates uPAR interactions with other cellular components that play a pivotal role in diverse (patho-)physiological processes including wound healing, angiogenesis, inflammation, and cancer metastasis. However, notwithstanding the wealth of biochemical data available describing the activities of uPAR, little is known as to the exact mode of uPAR-uPA interactions and the presumed conformational changes that accompanying uPA-uPAR engagement. Here we report the crystal structure of soluble urokinase plasminogen activator receptor (suPAR), which contains the three domains of the wild-type receptor but lacks the cell surface anchoring sequence, in complex with the amino terminal fragment of urokinase-type plasminogen activator (ATF), at the resolution of 2.8 Å. We also report the 1.9 Å crystal structure of the free ATF. Our results provide a structural basis, represented by conformational changes induced in uPAR, for several published biochemical observations describing the nature of uPAR-uPA interactions and provide insight into mechanisms that may be responsible for the cellular responses induced by uPA binding. PMID:16979660

Hematin−Hematin Self-Association States Involved in the Formation and Reactivity of the Malaria Parasite Pigment, Hemozoin

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

Klonis, Nectarios; Dilanian, Ruben; Hanssen, Eric

The malaria parasite pigment, hemozoin, is a crystal of ferriprotoporphyrin IX (FP-Fe(III)), a product of hemoglobin digestion. Hemozoin formation is essential for FP-Fe(III) detoxification in the parasite; it is the main target of quinoline antimalarials and can modulate immune and inflammation responses. To gain further insight into the likely mechanisms of crystal formation and hemozoin reactivity, we have reanalyzed the crystal structure data for {beta}-hematin and solved the crystal structure of Plasmodium falciparum hemozoin. The analysis reveals that the structures are very similar and highlights two previously unexplored modes of FP-Fe(III) self-association involving {pi}-{pi} interactions that may initiate crystal formationmore » and help to stabilize the extended structure. Hemozoin can be considered to be a crystal composed of {pi}-{pi} dimers stabilized by iron-carboxylate linkages. As a result, it is predicted that two surfaces of the crystal would consist of {pi}-{pi} dimers with Fe(III) partly exposed to solvent and capable of undergoing redox reactions. Accordingly, we demonstrate that the crystal possesses both general peroxidase activity and the ability to cause lipid oxidation.« less

Molecular Architecture and Functional Analysis of NetB, a Pore-forming Toxin from Clostridium perfringens*

PubMed Central

Savva, Christos G.; Fernandes da Costa, Sérgio P.; Bokori-Brown, Monika; Naylor, Claire E.; Cole, Ambrose R.; Moss, David S.; Titball, Richard W.; Basak, Ajit K.

2013-01-01

NetB is a pore-forming toxin produced by Clostridium perfringens and has been reported to play a major role in the pathogenesis of avian necrotic enteritis, a disease that has emerged due to the removal of antibiotics in animal feedstuffs. Here we present the crystal structure of the pore form of NetB solved to 3.9 Å. The heptameric assembly shares structural homology to the staphylococcal α-hemolysin. However, the rim domain, a region that is thought to interact with the target cell membrane, shows sequence and structural divergence leading to the alteration of a phosphocholine binding pocket found in the staphylococcal toxins. Consistent with the structure we show that NetB does not bind phosphocholine efficiently but instead interacts directly with cholesterol leading to enhanced oligomerization and pore formation. Finally we have identified conserved and non-conserved amino acid positions within the rim loops that significantly affect binding and toxicity of NetB. These findings present new insights into the mode of action of these pore-forming toxins, enabling the design of more effective control measures against necrotic enteritis and providing potential new tools to the field of bionanotechnology. PMID:23239883

The Structural Basis for Recognition of the PreQ0 Metabolite by an Unusually Small Riboswitch Aptamer Domain*S⃞♦

PubMed Central

Spitale, Robert C.; Torelli, Andrew T.; Krucinska, Jolanta; Bandarian, Vahe; Wedekind, Joseph E.

2009-01-01

Riboswitches are RNA elements that control gene expression through metabolite binding. The preQ1 riboswitch exhibits the smallest known ligand-binding domain and is of interest for its economical organization and high affinity interactions with guanine-derived metabolites required to confer tRNA wobbling. Here we present the crystal structure of a preQ1 aptamer domain in complex with its precursor metabolite preQ0. The structure is highly compact with a core that features a stem capped by a well organized decaloop. The metabolite is recognized within a deep pocket via Watson-Crick pairing with C15. Additional hydrogen bonds are made to invariant bases U6 and A29. The ligand-bound state confers continuous helical stacking throughout the core fold, thus providing a platform to promote Watson-Crick base pairing between C9 of the decaloop and the first base of the ribosome-binding site, G33. The structure offers insight into the mode of ribosome-binding site sequestration by a minimal RNA fold stabilized by metabolite binding and has implications for understanding the molecular basis by which bacterial genes are regulated. PMID:19261617

ITG modes in the presence of inhomogeneous field-aligned flow

NASA Astrophysics Data System (ADS)

Sen, S.; McCarthy, D. R.; Lontano, M.; Lazzaro, E.; Honary, F.

2010-02-01

In a recent paper, Varischetti et al. (Plasma Phys. Contr. F. 2008, 50, 105008-1-15) have found that in a slab geometry the effect of the flow shear in the field-aligned parallel flow on the linear mode stability of the ion temperature gradient (ITG)-driven modes is not very prominent. They found that the flow shear also has a negligible effect on the mode characteristics. The work in this paper shows that the inclusion of flow curvature in the field-aligned flow can have a considerable effect on the mode stability; it can also change the mode structure so as to effect the mixing length transport in the core region of a fusion device. Flow shear, on the other hand, has indeed an insignificant role in the mode stability and mode structure. Inhomogeneous field-aligned flow should therefore still be considered for a viable candidate in controlling the ITG mode stability and mode structure.

Whispering-gallery-mode-based seismometer

DOEpatents

Fourguette, Dominique Claire; Otugen, M Volkan; Larocque, Liane Marie; Ritter, Greg Aan; Meeusen, Jason Jeffrey; Ioppolo, Tindaro

2014-06-03

A whispering-gallery-mode-based seismometer provides for receiving laser light into an optical fiber, operatively coupling the laser light from the optical fiber into a whispering-gallery-mode-based optical resonator, operatively coupling a spring of a spring-mass assembly to a housing structure; and locating the whispering-gallery-mode-based optical resonator between the spring-mass assembly and the housing structure so as to provide for compressing the whispering-gallery-mode-based optical resonator between the spring-mass assembly and the housing structure responsive to a dynamic compression force from the spring-mass assembly responsive to a motion of the housing structure relative to an inertial frame of reference.

ELM Suppression and Pedestal Structure in I-Mode Plasmas

NASA Astrophysics Data System (ADS)

Walk, John

2013-10-01

The I-mode regime is characterized by the formation of a temperature pedestal and enhanced energy confinement (H98 up to 1.2), without an accompanying density pedestal or drop in particle transport. Unlike ELMy H-modes, I-mode operation appears to have naturally-occurring suppression of large ELMs in addition to its highly favorable scalings of pedestal structure (and therefore overall performance). Instead, continuous Weakly Coherent Modes help to regulate density. Extensive study of the ELMy H-mode has led to the development of the EPED model, which utilizes calculations of coupled peeling-ballooning MHD modes and kinetic-ballooning mode (KBM) stability limits to predict the pedestal structure preceding an ELM crash. We apply similar tools to the structure and ELM stability of I-mode pedestals. Peeling-ballooning MHD calculations are completed using the ELITE code, showing I-mode pedestals to be generally MHD-stable. Under certain conditions, intermittent ELMs are observed in I-mode at reduced field, typically triggered by sawtooth crashes; modification of the temperature pedestal (and therefore the pressure profile stability) by sawtooth heat pulses is being examined in ELITE. Modeled stability to KBM turbulence in I-mode and ELMy H-mode suggests that typical I-modes are stable against KBM turbulence. Measured I-mode pedestals are significantly wider (more stable) than the width scaling with the square root of poloidal beta characteristic of the KBM-limited pedestals in ELMy H-mode. Finally, we explore scalings of pedestal structure with engineering parameters compared to ELMy H-modes on C-Mod. In particular, we focus on scalings of the pressure pedestal with heating power (and its relation to the favorable scaling of confinement with power in I-mode) and on relationships between heat flux and pedestal temperature gradients. This work is supported by DOE agreement DE-FC02-99ER54512. Theory work at General Atomics is supported by DOE agreement DE-FG02-99ER54309.

Nonlinear Structural Analysis Methodology and Dynamics Scaling of Inflatable Parabolic Reflector Antenna Concepts

NASA Technical Reports Server (NTRS)

Sreekantamurthy, Tham; Gaspar, James L.; Mann, Troy; Behun, Vaughn; Pearson, James C., Jr.; Scarborough, Stephen

2007-01-01

Ultra-light weight and ultra-thin membrane inflatable antenna concepts are fast evolving to become the state-of-the-art antenna concepts for deep-space applications. NASA Langley Research Center has been involved in the structural dynamics research on antenna structures. One of the goals of the research is to develop structural analysis methodology for prediction of the static and dynamic response characteristics of the inflatable antenna concepts. This research is focused on the computational studies to use nonlinear large deformation finite element analysis to characterize the ultra-thin membrane responses of the antennas. Recently, structural analyses have been performed on a few parabolic reflector antennas of varying size and shape, which are referred in the paper as 0.3 meters subscale, 2 meters half-scale, and 4 meters full-scale antenna. The various aspects studied included nonlinear analysis methodology and solution techniques, ways to speed convergence in iterative methods, the sensitivities of responses with respect to structural loads, such as inflation pressure, gravity, and pretension loads in the ground and in-space conditions, and the ultra-thin membrane wrinkling characteristics. Several such intrinsic aspects studied have provided valuable insight into evaluation of structural characteristics of such antennas. While analyzing these structural characteristics, a quick study was also made to assess the applicability of dynamics scaling of the half-scale antenna. This paper presents the details of the nonlinear structural analysis results, and discusses the insight gained from the studies on the various intrinsic aspects of the analysis methodology. The predicted reflector surface characteristics of the three inflatable ultra-thin membrane parabolic reflector antenna concepts are presented as easily observable displacement fringe patterns with associated maximum values, and normal mode shapes and associated frequencies. Wrinkling patterns are presented to show how surface wrinkle progress with increasing tension loads. Antenna reflector surface accuracies were found to be very much dependent on the type and size of the antenna, the reflector surface curvature, reflector membrane supports in terms of spacing of catenaries, as well as the amount of applied load.

Binding of Pediocin PA-1 with Anionic Lipid Induces Model Membrane Destabilization

PubMed Central

Gaussier, Hélène; Lefèvre, Thierry; Subirade, Muriel

2003-01-01

To obtain molecular insights into the action mode of antimicrobial activity of pediocin PA-1, the interactions between this bacteriocin and dimyristoylphosphatidylcholine (DMPC) or dimyristoylphosphatidylglycerol (DMPG) model membranes have been investigated in D2O at pD 6 by Fourier transform infrared spectroscopy. The interactions were monitored with respect to alteration of the secondary structure of pediocin, as registered by the amide I′ band, and phospholipid conformation, as revealed by the methylene νs(CH2) and carbonyl ν(C=O) stretching vibrations. The results show that no interaction between pediocin and DMPC occurs. By contrast, pediocin undergoes a structural reorganization in the presence of DMPG. Upon heating, pediocin self-aggregates, which is not observed for this pD in aqueous solution. The gel-to-crystalline phase transition of DMPG shifts to higher temperatures with a concomitant dehydration of the interfacial region. Our results indicate that pediocin is an extrinsic peptide and that its action mechanism may lie in a destabilization of the cell membrane. PMID:14602640

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

NASA Astrophysics Data System (ADS)

Hutchinson, Jonathan P.; Rowland, Paul; Taylor, Mark R. D.; Christodoulou, Erica M.; Haslam, Carl; Hobbs, Clare I.; Holmes, Duncan S.; Homes, Paul; Liddle, John; Mole, Damian J.; Uings, Iain; Walker, Ann L.; Webster, Scott P.; Mowat, Christopher G.; Chung, Chun-Wa

2017-06-01

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

Statistical inference to advance network models in epidemiology.

PubMed

Welch, David; Bansal, Shweta; Hunter, David R

2011-03-01

Contact networks are playing an increasingly important role in the study of epidemiology. Most of the existing work in this area has focused on considering the effect of underlying network structure on epidemic dynamics by using tools from probability theory and computer simulation. This work has provided much insight on the role that heterogeneity in host contact patterns plays on infectious disease dynamics. Despite the important understanding afforded by the probability and simulation paradigm, this approach does not directly address important questions about the structure of contact networks such as what is the best network model for a particular mode of disease transmission, how parameter values of a given model should be estimated, or how precisely the data allow us to estimate these parameter values. We argue that these questions are best answered within a statistical framework and discuss the role of statistical inference in estimating contact networks from epidemiological data. Copyright © 2011 Elsevier B.V. All rights reserved.

Direct TEM observations of growth mechanisms of two-dimensional MoS2 flakes

PubMed Central

Fei, Linfeng; Lei, Shuijin; Zhang, Wei-Bing; Lu, Wei; Lin, Ziyuan; Lam, Chi Hang; Chai, Yang; Wang, Yu

2016-01-01

A microscopic understanding of the growth mechanism of two-dimensional materials is of particular importance for controllable synthesis of functional nanostructures. Because of the lack of direct and insightful observations, how to control the orientation and the size of two-dimensional material grains is still under debate. Here we discern distinct formation stages for MoS2 flakes from the thermolysis of ammonium thiomolybdates using in situ transmission electron microscopy. In the initial stage (400 °C), vertically aligned MoS2 structures grow in a layer-by-layer mode. With the increasing temperature of up to 780 °C, the orientation of MoS2 structures becomes horizontal. When the growth temperature reaches 850 °C, the crystalline size of MoS2 increases by merging adjacent flakes. Our study shows direct observations of MoS2 growth as the temperature evolves, and sheds light on the controllable orientation and grain size of two-dimensional materials. PMID:27412892

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase.

PubMed

Hutchinson, Jonathan P; Rowland, Paul; Taylor, Mark R D; Christodoulou, Erica M; Haslam, Carl; Hobbs, Clare I; Holmes, Duncan S; Homes, Paul; Liddle, John; Mole, Damian J; Uings, Iain; Walker, Ann L; Webster, Scott P; Mowat, Christopher G; Chung, Chun-Wa

2017-06-12

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

PubMed Central

Hutchinson, Jonathan P.; Rowland, Paul; Taylor, Mark R. D.; Christodoulou, Erica M.; Haslam, Carl; Hobbs, Clare I.; Holmes, Duncan S.; Homes, Paul; Liddle, John; Mole, Damian J.; Uings, Iain; Walker, Ann L.; Webster, Scott P.; Mowat, Christopher G.; Chung, Chun-wa

2017-01-01

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design. PMID:28604669

Probing protein flexibility reveals a mechanism for selective promiscuity

PubMed Central

Pabon, Nicolas A; Camacho, Carlos J

2017-01-01

Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anticancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets. DOI: http://dx.doi.org/10.7554/eLife.22889.001 PMID:28432789

Computer simulation studies on passive recruitment dynamics of lipids induced by the adsorption of charged nanoparticles.

PubMed

Li, Yang

2014-07-07

The recruitment dynamics of lipids in the biomembrane is believed to play an important role in a variety of cellular processes. In this work, we investigate the nanoparticle-induced recruitment dynamics of lipids in the heterogeneous phospholipid bilayers of distearoyl-phosphatidylcholine (DSPC) and dioleoyl-phosphatidylglycerol (DOPG) via coarse-grained molecular dynamics simulations. Three dynamic modes of individual charged DOPG lipid molecules have been taken into account in the recruitment process: lateral diffusion, protrusions, and flip-flops. Based on analysis of the mobility pattern of lipids, structural variations in the membrane as well as activation energy of the structure of lipid eyelids characterized by the potential of mean force, we have concluded that the electrostatic attraction of nanoparticles plays a crucial role in the recruitment process of lipids in phospholipid bilayers. These studies are consistent with experimental observations and to some extent give insight into the origin of some cellular processes such as signaling, formation of lipid rafts, and endocytosis.

Bacterial community compositions of coking wastewater treatment plants in steel industry revealed by Illumina high-throughput sequencing.

PubMed

Ma, Qiao; Qu, Yuanyuan; Shen, Wenli; Zhang, Zhaojing; Wang, Jingwei; Liu, Ziyan; Li, Duanxing; Li, Huijie; Zhou, Jiti

2015-03-01

In this study, Illumina high-throughput sequencing was used to reveal the community structures of nine coking wastewater treatment plants (CWWTPs) in China for the first time. The sludge systems exhibited a similar community composition at each taxonomic level. Compared to previous studies, some of the core genera in municipal wastewater treatment plants such as Zoogloea, Prosthecobacter and Gp6 were detected as minor species. Thiobacillus (20.83%), Comamonas (6.58%), Thauera (4.02%), Azoarcus (7.78%) and Rhodoplanes (1.42%) were the dominant genera shared by at least six CWWTPs. The percentages of autotrophic ammonia-oxidizing bacteria and nitrite-oxidizing bacteria were unexpectedly low, which were verified by both real-time PCR and fluorescence in situ hybridization analyses. Hierarchical clustering and canonical correspondence analysis indicated that operation mode, flow rate and temperature might be the key factors in community formation. This study provides new insights into our understanding of microbial community compositions and structures of CWWTPs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mode structure of a quantum cascade laser

NASA Astrophysics Data System (ADS)

Bogdanov, A. A.; Suris, R. A.

2011-03-01

We analyze the mode structure of a quantum cascade laser (QCL) cavity considering the surface plasmon-polariton modes and familiar modes of hollow resonator jointly, within a single model. We present a comprehensive mode structure analysis of the laser cavity, varying its geometric parameters and free electron concentration inside cavity layers within a wide range. Our analysis covers, in particular, the cases of metal-insulator-metal and insulator-metal-insulator waveguides. We discuss the phenomenon of negative dispersion for eigenmodes in detail and explain the nature of this phenomenon. We specify a waveguide parameters domain in which negative dispersion exists. The mode structure of QCL cavity is considered in the case of the anisotropic electrical properties of the waveguide materials. We show that anisotropy of the waveguide core results in propagation of Langmuir modes that are degenerated in the case of the isotropic core. Comparative analysis of optical losses due to free carrier absorption is presented for different modes within the frequency range from terahertz to ultraviolet frequencies.

PREFACE: Vibrations at surfaces Vibrations at surfaces

NASA Astrophysics Data System (ADS)

Rahman, Talat S.

2011-12-01

This special issue is dedicated to the phenomenon of vibrations at surfaces—a topic that was indispensible a couple of decades ago, since it was one of the few phenomena capable of revealing the nature of binding at solid surfaces. For clean surfaces, the frequencies of modes with characteristic displacement patterns revealed how surface geometry, as well as the nature of binding between atoms in the surface layers, could be different from that in the bulk solid. Dispersion of the surface phonons provided further measures of interatomic interactions. For chemisorbed molecules on surfaces, frequencies and dispersion of the vibrational modes were also critical for determining adsorption sites. In other words, vibrations at surfaces served as a reliable means of extracting information about surface structure, chemisorption and overlayer formation. Experimental techniques, such as electron energy loss spectroscopy and helium-atom-surface scattering, coupled with infra-red spectroscopy, were continually refined and their resolutions enhanced to capture subtleties in the dynamics of atoms and molecules at surfaces. Theoretical methods, whether based on empirical and semi-empirical interatomic potential or on ab initio electronic structure calculations, helped decipher experimental observations and provide deeper insights into the nature of the bond between atoms and molecules in regions of reduced symmetry, as encountered on solid surfaces. Vibrations at surfaces were thus an integral part of the set of phenomena that characterized surface science. Dedicated workshops and conferences were held to explore the variety of interesting and puzzling features revealed in experimental and theoretical investigations of surface vibrational modes and their dispersion. One such conference, Vibrations at Surfaces, first organized by Harald Ibach in Juelich in 1980, continues to this day. The 13th International Conference on Vibrations at Surfaces was held at the University of Central Florida, Orlando, in March 2010. Several speakers at this meeting were invited to contribute to the special section in this issue. As is clear from the articles in this special section, the phenomenon of vibrations at surfaces continues to be a dynamic field of investigation. In fact, there is a resurgence of effort because the insights provided by surface dynamics are still fundamental to the development of an understanding of the microscopic factors that control surface structure formation, diffusion, reaction and structural stability. Examination of dynamics at surfaces thus complements and supplements the wealth of information that is obtained from real-space techniques such as scanning tunneling microscopy. Vibrational dynamics is, of course, not limited to surfaces. Surfaces are important since they provide immediate deviation from the bulk. They display how lack of symmetry can lead to new structures, new local atomic environments and new types of dynamical modes. Nanoparticles, large molecules and nanostructures of all types, in all kinds of local environments, provide further examples of regions of reduced symmetry and coordination, and hence display characteristic vibrational modes. Given the tremendous advance in the synthesis of a variety of nanostructures whose functionalization would pave the way for nanotechnology, there is even greater need to engage in experimental and theoretical techniques that help extract their vibrational dynamics. Such knowledge would enable a more complete understanding and characterization of these nanoscale systems than would otherwise be the case. The papers presented here provide excellent examples of the kind of information that is revealed by vibrations at surfaces. Vibrations at surface contents Poisoning and non-poisoning oxygen on Cu(410)L Vattuone, V Venugopal, T Kravchuk, M Smerieri, L Savio and M Rocca Modifying protein adsorption by layers of glutathione pre-adsorbed on Au(111)Anne Vallée, Vincent Humblot, Christophe Méthivier, Paul Dumas and Claire-Marie Pradier Relating temperature dependence of atom scattering spectra to surface corrugationW W Hayes and J R Manson Effects of the commensurability and disorder on friction for the system Xe/CuA Franchini, V Bortolani, G Santoro and K Xheka Switching ability of nitro-spiropyran on Au(111): electronic structure changes as a sensitive probe during a ring-opening reactionChristopher Bronner, Gunnar Schulze, Katharina J Franke, José Ignacio Pascual and Petra Tegeder High-resolution phonon study of the Ag(100) surfaceK L Kostov, S Polzin and W Widdra On the interpretation of IETS spectra of a small organic molecule Karina Morgenstern

Microscopic Analysis of Current and Mechanical Properties of Nafion® Studied by Atomic Force Microscopy

PubMed Central

Hiesgen, Renate; Helmly, Stefan; Galm, Ines; Morawietz, Tobias; Handl, Michael; Friedrich, K. Andreas

2012-01-01

The conductivity of fuel cell membranes as well as their mechanical properties at the nanometer scale were characterized using advanced tapping mode atomic force microscopy (AFM) techniques. AFM produces high-resolution images under continuous current flow of the conductive structure at the membrane surface and provides some insight into the bulk conducting network in Nafion membranes. The correlation of conductivity with other mechanical properties, such as adhesion force, deformation and stiffness, were simultaneously measured with the current and provided an indication of subsurface phase separations and phase distribution at the surface of the membrane. The distribution of conductive pores at the surface was identified by the formation of water droplets. A comparison of nanostructure models with high-resolution current images is discussed in detail. PMID:24958429

On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme.

PubMed

Leopoldini, Monica; Malaj, Naim; Toscano, Marirosa; Sindona, Giovanni; Russo, Nino

2010-10-13

Density functional theory was applied to study the binding mode of new flavonoids as possible inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), an enzyme that catalyzes the four-electron reduction of HMGCoA to mevalonate, the committed step in the biosynthesis of sterols. The investigated flavonoid conjugates brutieridin and melitidin were recently quantified in the bergamot fruit extracts and identified to be structural analogues of statins, lipids concentration lowering drugs that inhibit HMGR. Computations allowed us to perform a detailed analysis of the geometrical and electronic features affecting the binding of these compounds, as well as that of the excellent simvastatin drug, to the active site of the enzyme and to give better insight into the inhibition process.

Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy

PubMed Central

Myers, Stephanie M.; Collins, Ian

2016-01-01

The kinesin class of microtubule-associated motor proteins present attractive anti-cancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms, and explore the implications for future anticancer drug development against these targets. PMID:26976726

Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy.

PubMed

Myers, Stephanie M; Collins, Ian

2016-01-01

The kinesin class of microtubule-associated motor proteins present attractive anticancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms and explore the implications for future anticancer drug development against these targets.

Monitoring morphology and hydrogen coverage of nanometric Pt/γ-Al2 O3 particles by in situ HERFD-XANES and quantum simulations.

PubMed

Gorczyca, Agnes; Moizan, Virginie; Chizallet, Celine; Proux, Olivier; Del Net, William; Lahera, Eric; Hazemann, Jean-Louis; Raybaud, Pascal; Joly, Yves

2014-11-10

Platinum nanoclusters highly dispersed on γ-alumina are widely used as heterogeneous catalysts. To understand the chemical interplay between the Pt nanoparticles, the support, and the reductive atmosphere, we performed X-ray absorption near edge structure (XANES) in situ experiments recorded in high energy resolution fluorescence detection (HERFD) mode. Spectra are assigned by comparison with simulated XANES spectra on models obtained by molecular dynamics (DFT-MD). We propose platinum cluster morphologies and quantify the hydrogen coverages compatible with XANES spectra recorded at variable hydrogen pressures and temperatures. Using cutting-edge methodologies to assign XANES spectra, this work gives unequalled atomic insights into the characterization of supported nanoclusters. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The glassy state of crambin and the THz time scale protein-solvent fluctuations possibly related to protein function

PubMed Central

2014-01-01

Background THz experiments have been used to characterize the picosecond time scale fluctuations taking place in the model, globular protein crambin. Results Using both hydration and temperature as an experimental parameter, we have identified collective fluctuations (<= 200 cm−1) in the protein. Observation of the protein dynamics in the THz spectrum from both below and above the glass transition temperature (Tg) has provided unique insight into the microscopic interactions and modes that permit the solvent to effectively couple to the protein thermal fluctuations. Conclusions Our findings suggest that the solvent dynamics on the picosecond time scale not only contribute to protein flexibility but may also delineate the types of fluctuations that are able to form within the protein structure. PMID:25184036

Biophysical insights into the interaction of clofazimine with human alpha 1-acid glycoprotein: a multitechnique approach.

PubMed

Ajmal, Mohammad Rehan; Almutairi, Fahad; Zaidi, Nida; Alam, Parvez; Siddiqi, Mohammad Khursheed; Khan, Mohsin Vahid; Zaman, Masihuz; Ishtikhar, Mohd; Khan, Rizwan Hasan

2018-04-25

Alpha1-acid glycoprotein (AAG) is a major acute phase protein of human plasma. Binding of clofazimine to AAG is investigated using optical spectroscopy and molecular docking tools. We found significant quenching of intrinsic fluorescence of AAG upon the binding of clofazimine, binding mode is static with binding constant of 3.52 × 10 4 at 298 K. The Gibbs free energy change is found to be negative for the interaction of clofazimine with AAG indicating spontaneity of the binding process. Binding of clofazimine induced ordered structure in protein and lead to molecular compaction. Molecular docking results indicate the binding site is located in the central beta barrel, hydrogen bonding and hydrophobic interactions are main bonding forces between AAG-clofazimine.

Parasitic modes removal out of operating mode neighbourhood in the DAW accelerating structure

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

Andreev, V.G.; Belugin, V.M.; Esin, S.K.

1983-08-01

The disk and washer (DAW) accelerating structure finds its use in a number of new projects (PIGMI, SNQ etc ). It composes the main part of the accelerating structure of the meson factory now under construction in the Institute for Nuclear Research (INR), Moscow. It is known that the parasitic modes with azimuthal field variations exist at the operating mode region. In this report different methods of the parasitic modes frequency shift are considered. The main attention is given to the resonant methods, which are the most efficient.

The Interference of Selected Cytotoxic Alkaloids with the Cytoskeleton: An Insight into Their Modes of Action.

PubMed

Wang, Xiaojuan; Tanaka, Mine; Krstin, Sonja; Peixoto, Herbenya Silva; Wink, Michael

2016-07-12

Alkaloids, the largest group among the nitrogen-containing secondary metabolites of plants, usually interact with several molecular targets. In this study, we provide evidence that six cytotoxic alkaloids (sanguinarine, chelerythrine, chelidonine, noscapine, protopine, homoharringtonine), which are known to affect neuroreceptors, protein biosynthesis and nucleic acids, also interact with the cellular cytoskeleton, such as microtubules and actin filaments, as well. Sanguinarine, chelerythrine and chelidonine depolymerized the microtubule network in living cancer cells (Hela cells and human osteosarcoma U2OS cells) and inhibited tubulin polymerization in vitro with IC50 values of 48.41 ± 3.73, 206.39 ± 4.20 and 34.51 ± 9.47 μM, respectively. However, sanguinarine and chelerythrine did not arrest the cell cycle while 2.5 μM chelidonine arrested the cell cycle in the G₂/M phase with 88.27% ± 0.99% of the cells in this phase. Noscapine and protopine apparently affected microtubule structures in living cells without affecting tubulin polymerization in vitro, which led to cell cycle arrest in the G2/M phase, promoting this cell population to 73.42% ± 8.31% and 54.35% ± 11.26% at a concentration of 80 μM and 250.9 μM, respectively. Homoharringtonine did not show any effects on microtubules and cell cycle, while the known microtubule-stabilizing agent paclitaxel was found to inhibit tubulin polymerization in the presence of MAPs in vitro with an IC50 value of 38.19 ± 3.33 μM. Concerning actin filaments, sanguinarine, chelerythrine and chelidonine exhibited a certain effect on the cellular actin filament network by reducing the mass of actin filaments. The interactions of these cytotoxic alkaloids with microtubules and actin filaments present new insights into their molecular modes of action.

System for determining the angle of impact of an object on a structure

NASA Technical Reports Server (NTRS)

Prosser, William H. (Inventor); Gorman, Michael R. (Inventor)

1993-01-01

A method for determining the angle of impact of an object on a thin-walled structure which determines the angle of impact through analysis of the acoustic waves which result when an object impacts a structure is presented. Transducers are placed on and in the surface of the structure which sense the wave caused in the structure by impact. The waves are recorded and saved for analysis. For source motion normal to the surface, the antisymmetric mode has a large amplitude while that of the symmetric mode is very small. As the source angle increases with respect to the surface normal, the symmetric mode amplitude increases while the antisymmetric mode amplitude decreases. Thus, the angle of impact is determined by measuring the relative amplitudes of these two lowest order modes.

Numerical studies of edge localized instabilities in tokamaks

NASA Astrophysics Data System (ADS)

Wilson, H. R.; Snyder, P. B.; Huysmans, G. T. A.; Miller, R. L.

2002-04-01

A new computational tool, edge localized instabilities in tokamaks equilibria (ELITE), has been developed to help our understanding of short wavelength instabilities close to the edge of tokamak plasmas. Such instabilities may be responsible for the edge localized modes observed in high confinement H-mode regimes, which are a serious concern for next step tokamaks because of the high transient power loads which they can impose on divertor target plates. ELITE uses physical insight gained from analytic studies of peeling and ballooning modes to provide an efficient way of calculating the edge ideal magnetohydrodynamic stability properties of tokamaks. This paper describes the theoretical formalism which forms the basis for the code.

FLEXAN (version 2.0) user's guide

NASA Technical Reports Server (NTRS)

Stallcup, Scott S.

1989-01-01

The FLEXAN (Flexible Animation) computer program, Version 2.0 is described. FLEXAN animates 3-D wireframe structural dynamics on the Evans and Sutherland PS300 graphics workstation with a VAX/VMS host computer. Animation options include: unconstrained vibrational modes, mode time histories (multiple modes), delta time histories (modal and/or nonmodal deformations), color time histories (elements of the structure change colors through time), and rotational time histories (parts of the structure rotate through time). Concurrent color, mode, delta, and rotation, time history animations are supported. FLEXAN does not model structures or calculate the dynamics of structures; it only animates data from other computer programs. FLEXAN was developed to aid in the study of the structural dynamics of spacecraft.

Psychiatrists' accounts of insight.

PubMed

Galasinski, Dariusz; Opalinski, Konrad

2012-11-01

Our main aim was to examine how insight into schizophrenia is discursively represented in psychiatrists' accounts, how these accounts relate to the current psychiatric literature on insight, and their potential clinical consequences. The article is anchored in the constructionist view of discourse and is based on nine semistructured interviews with specialist psychiatrists. We discuss three dimensions of insight into schizophrenia in the data we collected: a sense of illness, criticism, and readiness to receive treatment. We argue that they are embodiments of the dominant medical perspective in the relations between patients and physicians. Whereas in the former two it is possessing and accepting psychiatric knowledge which constitutes having insight, in the latter it is unquestioning acceptance and trust in whatever treatment the doctor deems fit to administer. We conclude with a discussion of medicalization of experience of mental illness, which appears to be the preferred mode of patient narrative for psychiatrists.

Structural Analysis of HMGD-DNA Complexes Reveal Influence of Intercalation on Sequence Selectivity and DNA Bending

PubMed Central

Churchill, Mair E.A.; Klass, Janet; Zoetewey, David L.

2010-01-01

The ubiquitous eukaryotic High-Mobility-Group-Box (HMGB) chromosomal proteins promote many chromatin-mediated cellular activities through their non-sequence-specific binding and bending of DNA. Minor groove DNA binding by the HMG box results in substantial DNA bending toward the major groove owing to electrostatic interactions, shape complementarity and DNA intercalation that occurs at two sites. Here, the structures of the complexes formed with DNA by a partially DNA intercalation-deficient mutant of Drosophila melanogaster HMGD have been determined by X-ray crystallography at a resolution of 2.85 Å. The six proteins and fifty base pairs of DNA in the crystal structure revealed a variety of bound conformations. All of the proteins bound in the minor groove, bridging DNA molecules, presumably because these DNA regions are easily deformed. The loss of the primary site of DNA intercalation decreased overall DNA bending and shape complementarity. However, DNA bending at the secondary site of intercalation was retained and most protein-DNA contacts were preserved. The mode of binding resembles the HMGB1-boxA-cisplatin-DNA complex, which also lacks a primary intercalating residue. This study provides new insights into the binding mechanisms used by HMG boxes to recognize varied DNA structures and sequences as well as modulate DNA structure and DNA bending. PMID:20800069

Structure prediction and binding sites analysis of curcin protein of Jatropha curcas using computational approaches.

PubMed

Srivastava, Mugdha; Gupta, Shishir K; Abhilash, P C; Singh, Nandita

2012-07-01

Ribosome inactivating proteins (RIPs) are defense proteins in a number of higher-plant species that are directly targeted toward herbivores. Jatropha curcas is one of the biodiesel plants having RIPs. The Jatropha seed meal, after extraction of oil, is rich in curcin, a highly toxic RIP similar to ricin, which makes it unsuitable for animal feed. Although the toxicity of curcin is well documented in the literature, the detailed toxic properties and the 3D structure of curcin has not been determined by X-ray crystallography, NMR spectroscopy or any in silico techniques to date. In this pursuit, the structure of curcin was modeled by a composite approach of 3D structure prediction using threading and ab initio modeling. Assessment of model quality was assessed by methods which include Ramachandran plot analysis and Qmean score estimation. Further, we applied the protein-ligand docking approach to identify the r-RNA binding residue of curcin. The present work provides the first structural insight into the binding mode of r-RNA adenine to the curcin protein and forms the basis for designing future inhibitors of curcin. Cloning of a future peptide inhibitor within J. curcas can produce non-toxic varieties of J. curcas, which would make the seed-cake suitable as animal feed without curcin detoxification.

Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective

PubMed Central

Gupta, Sneha; Biswas, Arijit; Akhter, Mohammad Suhail; Krettler, Christoph; Reinhart, Christoph; Dodt, Johannes; Reuter, Andreas; Philippou, Helen; Ivaskevicius, Vytautas; Oldenburg, Johannes

2016-01-01

The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA2B2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis. PMID:27453290

Multi-scale gyrokinetic simulations of an Alcator C-Mod, ELM-y H-mode plasma

NASA Astrophysics Data System (ADS)

Howard, N. T.; Holland, C.; White, A. E.; Greenwald, M.; Rodriguez-Fernandez, P.; Candy, J.; Creely, A. J.

2018-01-01

High fidelity, multi-scale gyrokinetic simulations capable of capturing both ion ({k}θ {ρ }s∼ { O }(1.0)) and electron-scale ({k}θ {ρ }e∼ { O }(1.0)) turbulence were performed in the core of an Alcator C-Mod ELM-y H-mode discharge which exhibits reactor-relevant characteristics. These simulations, performed with all experimental inputs and realistic ion to electron mass ratio ({({m}i/{m}e)}1/2=60.0) provide insight into the physics fidelity that may be needed for accurate simulation of the core of fusion reactor discharges. Three multi-scale simulations and series of separate ion and electron-scale simulations performed using the GYRO code (Candy and Waltz 2003 J. Comput. Phys. 186 545) are presented. As with earlier multi-scale results in L-mode conditions (Howard et al 2016 Nucl. Fusion 56 014004), both ion and multi-scale simulations results are compared with experimentally inferred ion and electron heat fluxes, as well as the measured values of electron incremental thermal diffusivities—indicative of the experimental electron temperature profile stiffness. Consistent with the L-mode results, cross-scale coupling is found to play an important role in the simulation of these H-mode conditions. Extremely stiff ion-scale transport is observed in these high-performance conditions which is shown to likely play and important role in the reproduction of measurements of perturbative transport. These results provide important insight into the role of multi-scale plasma turbulence in the core of reactor-relevant plasmas and establish important constraints on the the fidelity of models needed for predictive simulations.

Shuttle structural dynamics characteristics: The analysis and verification

NASA Technical Reports Server (NTRS)

Modlin, C. T., Jr.; Zupp, G. A., Jr.

1985-01-01

The space shuttle introduced a new dimension in the complexity of the structural dynamics of a space vehicle. The four-body configuration exhibited structural frequencies as low as 2 hertz with a model density on the order of 10 modes per hertz. In the verification process, certain mode shapes and frequencies were identified by the users as more important than others and, as such, the test objectives were oriented toward experimentally extracting those modes and frequencies for analysis and test correlation purposes. To provide the necessary experimental data, a series of ground vibration tests (GVT's) was conducted using test articles ranging from the 1/4-scale structural replica of the space shuttle to the full-scale vehicle. The vibration test and analysis program revealed that the mode shapes and frequency correlations below 10 hertz were good. The quality of correlation of modes between 10 and 20 hertz ranged from good to fair and that of modes above 20 hertz ranged from poor to good. Since the most important modes, based on user preference, were below 10 hertz, it was judged that the shuttle structural dynamic models were adequate for flight certifications.

Bias field tunable magnetic configuration and magnetization dynamics in Ni80Fe20 nano-cross structures with varying arm length

NASA Astrophysics Data System (ADS)

Adhikari, K.; Choudhury, S.; Mandal, R.; Barman, S.; Otani, Y.; Barman, A.

2017-01-01

Ferromagnetic nano-cross structures promise exotic static magnetic configurations and very rich and tunable magnetization dynamics leading towards potential applications in magnetic logic and communication devices. Here, we report an experimental study of external magnetic field tunable static magnetic configurations and magnetization dynamics in Ni80Fe20 nano-cross structures with varying arm lengths (L). Broadband ferromagnetic resonance measurements showed a strong variation in the number of spin-wave (SW) modes and mode frequencies (f) with bias field magnitude (H). Simulated static magnetic configurations and SW mode profiles explain the rich variation of the SW spectra, including mode softening, mode crossover, mode splitting, and mode merging. Such variation of SW spectra is further modified by the size of the nano-cross. Remarkably, with decreasing arm length of nano-cross structures, the onion magnetization ground state becomes more stable. Calculated magnetostatic field distributions support the above observations and revealed the non-collective nature of the dynamics in closely packed nano-cross structures. The latter is useful for their possible applications in magnetic storage and memory devices.

Protein architecture and core residues in unwound α-helices provide insights to the transport function of plant AtCHX17

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

Czerny, Daniel D.; Padmanaban, Senthilkumar; Anishkin, Andriy

Using Arabidopsis thaliana AtCHX17 as an example, we combine structural modeling and mutagenesis to provide insights on its protein architecture and transport function which is poorly characterized. This approach is based on the observation that protein structures are significantly more conserved in evolution than linear sequences, and mechanistic similarities among diverse transporters are emerging. Two homology models of AtCHX17 were obtained that show a protein fold similar to known structures of bacterial Na +/H + antiporters, EcNhaA and TtNapA. The distinct secondary and tertiary structure models highlighted residues at positions potentially important for CHX17 activity. Mutagenesis showed that asparagine-N200 andmore » aspartate-D201 inside transmembrane5 (TM5), and lysine-K355 inside TM10 are critical for AtCHX17 activity. We reveal previously unrecognized threonine-T170 and lysine-K383 as key residues at unwound regions in the middle of TM4 and TM11 α-helices, respectively. Mutation of glutamate-E111 located near the membrane surface inhibited AtCHX17 activity, suggesting a role in pH sensing. The long carboxylic tail of unknown purpose has an alternating β-sheet and α-helix secondary structure that is conserved in prokaryote universal stress proteins. Here, these results support the overall architecture of AtCHX17 and identify D201, N200 and novel residues T170 and K383 at the functional core which likely participates in ion recognition, coordination and/or translocation, similar to characterized cation/H + exchangers. The core of AtCHX17 models according to EcNhaA and TtNapA templates faces inward and outward, respectively, which may reflect two conformational states of the alternating access transport mode for proteins belonging to the plant CHX family.« less

Protein architecture and core residues in unwound α-helices provide insights to the transport function of plant AtCHX17

DOE PAGES

Czerny, Daniel D.; Padmanaban, Senthilkumar; Anishkin, Andriy; ...

2016-05-11

Using Arabidopsis thaliana AtCHX17 as an example, we combine structural modeling and mutagenesis to provide insights on its protein architecture and transport function which is poorly characterized. This approach is based on the observation that protein structures are significantly more conserved in evolution than linear sequences, and mechanistic similarities among diverse transporters are emerging. Two homology models of AtCHX17 were obtained that show a protein fold similar to known structures of bacterial Na +/H + antiporters, EcNhaA and TtNapA. The distinct secondary and tertiary structure models highlighted residues at positions potentially important for CHX17 activity. Mutagenesis showed that asparagine-N200 andmore » aspartate-D201 inside transmembrane5 (TM5), and lysine-K355 inside TM10 are critical for AtCHX17 activity. We reveal previously unrecognized threonine-T170 and lysine-K383 as key residues at unwound regions in the middle of TM4 and TM11 α-helices, respectively. Mutation of glutamate-E111 located near the membrane surface inhibited AtCHX17 activity, suggesting a role in pH sensing. The long carboxylic tail of unknown purpose has an alternating β-sheet and α-helix secondary structure that is conserved in prokaryote universal stress proteins. Here, these results support the overall architecture of AtCHX17 and identify D201, N200 and novel residues T170 and K383 at the functional core which likely participates in ion recognition, coordination and/or translocation, similar to characterized cation/H + exchangers. The core of AtCHX17 models according to EcNhaA and TtNapA templates faces inward and outward, respectively, which may reflect two conformational states of the alternating access transport mode for proteins belonging to the plant CHX family.« less

And the dish ran away with the spoon: a hodgepodge of reflections, as rigorous as they are rambling, on the true subject.

PubMed

Mogenson, Greg

2018-02-01

In this article, the topic of 'the true subject' is explored in terms of a dialectical mode thinking which is in keeping with Jung's great insight concerning psychology's lack of an Archimedean vantage-point distinct from its topics and subject matters. Evocative and expository, the emphasis is upon the performative poetics of such thinking within the sphere of our soul-making. The interpretative mode of practice presented in the article is richly illustrated with examples from Biblical texts, literary images, and proverbial sayings, as well as from the sur-real of nursery rhyme and the genre of the murder mystery. Essential insights of Jung's concerning the infinite and the finite as dimensions of self are revisited in terms of that contemporary trend of Jungian thought known as psychology as the discipline of interiority. © 2018, The Society of Analytical Psychology.

Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies.

PubMed

Lee, Jin Hee; Lee, Yoonji; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Lazar, Jozsef; Pearce, Larry V; Pavlyukovets, Vladimir A; Blumberg, Peter M; Choi, Sun

2011-04-01

The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.

Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies

NASA Astrophysics Data System (ADS)

Lee, Jin Hee; Lee, Yoonji; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Lazar, Jozsef; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Blumberg, Peter M.; Choi, Sun

2011-04-01

The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.

Insights into the regioselectivity and RNA-binding affinity of HIV-1 nucleocapsid protein from linear-scaling quantum methods.

PubMed

Khandogin, Jana; Musier-Forsyth, Karin; York, Darrin M

2003-07-25

Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein (NC) plays several important roles in the viral life-cycle and presents an attractive target for rational drug design. Here, the macromolecular reactivity of NC and its binding to RNA is characterized through determination of electrostatic and chemical descriptors derived from linear-scaling quantum calculations in solution. The computational results offer a rationale for the experimentally observed susceptibility of the Cys49 thiolate toward small-molecule electrophilic agents, and support the recently proposed stepwise protonation mechanism of the C-terminal Zn-coordination complex. The distinctive binding mode of NC to SL2 and SL3 stem-loops of the HIV-1 genomic RNA packaging signal is studied on the basis of protein side-chain contributions to the electrostatic binding energies. These results indicate the importance of several basic residues in the 3(10) helical region and the N-terminal zinc finger, and rationalize the presence of several evolutionarily conserved residues in NC. The combined reactivity and RNA-binding study provides new insights that may contribute toward the structure-based design of anti-HIV therapies.

Key Structures and Interactions for Binding of Mycobacterium tuberculosis Protein Kinase B Inhibitors from Molecular Dynamics Simulation.

PubMed

Punkvang, Auradee; Kamsri, Pharit; Saparpakorn, Patchreenart; Hannongbua, Supa; Wolschann, Peter; Irle, Stephan; Pungpo, Pornpan

2015-07-01

Substituted aminopyrimidine inhibitors have recently been introduced as antituberculosis agents. These inhibitors show impressive activity against protein kinase B, a Ser/Thr protein kinase that is essential for cell growth of M. tuberculosis. However, up to now, X-ray structures of the protein kinase B enzyme complexes with the substituted aminopyrimidine inhibitors are currently unavailable. Consequently, structural details of their binding modes are questionable, prohibiting the structural-based design of more potent protein kinase B inhibitors in the future. Here, molecular dynamics simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the complex structures of the protein kinase B inhibitors and their binding energetics. The complex structures obtained by the molecular dynamics simulations show binding free energies in good agreement with experiment. The detailed analysis of molecular dynamics results shows that Glu93, Val95, and Leu17 are key residues responsible to the binding of the protein kinase B inhibitors. The aminopyrazole group and the pyrimidine core are the crucial moieties of substituted aminopyrimidine inhibitors for interaction with the key residues. Our results provide a structural concept that can be used as a guide for the future design of protein kinase B inhibitors with highly increased antagonistic activity. © 2014 John Wiley & Sons A/S.

What limits the achievable areal densities of large aperture space telescopes?

NASA Astrophysics Data System (ADS)

Peterson, Lee D.; Hinkle, Jason D.

2005-08-01

This paper examines requirements trades involving areal density for large space telescope mirrors. A segmented mirror architecture is used to define a quantitative example that leads to relevant insight about the trades. In this architecture, the mirror consists of segments of non-structural optical elements held in place by a structural truss that rests behind the segments. An analysis is presented of the driving design requirements for typical on-orbit loads and ground-test loads. It is shown that the driving on-orbit load would be the resonance of the lowest mode of the mirror by a reaction wheel static unbalance. The driving ground-test load would be dynamics due to ground-induced random vibration. Two general conclusions are derived from these results. First, the areal density that can be allocated to the segments depends on the depth allocated to the structure. More depth in the structure allows the allocation of more mass to the segments. This, however, leads to large structural depth that might be a significant development challenge. Second, the requirement for ground-test-ability results in an order of magnitude or more depth in the structure than is required by the on-orbit loads. This leads to the proposition that avoiding ground test as a driving requirement should be a fundamental technology on par with the provision of deployable depth. Both are important structural challenges for these future systems.

Hierarchical super-structure identified by polarized light microscopy, electron microscopy and nanoindentation: Implications for the limits of biological control over the growth mode of abalone sea shells

PubMed Central

2012-01-01

Background Mollusc shells are commonly investigated using high-resolution imaging techniques based on cryo-fixation. Less detailed information is available regarding the light-optical properties. Sea shells of Haliotis pulcherina were embedded for polishing in defined orientations in order to investigate the interface between prismatic calcite and nacreous aragonite by standard materialographic methods. A polished thin section of the interface was prepared with a defined thickness of 60 μm for quantitative birefringence analysis using polarized light and LC-PolScope microscopy. Scanning electron microscopy images were obtained for comparison. In order to study structural-mechanical relationships, nanoindentation experiments were performed. Results Incident light microscopy revealed a super-structure in semi-transparent regions of the polished cross-section under a defined angle. This super-structure is not visible in transmitted birefringence analysis due to the blurred polarization of small nacre platelets and numerous organic interfaces. The relative orientation and homogeneity of calcite prisms was directly identified, some of them with their optical axes exactly normal to the imaging plane. Co-oriented "prism colonies" were identified by polarized light analyses. The nacreous super-structure was also visualized by secondary electron imaging under defined angles. The domains of the super-structure were interpreted to consist of crystallographically aligned platelet stacks. Nanoindentation experiments showed that mechanical properties changed with the same periodicity as the domain size. Conclusions In this study, we have demonstrated that insights into the growth mechanisms of nacre can be obtained by conventional light-optical methods. For example, we observed super-structures formed by co-oriented nacre platelets as previously identified using X-ray Photo-electron Emission Microscopy (X-PEEM) [Gilbert et al., Journal of the American Chemical Society 2008, 130:17519–17527]. Polarized optical microscopy revealed unprecedented super-structures in the calcitic shell part. This bears, in principle, the potential for in vivo studies, which might be useful for investigating the growth modes of nacre and other shell types. PMID:22967319

Normal modes of the world's oceans: A numerical investigation using Proudman functions

NASA Technical Reports Server (NTRS)

Sanchez, Braulio V.; Morrow, Dennis

1993-01-01

The numerical modeling of the normal modes of the global oceans is addressed. The results of such modeling could be expected to serve as a guide in the analysis of observations and measurements intended to detect these modes. The numerical computation of normal modes of the global oceans is a field in which several investigations have obtained results during the past 15 years. The results seem to be model-dependent to an unsatisfactory extent. Some modeling areas, such as higher resolution of the bathymetry, inclusion of self-attraction and loading, the role of the Arctic Ocean, and systematic testing by means of diagnostic models are addressed. The results show that the present state of the art is such that a final solution to the normal mode problem still lies in the future. The numerical experiments show where some of the difficulties are and give some insight as to how to proceed in the future.

Generation and Micro-scale Effects of Electrostatic Waves in an Oblique Shock

NASA Astrophysics Data System (ADS)

Goodrich, K.; Ergun, R.; Schwartz, S. J.; Newman, D.; Johlander, A.; Argall, M. R.; Wilder, F. D.; Torbert, R. B.; Khotyaintsev, Y. V.; Lindqvist, P. A.; Strangeway, R. J.; Russell, C. T.; Giles, B. L.; Gershman, D. J.; Burch, J. L.

2017-12-01

We present an analysis of large amplitude (>100 mV/m), high frequency (≤1 kHz), electrostatic waves observed by MMS during an oblique bow shock crossing event. The observed waves primarily consist of electrostatic solitary waves (ESWs) and oblique ion plasma waves (IPWs). ESWs typically include nonlinear structures such as double layers, ion phase-space holes, and electron phase-space holes. Oblique IPWs are observed to be similar to ion acoustic waves, but can propagate up to 70° from the ambient magnetic field direction. Both wave-modes, particularly IPWs, are observed to have very short wavelengths ( 100 m) and are highly localized. While such wave-modes have been previously observed in the terrestrial bow shock, instrumental constraints have limited detailed insight into their generation and their effect on their plasma shock environment. Analysis of this oblique shock event shows evidence that ESWs and oblique IPWs can be generated through field-aligned currents associated with magnetic turbulence and through a counterstreaming ion instability respectively. We also present evidence that this wave activity can facilitate momentum exchange between ion populations, resulting in deceleration of incoming solar wind, and localized electron heating.

Emotional responses to Hindustani raga music: the role of musical structure

PubMed Central

Mathur, Avantika; Vijayakumar, Suhas H.; Chakrabarti, Bhismadev; Singh, Nandini C.

2015-01-01

In Indian classical music, ragas constitute specific combinations of tonic intervals potentially capable of evoking distinct emotions. A raga composition is typically presented in two modes, namely, alaap and gat. Alaap is the note by note delineation of a raga bound by a slow tempo, but not bound by a rhythmic cycle. Gat on the other hand is rendered at a faster tempo and follows a rhythmic cycle. Our primary objective was to (1) discriminate the emotions experienced across alaap and gat of ragas, (2) investigate the association of tonic intervals, tempo and rhythmic regularity with emotional response. 122 participants rated their experienced emotion across alaap and gat of 12 ragas. Analysis of the emotional responses revealed that (1) ragas elicit distinct emotions across the two presentation modes, and (2) specific tonic intervals are robust predictors of emotional response. Specifically, our results showed that the ‘minor second’ is a direct predictor of negative valence. (3) Tonality determines the emotion experienced for a raga where as rhythmic regularity and tempo modulate levels of arousal. Our findings provide new insights into the emotional response to Indian ragas and the impact of tempo, rhythmic regularity and tonality on it. PMID:25983702

Two-photon absorption and transient photothermal imaging of pigments in tissues

NASA Astrophysics Data System (ADS)

Ye, Tong; Fu, Dan; Matthews, Thomas E.; Hong, Lian; Simon, John D.; Warren, Warren S.

2008-02-01

As a main pigment in skin tissues, melanin plays an important role in photo-protecting skin from UV radiation. However, melanogenesis may be altered due to disease or environmental factors; for example, sun exposure may cause damage and mutation of melanocytes and induce melanoma. Imaging pigmentation changes may provide invaluable information to catch the malignant transformation in its early stage and in turn improve the prognosis of patients. We have demonstrated previously that transmission mode, two-photon, one- or two-color absorption microscopy could provide remarkable contrast in imaging melanin in skin. In this report we demonstrate significantly improved sensitivity, so that we are now able to image in epi-mode (or back reflection) in two-photon absorption. This improvement makes possible for us to characterize the different types of pigmentation on the skin in vivo at virtually any location. Another finding is that we can also image transient photothermal dynamics due to the light absorption of melanin. By carefully choosing excitation and probe wavelengths, we might be able to image melanin in different structures under different micro-environments in skin, which could provide useful photochemical and photophysical insights in understanding how pigments are involved in photoprotection and photodamage of cells.

Emotional responses to Hindustani raga music: the role of musical structure.

PubMed

Mathur, Avantika; Vijayakumar, Suhas H; Chakrabarti, Bhismadev; Singh, Nandini C

2015-01-01

In Indian classical music, ragas constitute specific combinations of tonic intervals potentially capable of evoking distinct emotions. A raga composition is typically presented in two modes, namely, alaap and gat. Alaap is the note by note delineation of a raga bound by a slow tempo, but not bound by a rhythmic cycle. Gat on the other hand is rendered at a faster tempo and follows a rhythmic cycle. Our primary objective was to (1) discriminate the emotions experienced across alaap and gat of ragas, (2) investigate the association of tonic intervals, tempo and rhythmic regularity with emotional response. 122 participants rated their experienced emotion across alaap and gat of 12 ragas. Analysis of the emotional responses revealed that (1) ragas elicit distinct emotions across the two presentation modes, and (2) specific tonic intervals are robust predictors of emotional response. Specifically, our results showed that the 'minor second' is a direct predictor of negative valence. (3) Tonality determines the emotion experienced for a raga where as rhythmic regularity and tempo modulate levels of arousal. Our findings provide new insights into the emotional response to Indian ragas and the impact of tempo, rhythmic regularity and tonality on it.

Characterizing Pedagogical Practices of University Physics Students in Informal Learning Environments

NASA Astrophysics Data System (ADS)

Hinko, Kathleen

2016-03-01

University educators (UEs) have a long history of teaching physics not only in formal classroom settings but also in informal outreach environments. The pedagogical practices of UEs in informal physics teaching have not been widely studied, and they may provide insight into formal practices and preparation. We investigate the interactions between UEs and children in an afterschool physics program facilitated by university physics students from the University of Colorado Boulder. In this program, physics undergraduates, graduate students and post-doctoral researchers work with K-8 children on hands-on physics activities on a weekly basis over the course of a semester. We use an Activity Theoretic framework as a tool to examine situational aspects of individuals' behavior in the complex structure of the afterschool program. Using this framework, we analyze video of UE-child interactions and identify three main pedagogical modalities that UEs display during activities: Instruction, Consultation and Participation modes. These modes are characterized by certain language, physical location, and objectives that establish differences in UE-child roles and division of labor. Based on this analysis, we discuss implications for promoting pedagogical strategies through purposeful curriculum development and university educator preparation.

Entangled singularity patterns of photons in Ince-Gauss modes

NASA Astrophysics Data System (ADS)

Krenn, Mario; Fickler, Robert; Huber, Marcus; Lapkiewicz, Radek; Plick, William; Ramelow, Sven; Zeilinger, Anton

2013-01-01

Photons with complex spatial mode structures open up possibilities for new fundamental high-dimensional quantum experiments and for novel quantum information tasks. Here we show entanglement of photons with complex vortex and singularity patterns called Ince-Gauss modes. In these modes, the position and number of singularities vary depending on the mode parameters. We verify two-dimensional and three-dimensional entanglement of Ince-Gauss modes. By measuring one photon and thereby defining its singularity pattern, we nonlocally steer the singularity structure of its entangled partner, while the initial singularity structure of the photons is undefined. In addition we measure an Ince-Gauss specific quantum-correlation function with possible use in future quantum communication protocols.

Tomography and Purification of the Temporal-Mode Structure of Quantum Light

NASA Astrophysics Data System (ADS)

Ansari, Vahid; Donohue, John M.; Allgaier, Markus; Sansoni, Linda; Brecht, Benjamin; Roslund, Jonathan; Treps, Nicolas; Harder, Georg; Silberhorn, Christine

2018-05-01

High-dimensional quantum information processing promises capabilities beyond the current state of the art, but addressing individual information-carrying modes presents a significant experimental challenge. Here we demonstrate effective high-dimensional operations in the time-frequency domain of nonclassical light. We generate heralded photons with tailored temporal-mode structures through the pulse shaping of a broadband parametric down-conversion pump. We then implement a quantum pulse gate, enabled by dispersion-engineered sum-frequency generation, to project onto programmable temporal modes, reconstructing the quantum state in seven dimensions. We also manipulate the time-frequency structure by selectively removing temporal modes, explicitly demonstrating the effectiveness of engineered nonlinear processes for the mode-selective manipulation of quantum states.

Development and applications of two computational procedures for determining the vibration modes of structural systems. [aircraft structures - aerospaceplanes

NASA Technical Reports Server (NTRS)

Kvaternik, R. G.

1975-01-01

Two computational procedures for analyzing complex structural systems for their natural modes and frequencies of vibration are presented. Both procedures are based on a substructures methodology and both employ the finite-element stiffness method to model the constituent substructures. The first procedure is a direct method based on solving the eigenvalue problem associated with a finite-element representation of the complete structure. The second procedure is a component-mode synthesis scheme in which the vibration modes of the complete structure are synthesized from modes of substructures into which the structure is divided. The analytical basis of the methods contains a combination of features which enhance the generality of the procedures. The computational procedures exhibit a unique utilitarian character with respect to the versatility, computational convenience, and ease of computer implementation. The computational procedures were implemented in two special-purpose computer programs. The results of the application of these programs to several structural configurations are shown and comparisons are made with experiment.

Correlation among far-infrared reflection modes, crystal structures and dielectric properties of Ba(Zn{sub 1/3}Nb{sub 2/3})O{sub 3}–CaTiO{sub 3} ceramics

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

Shi, Feng, E-mail: sf751106@sina.com.cn; Sun, Haiqing; Liu, Hongquan

Highlights: • Crystal symmetry decreases with CT concentration from cubic to hexagonal structure. • Lattice constants as well as the ordered degree change with CT concentration. • Ordered structures turn from 1:1 to 1:2 ordering with change of crystal structures. • There is a correlation between FIR phonon modes and dielectric properties. • There is a correlation between FIR phonon modes and crystal structures. - Abstract: Ba(Zn{sub 1/3}Nb{sub 2/3})O{sub 3} (BZN)–CaTiO{sub 3} (CT) microwave dielectric ceramics were synthesized at 1395 °C for 4 h using conventional solid-state sintering technique with different CT contents. The ceramics were characterized by X-ray diffractionmore » (XRD) and far-infrared reflection (FIR) spectroscopy to evaluate correlations among crystal structures, dielectric properties, and infrared modes. XRD results showed that crystal symmetry decreased with increased CT concentration from cubic to hexagonal structure, and lattice constants and ordered degree changed accordingly. Ordered phases transformed from 1:1 to 1:2 ordered structure with crystal-structure change. FIR results demonstrated that two new IR active modes appeared at 300 cm{sup −1}, and another new mode appeared at 600 cm{sup −1} for the x ≥ 0.60 sample, which agreed with the change in crystal structures as confirmed by XRD results. Correlations between FIR modes and dielectric properties were established.« less

Intramolecular energy transfer and the driving mechanisms for large-amplitude collective motions of clusters

NASA Astrophysics Data System (ADS)

Yanao, Tomohiro; Koon, Wang Sang; Marsden, Jerrold E.

2009-04-01

This paper uncovers novel and specific dynamical mechanisms that initiate large-amplitude collective motions in polyatomic molecules. These mechanisms are understood in terms of intramolecular energy transfer between modes and driving forces. Structural transition dynamics of a six-atom cluster between a symmetric and an elongated isomer is highlighted as an illustrative example of what is a general message. First, we introduce a general method of hyperspherical mode analysis to analyze the energy transfer among internal modes of polyatomic molecules. In this method, the (3n-6) internal modes of an n-atom molecule are classified generally into three coarse level gyration-radius modes, three fine level twisting modes, and (3n-12) fine level shearing modes. We show that a large amount of kinetic energy flows into the gyration-radius modes when the cluster undergoes structural transitions by changing its mass distribution. Based on this fact, we construct a reactive mode as a linear combination of the three gyration-radius modes. It is shown that before the reactive mode acquires a large amount of kinetic energy, activation or inactivation of the twisting modes, depending on the geometry of the isomer, plays crucial roles for the onset of a structural transition. Specifically, in a symmetric isomer with a spherical mass distribution, activation of specific twisting modes drives the structural transition into an elongated isomer by inducing a strong internal centrifugal force, which has the effect of elongating the mass distribution of the system. On the other hand, in an elongated isomer, inactivation of specific twisting modes initiates the structural transition into a symmetric isomer with lower potential energy by suppressing the elongation effect of the internal centrifugal force and making the effects of the potential force dominant. This driving mechanism for reactions as well as the present method of hyperspherical mode analysis should be widely applicable to molecular reactions in which a system changes its overall mass distribution in a significant way.

Insights into the binding modes of CC chemokine receptor 4 (CCR4) inhibitors: a combined approach involving homology modelling, docking, and molecular dynamics simulation studies.

PubMed

Gadhe, Changdev G; Kim, Mi-hyun

2015-02-01

CC chemokine receptor 4 (CCR4), a G protein-coupled receptor (GPCR), plays a vital role in the progression of asthma, T-cell lymphoma, inflammation, and Alzheimer's disease. To date, the structure of CCR4 has not been determined. Therefore, the nature of the interactions between inhibitors and CCR4 is not well known. In this study, we used CCR5 as a template to model the structure of CCR4. Docking studies were performed for four naphthalene-sulphonamide derivatives and crucial ligand-protein interactions were analysed. Molecular dynamics (MD) simulations of these complexes (100 ns each) were carried out to gain insights into the interactions between ligands and CCR4. MD simulations revealed that the residues identified by the docking were displaced and new residues were inserted near the ligands. Results of a principal component analysis (PCA) suggested that CCR4 unfolds at the extracellular site surrounding the ligands. Our simulations identified crucial residues involved in CCR4 antagonism, which were supported by previous mutational studies. Additionally, we identified Ser3.29, Leu3.33, Ser5.39, Phe6.47, Ile7.35, Thr7.38, Thr7.40, and Ala7.42 as residues that play crucial roles in CCR4 antagonism. Mutational studies will help elucidate the significance of these residues in CCR4 antagonism. An understanding of ligand-CCR4 interactions might aid in the design of novel CCR4 inhibitors.

Effect of Deformation Mode on the Wear Behavior of NiTi Shape Memory Alloys

NASA Astrophysics Data System (ADS)

Yan, Lina; Liu, Yong

2016-06-01

Owing to good biocompatibility, good fatigue resistance, and excellent superelasticity, various types of bio-medical devices based on NiTi shape memory alloy (SMA) have been developed. Due to the complexity in deformation mode in service, for example NiTi implants, accurate assessment/prediction of the surface wear process is difficult. This study aims at providing a further insight into the effect of deformation mode on the wear behavior of NiTi SMA. In the present study, two types of wear testing modes were used, namely sliding wear mode and reciprocating wear mode, to investigate the effect of deformation mode on the wear behavior of NiTi SMA in both martensitic and austenitic states. It was found that, when in martensitic state and under high applied loads, sliding wear mode resulted in more surface damage as compared to that under reciprocating wear mode. When in austenitic state, although similar trends in the coefficient of friction were observed, the coefficient of friction and surface damage in general is less under reciprocating mode than under sliding mode. These observations were further discussed in terms of different deformation mechanisms involved in the wear tests, in particular, the reversibility of martensite variant reorientation and stress-induced phase transformation, respectively.

Topological phonon modes in filamentary structures

NASA Astrophysics Data System (ADS)

Berg, Nina; Joel, Kira; Koolyk, Miriam; Prodan, Emil

2011-02-01

This work describes a class of topological phonon modes, that is, mechanical vibrations localized at the edges of special structures that are robust against the deformations of the structures. A class of topological phonons was recently found in two-dimensional structures similar to that of microtubules. The present work introduces another class of topological phonons, this time occurring in quasi-one-dimensional filamentary structures with inversion symmetry. The phenomenon is exemplified using a structure inspired from that of actin microfilaments, present in most live cells. The system discussed here is probably the simplest structure that supports topological phonon modes, a fact that allows detailed analysis in both time and frequency domains. We advance the hypothesis that the topological phonon modes are ubiquitous in the biological world and that living organisms make use of them during various processes.

Leveraging insights from mainstream gameplay to inform STEM game design: great idea, but what comes next?

NASA Astrophysics Data System (ADS)

Biles, Melissa

2012-12-01

This response to Leah A. Bricker and Phillip Bell's paper, GodMode is his video game name, examines their assertion that the social nexus of gaming practices is an important factor to consider for those looking to design STEM video games. I propose that we need to go beyond the investigation into which aspects of games play a role in learning, and move on to thinking about how these insights can actually inform game design practice.

Transmission function properties for multi-layered structures: application to super-resolution.

PubMed

Mattiucci, N; D'Aguanno, G; Scalora, M; Bloemer, M J; Sibilia, C

2009-09-28

We discuss the properties of the transmission function in the k-space for a generic multi-layered structure. In particular we analytically demonstrate that a transmission greater than one in the evanescent spectrum (amplification of the evanescent modes) can be directly linked to the guided modes supported by the structure. Moreover we show that the slope of the phase of the transmission function in the propagating spectrum is inversely proportional to the ability of the structure to compensate the diffraction of the propagating modes. We apply these findings to discuss several examples where super-resolution is achieved thanks to the simultaneous availability of the amplification of the evanescent modes and the diffraction compensation of the propagating modes.

An Innovative Structural Mode Selection Methodology: Application for the X-33 Launch Vehicle Finite Element Model

NASA Technical Reports Server (NTRS)

Hidalgo, Homero, Jr.

2000-01-01

An innovative methodology for determining structural target mode selection and mode selection based on a specific criterion is presented. An effective approach to single out modes which interact with specific locations on a structure has been developed for the X-33 Launch Vehicle Finite Element Model (FEM). We presented Root-Sum-Square (RSS) displacement method computes resultant modal displacement for each mode at selected degrees of freedom (DOF) and sorts to locate modes with highest values. This method was used to determine modes, which most influenced specific locations/points on the X-33 flight vehicle such as avionics control components, aero-surface control actuators, propellant valve and engine points for use in flight control stability analysis and for flight POGO stability analysis. Additionally, the modal RSS method allows for primary or global target vehicle modes to also be identified in an accurate and efficient manner.

The Temporal Dynamics Model of Emotional Memory Processing: A Synthesis on the Neurobiological Basis of Stress-Induced Amnesia, Flashbulb and Traumatic Memories, and the Yerkes-Dodson Law

PubMed Central

Diamond, David M.; Campbell, Adam M.; Park, Collin R.; Halonen, Joshua; Zoladz, Phillip R.

2007-01-01

We have reviewed research on the effects of stress on LTP in the hippocampus, amygdala and prefrontal cortex (PFC) and present new findings which provide insight into how the attention and memory-related functions of these structures are influenced by strong emotionality. We have incorporated the stress-LTP findings into our “temporal dynamics” model, which provides a framework for understanding the neurobiological basis of flashbulb and traumatic memories, as well as stress-induced amnesia. An important feature of the model is the idea that endogenous mechanisms of plasticity in the hippocampus and amygdala are rapidly activated for a relatively short period of time by a strong emotional learning experience. Following this activational period, both structures undergo a state in which the induction of new plasticity is suppressed, which facilitates the memory consolidation process. We further propose that with the onset of strong emotionality, the hippocampus rapidly shifts from a “configural/cognitive map” mode to a “flashbulb memory” mode, which underlies the long-lasting, but fragmented, nature of traumatic memories. Finally, we have speculated on the significance of stress-LTP interactions in the context of the Yerkes-Dodson Law, a well-cited, but misunderstood, century-old principle which states that the relationship between arousal and behavioral performance can be linear or curvilinear, depending on the difficulty of the task. PMID:17641736

Impact of the green tea ingredient epigallocatechin gallate and a short pentapeptide (Ile-Ile-ala-Glu-Lys) on the structural organization of mixed micelles and the related uptake of cholesterol.

PubMed

Giangreco, Francesco; Höfinger, Siegfried; Bakalis, Evangelos; Zerbetto, Francesco

2018-06-07

High levels of blood cholesterol are conventionally linked to an increased risk of developing cardiovascular disease (Grundy, 1986). Here we examine the molecular mode of action of natural products with known cholesterol-lowering activity, such as for example the green tea ingredient epigallocatechin gallate and a short pentapeptide, Ile-Ile-Ala-Glu-Lys. Molecular Dynamics simulations are used to gain insight into the formation process of mixed micelles and, correspondingly, how active agents epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys could possibly interfere with it. Self-assembly of physiological micelles occurs on the order of 35-50 ns; most of the structural properties of mixed micelles are unaffected by epigallocatechin gallate or Ile-Ile-Ala-Glu-Lys which integrate into the micellar surface; the diffusive motion of constituting lipids palmitoyl-oleoyl-phosphatidylcholine and cholesterol is significantly down-regulated by both epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys; CONCLUSIONS: The molecular mode of action of natural compounds epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys is a significant down-regulation of the diffusive motion of micellar lipids. Natural compounds like the green tea ingredient epigallocatechin gallate and a short pentapeptide, Ile-Ile-Ala-Glu-Lys, lead to a significant down-regulation of the diffusive motion of micellar lipids thereby modulating cholesterol absorption into physiological micelles. Copyright © 2018. Published by Elsevier B.V.

Understanding reverberating chambers as an alternative facility for EMC testing

NASA Astrophysics Data System (ADS)

Ma, M. T.

A relatively new facility called a reverberating chamber designed for EMC testing is described. The purpose is to create a statistically uniform electric field inside a metal enclosure for testing radiated susceptibility or immunity of equipment. Design criteria in terms of the number of cavity modes, mode density, and composite quality factor are presented in details in order to understand the physical insight and to enhance interpretations of measurement results. Recent experimental data are included to illustrate the underlying principle.

Propagating annular modes

NASA Astrophysics Data System (ADS)

Sheshadri, A.; Plumb, R. A.

2017-12-01

The leading "annular mode", defined as the dominant EOF of surface pressure or of zonal mean zonal wind variability, appears as a dipolar structure straddling the mean midlatitude jet and thus seems to describe north-south wobbling of the jet latitude. However, extratropical zonal wind anomalies frequently tend to migrate poleward. This behavior can be described by the first two EOFs, the first (AM1) being the dipolar structure, and the second (AM2) having a tripolar structure centered on the mean jet. Taken in isolation, AM1 thus describes a north-south wobbling of the jet position, while AM2 describes a strengthening and narrowing of the jet. However, despite the fact that they are spatially orthogonal, and their corresponding time series temporally orthogonal, AM1 and AM2 are not independent, but show significant lag-correlations which reveal the propagation. The EOFs are not modes of the underlying dynamical system governing the zonal flow evolution. The true modes can be estimated using principal oscillation pattern (POP) analysis. In the troposphere, the leading POPs manifest themselves as a pair of complex conjugate structures with conjugate eigenvalues thus, in reality, constituting a single, complex, mode that describes propagating anomalies. Even though the principal components associated with the two leading EOFs decay at different rates, each decays faster than the true mode. These facts have implications for eddy feedback and the susceptibility of the mode to external perturbations. If one interprets the annular modes as the modes of the system, then simple theory predicts that the response to steady forcing will usually be dominated by AM1 (with the longest time scale). However, such arguments should really be applied to the true modes. Experiments with a simplified GCM show that climate response to perturbations do not necessarily have AM1 structures. Implications of these results for stratosphere-troposphere interactions are explored. The POP structures are shown to be independent of any weighting (unlike the EOFs, the structures and time scales of which change substantially with pressure weighting), a fact that is particularly important for a deep system such as the troposphere and stratospere. The structure and time evolution of coupled modes of the troposphere-stratosphere system are studied.

A Mixed-Mode (I-II) Fracture Criterion for AS4/8552 Carbon/Epoxy Composite Laminate

NASA Astrophysics Data System (ADS)

Karnati, Sidharth Reddy

A majority of aerospace structures are subjected to bending and stretching loads that introduce peel and shear stresses between the plies of a composite laminate. These two stress components cause a combination of mode I and II fracture modes in the matrix layer of the composite laminate. The most common failure mode in laminated composites is delamination that affects the structural integrity of composite structures. Damage tolerant designs of structures require two types of materials data: mixed-mode (I-II) delamination fracture toughness that predicts failure and delamination growth rate that predicts the life of the structural component. This research focuses determining mixed-mode (I-II) fracture toughness under a combination of mode I and mode II stress states and then a fracture criterion for AS4/8552 composite laminate, which is widely used in general aviation. The AS4/8552 prepreg was supplied by Hexcel Corporation and autoclave fabricated into a 20-ply unidirectional laminate with an artificial delamination by a Fluorinated Ethylene Propylene (FEP) film at the mid-plane. Standard split beam specimens were prepared and tested in double cantilever beam (DCB) and end notched flexure modes to determine mode I (GIC) and II (GIIC) fracture toughnesses, respectively. The DCB specimens were also tested in a modified mixed-mode bending apparatus at GIIm /GT ratios of 0.18, 0.37, 0.57 and 0.78, where GT is total and GIIm is the mode II component of energy release rates. The measured fracture toughness, GC, was found to follow the locus a power law equation. The equation was validated for the present and literature experimental data.

Ten key issues in modern flow chemistry.

PubMed

Wegner, Jens; Ceylan, Sascha; Kirschning, Andreas

2011-04-28

Ten essentials of synthesis in the flow mode, a new enabling technology in organic chemistry, are highlighted as flashlighted providing an insight into current and future issues and developments in this field. © The Royal Society of Chemistry 2011

Structural, vibrational, and electronic properties of an uncoordinated pseudoephedrine derivative and its mononuclear and trinuclear copper(II)-coordinated compounds: A combined theoretical and experimental study

NASA Astrophysics Data System (ADS)

Valencia, Israel; Ávila-Torres, Yenny; Barba-Behrens, Norah; Garzón, Ignacio L.

2014-11-01

Multicopper oxidases are fundamental in a variety of biological processes in bacteria, fungi and vertebrates. The catalytic center in these enzymes is formed basically by three copper ions, bridged by oxygen bonds. In order to get insights into the reactivity of these complex systems, biomimetic compounds are usually synthesized. Accordingly, in this work, we studied structural, vibrational, and electronic properties of an uncoordinated pseudoephedrine derivative, as well as its corresponding mononuclear and trinuclear copper(II)-coordinated complexes by means of density functional theory. The calculations are compared with experimental results using measurements of the infrared spectra. It is obtained that the molecular configuration of the pseudoephedrine amino-alcohol derivative is stabilized by hydrogen bonding Osbnd H⋯N and by Csbnd H⋯π interactions that are not present in the mononuclear and trinuclear compounds. The coordination compounds show octahedral and square pyramid geometries, respectively, which are slightly distorted by Jahn-Teller effects. The analysis of their theoretical and experimental IR spectra reveals signals related with hydrogen bonding as well as metal-ligand vibrational modes. Regarding the electronic structure, the density of states was calculated in order to analyze the atomic orbital contributions present in these compounds. This analysis would provide useful insights about the optical behavior, for example, in the visible region of the spectrum of the coordinated compounds. At these energies, the optical absorption would be influenced by the orbital interaction of the Cu2+d orbitals with sp ones of the ligand, reflecting a decrease of the HOMO-LUMO gap of the organic ligand due to the presence of the copper(II) ions.

2.4 GHz CMOS power amplifier with mode-locking structure to enhance gain.

PubMed

Lee, Changhyun; Park, Changkun

2014-01-01

We propose a mode-locking method optimized for the cascode structure of an RF CMOS power amplifier. To maximize the advantage of the typical mode-locking method in the cascode structure, the input of the cross-coupled transistor is modified from that of a typical mode-locking structure. To prove the feasibility of the proposed structure, we designed a 2.4 GHz CMOS power amplifier with a 0.18 μm RFCMOS process for polar transmitter applications. The measured power added efficiency is 34.9%, while the saturated output power is 23.32 dBm. The designed chip size is 1.4 × 0.6 mm(2).

2.4 GHz CMOS Power Amplifier with Mode-Locking Structure to Enhance Gain

PubMed Central

2014-01-01

We propose a mode-locking method optimized for the cascode structure of an RF CMOS power amplifier. To maximize the advantage of the typical mode-locking method in the cascode structure, the input of the cross-coupled transistor is modified from that of a typical mode-locking structure. To prove the feasibility of the proposed structure, we designed a 2.4 GHz CMOS power amplifier with a 0.18 μm RFCMOS process for polar transmitter applications. The measured power added efficiency is 34.9%, while the saturated output power is 23.32 dBm. The designed chip size is 1.4 × 0.6 mm2. PMID:25045755

Alcohol sensor based on single-mode-multimode-single-mode fiber structure

NASA Astrophysics Data System (ADS)

Mefina Yulias, R.; Hatta, A. M.; Sekartedjo, Sekartedjo

2016-11-01

Alcohol sensor based on Single-mode -Multimode-Single-mode (SMS) fiber structure is being proposed to sense alcohol concentration in alcohol-water mixtures. This proposed sensor uses refractive index sensing as its sensing principle. Fabricated SMS fiber structure had 40 m of multimode length. With power input -6 dBm and wavelength 1550 nm, the proposed sensor showed good response with sensitivity 1,983 dB per % v/v with measurement range 05 % v/v and measurement span 0,5% v/v.

Designing augmentative and alternative communication applications: the results of focus groups with speech-language pathologists and parents of children with autism spectrum disorder.

PubMed

Boster, Jamie B; McCarthy, John W

2018-05-01

The purpose of this study was to gain insight from speech-language pathologists (SLPs) and parents of children with autism spectrum disorder (ASD) regarding appealing features of augmentative and alternative communication (AAC) applications. Two separate 1-hour focus groups were conducted with 8 SLPs and 5 parents of children with ASD to identify appealing design features of AAC Apps, their benefits and potential concerns. Participants were shown novel interface designs for communication mode, play mode and incentive systems. Participants responded to poll questions and provided benefits and drawbacks of the features as part of structured discussion. SLPs and parents identified a range of appealing features in communication mode (customization, animation and colour-coding) as well as in play mode (games and videos). SLPs preferred interfaces that supported motor planning and instruction while parents preferred those features such as character assistants that would appeal to their child. Overall SLPs and parents agreed on features for future AAC Apps. SLPs and parents have valuable input in regards to future AAC app design informed by their experiences with children with ASD. Both groups are key stakeholders in the design process and should be included in future design and research endeavors. Implications for Rehabilitation AAC applications for the iPad are often designed based on previous devices without consideration of new features. Ensuring the design of new interfaces are appealing and beneficial for children with ASD can potentially further support their communication. This study demonstrates how key stakeholders in AAC including speech language pathologists and parents can provide information to support the development of future AAC interface designs. Key stakeholders may be an untapped resource in the development of future AAC interfaces for children with ASD.

Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis

PubMed Central

Thiele, S; Mungalpara, J; Steen, A; Rosenkilde, M M; Våbenø, J

2014-01-01

Background and Purpose The cyclopentapeptide FC131 (cyclo(-L-Arg1-L-Arg2-L-2-Nal3-Gly4-D-Tyr5-)) is an antagonist at the CXC chemokine receptor CXCR4, which plays a role in human immunodeficiency virus infection, cancer and stem cell recruitment. Binding modes for FC131 in CXCR4 have previously been suggested based on molecular docking guided by structure–activity relationship (SAR) data; however, none of these have been verified by in vitro experiments. Experimental Approach Heterologous 125I-12G5-competition binding and functional assays (inhibition of CXCL12-mediated activation) of FC131 and three analogues were performed on wild-type CXCR4 and 25 receptor mutants. Computational modelling was used to rationalize the experimental data. Key Results The Arg2 and 2-Nal3 side chains of FC131 interact with residues in TM-3 (His113, Asp171) and TM-5 (hydrophobic pocket) respectively. Arg1 forms charge-charge interactions with Asp187 in ECL-2, while D-Tyr5 points to the extracellular side of CXCR4. Furthermore, the backbone of FC131 interacts with the chemokine receptor-conserved Glu288 via two water molecules. Intriguingly, Tyr116 and Glu288 form a H-bond in CXCR4 crystal structures and mutation of either residue to Ala abolishes CXCR4 activity. Conclusions and Implications Ligand modification, receptor mutagenesis and computational modelling approaches were used to identify the binding mode of FC131 in CXCR4, which was in agreement with binding modes suggested from previous SAR studies. Furthermore, insights into the mechanism for CXCR4 activation by CXCL12 were gained. The combined findings will facilitate future design of novel CXCR4 antagonists. PMID:25039237

EH 11n modes E type in the disk and washer accelerating structure

NASA Astrophysics Data System (ADS)

Andreev, V. G.; Belugin, V. M.; Daikovsky, A. G.; Esin, S. K.; Kravchuk, L. V.; Paramonov, V. V.; Ryabov, A. D.

1983-01-01

The disk and washer accelerating structure has a great deal to do with high-beta structures progress. The frequencies and electromagnetic fields for modes, which have a different number of azimuthal variations, are calculated to determined the dispersion properties and other characteristics of parasitic modes in a disc and washer accelerating structure. The main attention was given to the accelerating structure of the linear accelerator of the Institute for Nuclear Research (INR) of the USSR Academy of Sciences. Modification of a structure for PIGMI accelerator (LANL, USA) is considered briefly.

Nonlinear Evolution of Counter-Propagating Whistler Mode Waves Excited by Anisotropic Electrons Within the Equatorial Source Region: 1-D PIC Simulations

NASA Astrophysics Data System (ADS)

Chen, Huayue; Gao, Xinliang; Lu, Quanming; Sun, Jicheng; Wang, Shui

2018-02-01

Nonlinear physical processes related to whistler mode waves are attracting more and more attention for their significant role in reshaping whistler mode spectra in the Earth's magnetosphere. Using a 1-D particle-in-cell simulation model, we have investigated the nonlinear evolution of parallel counter-propagating whistler mode waves excited by anisotropic electrons within the equatorial source region. In our simulations, after the linear phase of whistler mode instability, the strong electrostatic standing structures along the background magnetic field will be formed, resulting from the coupling between excited counter-propagating whistler mode waves. The wave numbers of electrostatic standing structures are about twice those of whistler mode waves generated by anisotropic hot electrons. Moreover, these electrostatic standing structures can further be coupled with either parallel or antiparallel propagating whistler mode waves to excite high-k modes in this plasma system. Compared with excited whistler mode waves, these high-k modes typically have 3 times wave number, same frequency, and about 2 orders of magnitude smaller amplitude. Our study may provide a fresh view on the evolution of whistler mode waves within their equatorial source regions in the Earth's magnetosphere.

One-way mode transmission in one-dimensional phononic crystal plates

NASA Astrophysics Data System (ADS)

Zhu, Xuefeng; Zou, Xinye; Liang, Bin; Cheng, Jianchun

2010-12-01

We investigate theoretically the band structures of one-dimensional phononic crystal (PC) plates with both antisymmetric and symmetric structures, and show how unidirectional transmission behavior can be obtained for either antisymmetric waves (A modes) or symmetric waves (S modes) by exploiting mode conversion and selection in the linear plate systems. The theoretical approach is illustrated for one PC plate example where unidirectional transmission behavior is obtained in certain frequency bands. Employing harmonic frequency analysis, we numerically demonstrate the one-way mode transmission for the PC plate with finite superlattice by calculating the steady-state displacement fields under A modes source (or S modes source) in forward and backward direction, respectively. The results show that the incident waves from A modes source (or S modes source) are transformed into S modes waves (or A modes waves) after passing through the superlattice in the forward direction and the Lamb wave rejections in the backward direction are striking with a power extinction ratio of more than 1000. The present structure can be easily extended to two-dimensional PC plate and efficiently encourage practical studies of experimental realization which is believed to have much significance for one-way Lamb wave mode transmission.

Crystal structure of the thioesterification conformation of Bacillus subtilis o-succinylbenzoyl-CoA synthetase reveals a distinct substrate-binding mode.

PubMed

Chen, Yaozong; Li, Tin Lok; Lin, Xingbang; Li, Xin; Li, Xiang David; Guo, Zhihong

2017-07-21

o -Succinylbenzoyl-CoA (OSB-CoA) synthetase (MenE) is an essential enzyme in bacterial vitamin K biosynthesis and an important target in the development of new antibiotics. It is a member of the adenylating enzymes (ANL) family, which reconfigure their active site in two different active conformations, one for the adenylation half-reaction and the other for a thioesterification half-reaction, in a domain-alternation catalytic mechanism. Although several aspects of the adenylating mechanism in MenE have recently been uncovered, its thioesterification conformation remains elusive. Here, using a catalytically competent Bacillus subtilis mutant protein complexed with an OSB-CoA analogue, we determined MenE high-resolution structures to 1.76 and 1.90 Å resolution in a thioester-forming conformation. By comparison with the adenylation conformation, we found that MenE's C-domain rotates around the Ser-384 hinge by 139.5° during domain-alternation catalysis. The structures also revealed a thioesterification active site specifically conserved among MenE orthologues and a substrate-binding mode distinct from those of many other acyl/aryl-CoA synthetases. Of note, using site-directed mutagenesis, we identified several residues that specifically contribute to the thioesterification half-reaction without affecting the adenylation half-reaction. Moreover, we observed a substantial movement of the activated succinyl group in the thioesterification half-reaction. These findings provide new insights into the domain-alternation catalysis of a bacterial enzyme essential for vitamin K biosynthesis and of its adenylating homologues in the ANL enzyme family. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Exploration of the Ca2+ interaction modes of the nifedipine calcium channel antagonist.

PubMed

Liu, Huichun; Zhang, Liang; Li, Ping; Cukier, Robert I; Bu, Yuxiang

2007-02-02

A comprehensive study is carried out using quantum chemical computation and molecular dynamics (MD) simulations to gain insight into the interaction between Ca(2+) ions and the most important class of calcium channel antagonists--nifedipine. First, the chelating structures and energetic characters of nifedipine-Ca(2+) in the gas phase are explored, and 25 isomers are found. The most favorable chelating mode is a tridentate one, that is, Ca(2+) binds to two carbonyl O atoms and one nitryl O atom, where Ca(2+) is above the plane of the three O atoms to form a pyramidal structure. Accurate geometric structures, relative stabilities, vertical and adiabatic binding energies, and charge distributions are discussed. The differences in the geometries and energies among these isomers are analyzed from the contributions of chelating sites, electrostatics and polarizations, steric repulsions, and charge distributions. The interconversions among isomers with similar geometries and energies are also investigated because of the importance of the geometric transformation in the biological system. Furthermore, certain numbers of water molecules are added to the nifedipine-Ca(2+) system to probe the effect of water. A detailed study is performed on the hydrated geometries on the basis of the most stable isomer 1. Stepwise hydration can weaken the nifedipine-Ca(2+) interaction, and the chelating sites of nifedipine are gradually replaced by the added water molecules. Hexacoordination is found to be the most favorable geometry no matter how many water molecules were added, which can be verified by the MD simulations. The transfer of water molecules from the inner shell to the outer shell is also supported by MD simulations of the hexahydrated complexes.

In situ DART-MS as a Versatile and Rapid Dereplication Tool in Lichenology: Chemical Fingerprinting of Ophioparma ventosa.

PubMed

Le Pogam, Pierre; Le Lamer, Anne-Cécile; Legouin, Béatrice; Boustie, Joël; Rondeau, David

2016-11-01

Lichens widely occur all over the world and are known to produce unique secondary metabolites with various biological activities. To develop high-throughput screening approaches requiring little to no sample preparation to alleviate the dereplication holdup and accelerate the discovery workflow of new structures from lichens. The extracellular distribution of lichen metabolites is incentive for in situ chemical profiling of lichens using the ambient mass spectrometry DART-MS. For this purpose, the chlorolichen Ophioparma ventosa, producing an array of lichen polyphenolics that encompass the main structural classes associated to lichen chemodiversity, represented a relevant model to assess the versatility of this platform. The feasibility of this approach was first established by analysing the pure compounds known from this species prior to being extended to different solid organs of the lichen. All tested compounds could be detected in positive and negative ion modes, most often with prevalent protonated or deprotonated molecules. Only depsides underwent a significant in-source fragmentation in both ionisation modes, which should be regarded as an added value for their structural elucidation. In situ DART-MS analyses of Ophioparma ventosa provided an extensive chemical profile and noteworthy pinpointed miriquidic acid, an unusual lichen depside so far unknown within this species. At last, in situ DART-MS granted a first insight into the distribution of the metabolites within the lichen. DART-MS represents a versatile tool to the wide field of lichenology, facilitating accelerated and sharp analyses of lichens and bypassing costly and tedious procedures of solvent extraction. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin.

PubMed

Kadam, Rameshwar U; Wilson, Ian A

2018-04-17

The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N -cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that N -cyclohexyltaurine binds to the heart of the conserved HA RBS. N -cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, N -cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.

Conserved and divergent features of the structure and function of La and La-related proteins (LARPs)

PubMed Central

Bayfield, Mark A.; Yang, Ruiqing; Maraia, Richard J.

2010-01-01

Genuine La proteins contain two RNA binding motifs, a La motif (LAM) followed by a RNA recognition motif (RRM), arranged in a unique way to bind RNA. These proteins interact with an extensive variety of cellular RNAs and exhibit activities in two broad categories: i) to promote the metabolism of nascent pol III transcripts, including precursor-tRNAs, by binding to their common, UUU-3’OH containing ends, and ii) to modulate the translation of certain mRNAs involving an unknown binding mechanism. Characterization of several La-RNA crystal structures as well as biochemical studies reveal insight into their unique two-motif domain architecture and how the LAM recognizes UUU-3’OH while the RRM binds other parts of a pre-tRNA. Recent studies of members of distinct families of conserved La-related proteins (LARPs) indicate that some of these harbor activity related to genuine La proteins, suggesting that their UUU-3’OH binding mode has been appropriated for the assembly and regulation of a specific snRNP (e.g., 7SK snRNA assembly by hLARP7/PIP7S). Analyses of other LARP family members (i.e., hLARP4, hLARP6) suggest more diverged RNA binding modes and specialization for cytoplasmic mRNA-related functions. Thus it appears that while genuine La proteins exhibit broad general involvement in both snRNA-related and mRNA-related functions, different LARP families may have evolved specialized activities in either snRNA or mRNA related functions. In this review, we summarize recent progress that has led to greater understanding of the structure and function of La proteins and their roles in tRNA processing and RNP assembly dynamics, as well as progress on the different LARPs. PMID:20138158

Conserved and divergent features of the structure and function of La and La-related proteins (LARPs).

PubMed

Bayfield, Mark A; Yang, Ruiqing; Maraia, Richard J

2010-01-01

Genuine La proteins contain two RNA binding motifs, a La motif (LAM) followed by a RNA recognition motif (RRM), arranged in a unique way to bind RNA. These proteins interact with an extensive variety of cellular RNAs and exhibit activities in two broad categories: i) to promote the metabolism of nascent pol III transcripts, including precursor-tRNAs, by binding to their common, UUU-3'OH containing ends, and ii) to modulate the translation of certain mRNAs involving an unknown binding mechanism. Characterization of several La-RNA crystal structures as well as biochemical studies reveal insight into their unique two-motif domain architecture and how the LAM recognizes UUU-3'OH while the RRM binds other parts of a pre-tRNA. Recent studies of members of distinct families of conserved La-related proteins (LARPs) indicate that some of these harbor activity related to genuine La proteins, suggesting that their UUU-3'OH binding mode has been appropriated for the assembly and regulation of a specific snRNP (e.g., 7SK snRNP assembly by hLARP7/PIP7S). Analyses of other LARP family members suggest more diverged RNA binding modes and specialization for cytoplasmic mRNA-related functions. Thus it appears that while genuine La proteins exhibit broad general involvement in both snRNA-related and mRNA-related functions, different LARP families may have evolved specialized activities in either snRNA or mRNA-related functions. In this review, we summarize recent progress that has led to greater understanding of the structure and function of La proteins and their roles in tRNA processing and RNP assembly dynamics, as well as progress on the different LARPs.

Self-Similarity of Plasmon Edge Modes on Koch Fractal Antennas.

PubMed

Bellido, Edson P; Bernasconi, Gabriel D; Rossouw, David; Butet, Jérémy; Martin, Olivier J F; Botton, Gianluigi A

2017-11-28

We investigate the plasmonic behavior of Koch snowflake fractal geometries and their possible application as broadband optical antennas. Lithographically defined planar silver Koch fractal antennas were fabricated and characterized with high spatial and spectral resolution using electron energy loss spectroscopy. The experimental data are supported by numerical calculations carried out with a surface integral equation method. Multiple surface plasmon edge modes supported by the fractal structures have been imaged and analyzed. Furthermore, by isolating and reproducing self-similar features in long silver strip antennas, the edge modes present in the Koch snowflake fractals are identified. We demonstrate that the fractal response can be obtained by the sum of basic self-similar segments called characteristic edge units. Interestingly, the plasmon edge modes follow a fractal-scaling rule that depends on these self-similar segments formed in the structure after a fractal iteration. As the size of a fractal structure is reduced, coupling of the modes in the characteristic edge units becomes relevant, and the symmetry of the fractal affects the formation of hybrid modes. This analysis can be utilized not only to understand the edge modes in other planar structures but also in the design and fabrication of fractal structures for nanophotonic applications.

Giant amplification in degenerate band edge slow-wave structures interacting with an electron beam

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

Othman, Mohamed A. K.; Veysi, Mehdi; Capolino, Filippo

2016-03-15

We propose a new amplification regime based on a synchronous operation of four degenerate electromagnetic (EM) modes in a slow-wave structure and the electron beam, referred to as super synchronization. These four EM modes arise in a Fabry-Pérot cavity when degenerate band edge (DBE) condition is satisfied. The modes interact constructively with the electron beam resulting in superior amplification. In particular, much larger gains are achieved for smaller beam currents compared to conventional structures based on synchronization with only a single EM mode. We demonstrate giant gain scaling with respect to the length of the slow-wave structure compared to conventionalmore » Pierce type single mode traveling wave tube amplifiers. We construct a coupled transmission line model for a loaded waveguide slow-wave structure exhibiting a DBE, and investigate the phenomenon of giant gain via super synchronization using the Pierce model generalized to multimode interaction.« less

A novel optical waveguide LP01/LP02 mode converter

NASA Astrophysics Data System (ADS)

Shen, Dongya; Wang, Changhui; Ma, Chuan; Mellah, Hakim; Zhang, Xiupu; Yuan, Hong; Ren, Wenping

2018-07-01

A novel optical waveguide LP01 /LP02 mode converter is proposed using combination of bicone structure based on the coupled-mode theory. It is composed of a cladding, a tapered core and combined bicone structure. It is found that this mode converter can have operating bandwidth of 1350-1700 nm, i.e. 350 nm, with a conversion efficiency of ∼90% (∼0.5 dB) and low crosstalk from other modes

Spatial frequency maps of power flow in metamaterials and photonic crystals: Investigating backward-wave modes across the electromagnetic spectrum

NASA Astrophysics Data System (ADS)

Aghanejad, Iman; Markley, Loïc

2017-11-01

We present spatial frequency maps of power flow in metamaterials and photonic crystals in order to provide insights into their electromagnetic responses and further our understanding of backward power in periodic structures. Since 2001, many different structures across the electromagnetic spectrum have been presented in the literature as exhibiting an isotropic negative effective index. Although these structures all exhibit circular or spherical equifrequency contours that resemble those of left-handed media, here we show through k -space diagrams that the distribution of power in the spatial frequency domain can vary considerably across these structures. In particular, we show that backward power arises from high-order right-handed harmonics in photonic crystals, magnetodielectric crystals, and across the layers of coupled-plasmonic-waveguide metamaterials, while arising from left-handed harmonic pairs in split-ring resonator and wire composites, plasmonic crystals, and along the layers of coupled-plasmonic-waveguide metamaterials. We also show that the fishnet structure exhibits the same left-handed harmonic pairs as the latter group. These observations allow us to categorize different metamaterials according to their spatial spectral source of backward power and identify the mechanism behind negative refraction at a given interface. Finally, we discuss how k -space maps of power flow can be used to explain the high or low transmittance of power into different metamaterial or photonic crystal structures.

Targeting G-quadruplex DNA structures in the telomere and oncogene promoter regions by benzimidazole‒carbazole ligands.

PubMed

Kaulage, Mangesh H; Maji, Basudeb; Pasadi, Sanjeev; Ali, Asfa; Bhattacharya, Santanu; Muniyappa, K

2018-03-25

Recent studies support the idea that G-quadruplex structures in the promoter regions of oncogenes and telomere DNA can serve as potential therapeutic targets in the treatment of cancer. Accordingly, several different types of organic small molecules that stabilize G-quadruplex structures and inhibit telomerase activity have been discerned. Here, we describe the binding of benzimidazole-carbazole ligands to G-quadruplex structures formed in G-rich DNA sequences containing the promoter regions of human c-MYC, c-KIT1, c-KIT2, VEGF and BCL2 proto-oncogenes. The fluorescence spectroscopic data indicate that benzimidazole-carbazole ligands bind and stabilize the G-quadruplexes in the promoter region of oncogenes. The molecular docking studies provide insights into the mode and extent of binding of this class of ligands to the G-quadruplexes formed in oncogene promoters. The high stability of these G-quadruplex structures was validated by thermal denaturation and telomerase-catalyzed extension of the 3' end. Notably, benzimidazole-carbazole ligands suppress the expression of oncogenes in cancer cells in a dose-dependent manner. We anticipate that benzimidazole-carbazole ligands, by virtue of their ability to stabilize G-quadruplex structures in the promoter regions of oncogenes, might reduce the risk of cancer through the loss of function in the proteins encoded by these genes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Analyses and tests of the B-1 aircraft structural mode control system

NASA Technical Reports Server (NTRS)

Wykes, J. H.; Byar, T. R.; Macmiller, C. J.; Greek, D. C.

1980-01-01

Analyses and flight tests of the B-1 structural mode control system (SMCS) are presented. Improvements in the total dynamic response of a flexible aircraft and the benefits to ride qualities, handling qualities, crew efficiency, and reduced dynamic loads on the primary structures, were investigated. The effectiveness and the performance of the SMCS, which uses small aerodynamic surfaces at the vehicle nose to provide damping to the structural modes, were evaluated.

Spillover stabilization and decentralized modal control of large space structures

NASA Technical Reports Server (NTRS)

Czajkowski, Eva A.; Preumont, Andre

1987-01-01

The stabilization of the neglected dynamics of the higher modes of vibration in large space structures is studied, and the influence of the structure of the plant noise intensity matrix of the Kalman-Bucy filter on the stability margin of the residual modes is shown. An optimization procedure uses information on the residual modes to minimize spillover of known residual modes while preserving robustness with respect to the unknown dynamics, and the optimum plant noise intensity matrix is selected to maximize the stability margins of the residual modes and to properly place the observer poles. Examples for both centralized and decentralized control are considered.

Analysis of complex elastic structures by a Rayleigh-Ritz component modes method using Lagrange multipliers. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Klein, L. R.

1974-01-01

The free vibrations of elastic structures of arbitrary complexity were analyzed in terms of their component modes. The method was based upon the use of the normal unconstrained modes of the components in a Rayleigh-Ritz analysis. The continuity conditions were enforced by means of Lagrange Multipliers. Examples of the structures considered are: (1) beams with nonuniform properties; (2) airplane structures with high or low aspect ratio lifting surface components; (3) the oblique wing airplane; and (4) plate structures. The method was also applied to the analysis of modal damping of linear elastic structures. Convergence of the method versus the number of modes per component and/or the number of components is discussed and compared to more conventional approaches, ad-hoc methods, and experimental results.

Improved Numerical Calculation of the Single-Mode-No-Core-Single-Mode Fiber Structure Using the Fields Far from Cutoff Approximation

PubMed Central

Yang, Xianchao; Xu, Degang; Rong, Feng; Zhao, Junfa; Yao, Jianquan

2017-01-01

Multimode interferometers based on the single-mode-no-core-single-mode fiber (SNCS) structure have been widely investigated as functional devices and sensors. However, the theoretical support for the sensing mechanism is still imperfect, especially for the cladding refractive index response. In this paper, a modified model of no-core fiber (NCF) based on far from cut-off approximation is proposed to investigate the spectrum characteristic and sensing mechanism of the SNCS structure. Guided-mode propagation analysis (MPA) is used to analyze the self-image effect and spectrum response to the cladding refractive index and temperature. Verified by experiments, the performance of the SNCS structure can be estimated specifically and easily by the proposed method. PMID:28961174

Direct evidence of stationary zonal flows and critical gradient behavior for Er during formation of the edge pedestal in JET

NASA Astrophysics Data System (ADS)

Hillesheim, Jon

2015-11-01

High spatial resolution measurements with Doppler backscattering in JET have provided new insights into the development of the edge radial electric field during pedestal formation. The characteristics of Er have been studied as a function of density at 2.5 MA plasma current and 3 T toroidal magnetic field. We observe fine-scale spatial structure in the edge Er well prior to the LH transition, consistent with stationary zonal flows. Zonal flows are a fundamental mechanism for the saturation of turbulence and this is the first direct evidence of stationary zonal flows in a tokamak. The radial wavelength of the zonal flows systematically decreases with density. The zonal flows are clearest in Ohmic conditions, weaker in L-mode, and absent in H-mode. Measurements also show that after neutral beam heating is applied, the edge Er builds up at a constant gradient into the core during L-mode, at radii where Er is mainly due to toroidal velocity. The local stability of velocity shear driven turbulence, such as the parallel velocity gradient mode, will be assessed with gyrokinetic simulations. This critical Er shear persists across the LH transition into H-mode. Surprisingly, a reduction in the apparent magnitude of the Er well depth is observed directly following the LH transition at high densities. Establishing the physics basis for the LH transition is important for projecting scalings to ITER and these observations challenge existing models based on increased Er shear or strong zonal flows as the trigger for the transition. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 under grant agreement No 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission.

A trade-off between model resolution and variance with selected Rayleigh-wave data

USGS Publications Warehouse

Xia, J.; Miller, R.D.; Xu, Y.

2008-01-01

Inversion of multimode surface-wave data is of increasing interest in the near-surface geophysics community. For a given near-surface geophysical problem, it is essential to understand how well the data, calculated according to a layered-earth model, might match the observed data. A data-resolution matrix is a function of the data kernel (determined by a geophysical model and a priori information applied to the problem), not the data. A data-resolution matrix of high-frequency (??? 2 Hz) Rayleigh-wave phase velocities, therefore, offers a quantitative tool for designing field surveys and predicting the match between calculated and observed data. First, we employed a data-resolution matrix to select data that would be well predicted and to explain advantages of incorporating higher modes in inversion. The resulting discussion using the data-resolution matrix provides insight into the process of inverting Rayleigh-wave phase velocities with higher mode data to estimate S-wave velocity structure. Discussion also suggested that each near-surface geophysical target can only be resolved using Rayleigh-wave phase velocities within specific frequency ranges, and higher mode data are normally more accurately predicted than fundamental mode data because of restrictions on the data kernel for the inversion system. Second, we obtained an optimal damping vector in a vicinity of an inverted model by the singular value decomposition of a trade-off function of model resolution and variance. In the end of the paper, we used a real-world example to demonstrate that selected data with the data-resolution matrix can provide better inversion results and to explain with the data-resolution matrix why incorporating higher mode data in inversion can provide better results. We also calculated model-resolution matrices of these examples to show the potential of increasing model resolution with selected surface-wave data. With the optimal damping vector, we can improve and assess an inverted model obtained by a damped least-square method.

Consistent assignment of the vibrations of symmetric and asymmetric ortho-disubstituted benzenes

NASA Astrophysics Data System (ADS)

Tuttle, William D.; Gardner, Adrian M.; Andrejeva, Anna; Kemp, David J.; Wakefield, Jonathan C. A.; Wright, Timothy G.

2018-02-01

The form of molecular vibrations, and changes in these, give valuable insights into geometric and electronic structure upon electronic excitation or ionization, and within families of molecules. Here, we give a description of the phenyl-ring-localized vibrational modes of the ground (S0) electronic states of a wide range of ortho-disubstituted benzene molecules including both symmetrically- and asymmetrically-substituted cases. We conclude that the use of the commonly-used Wilson or Varsányi mode labels, which are based on the vibrational motions of benzene itself, is misleading and ambiguous. In addition, we also find the use of the Mi labels for monosubstituted benzenes [A.M. Gardner, T.G. Wright. J. Chem. Phys. 135 (2011) 114305], or the recently-suggested labels for para-disubstituted benzenes [A. Andrejeva, A.M. Gardner, W.D. Tuttle, T.G. Wright, J. Molec. Spectrosc. 321, 28 (2016)] are not appropriate. Instead, we label the modes consistently based upon the Mulliken (Herzberg) method for the modes of ortho-difluorobenzene (pDFB) under Cs symmetry, since we wish the labelling scheme to cover both symmetrically- and asymmetrically-substituted molecules. By studying the vibrational wavenumbers from the same force field while varying the mass of the substituent, we are able to identify the corresponding modes across a wide range of molecules and hence provide consistent assignments. We assign the vibrations of the following sets of molecules: the symmetric o-dihalobenzenes, o-xylene and catechol (o-dihydroxybenzene); and the asymmetric o-dihalobenzenes, o-halotoluenes, o-halophenols and o-cresol. In the symmetrically-substituted species, we find a pair of in-phase and out-of-phase carbon-substituent stretches, and this motion persists in asymmetrically-substituted molecules for heavier substituents. When at least one of the substituents is light, then we find that these evolve into localized carbon-substituent stretches.

A symmetry measure for damage detection with mode shapes

NASA Astrophysics Data System (ADS)

Chen, Justin G.; Büyüköztürk, Oral

2017-11-01

This paper introduces a feature for detecting damage or changes in structures, the continuous symmetry measure, which can quantify the amount of a particular rotational, mirror, or translational symmetry in a mode shape of a structure. Many structures in the built environment have geometries that are either symmetric or almost symmetric, however damage typically occurs in a local manner causing asymmetric changes in the structure's geometry or material properties, and alters its mode shapes. The continuous symmetry measure can quantify these changes in symmetry as a novel indicator of damage for data-based structural health monitoring approaches. This paper describes the concept as a basis for detecting changes in mode shapes and detecting structural damage. Application of the method is demonstrated in various structures with different symmetrical properties: a pipe cross-section with a finite element model and experimental study, the NASA 8-bay truss model, and the simulated IASC-ASCE structural health monitoring benchmark structure. The applicability and limitations of the feature in applying it to structures of varying geometries is discussed.

Waves in a plane graphene - dielectric waveguide structure

NASA Astrophysics Data System (ADS)

Evseev, Dmitry A.; Eliseeva, Svetlana V.; Sementsov, Dmitry I.

2017-10-01

The features of the guided TE modes propagation have been investigated on the basis of computer simulations in a planar structure consisting of a set of alternating layers of dielectric and graphene. Within the framework of the effective medium approximation, the dispersion relations have been received for symmetric and antisymmetric waveguide modes, determined by the frequency range of their existence. The wave field distribution by structure, frequency dependences of the constants of propagation and transverse components of the wave vectors, as well as group and phase velocities of waveguide modes have been obtained, the effect of the graphene part in a structure on the waveguide mode behavior has been shown.

Stepping stone or stumbling block? Mode 2 knowledge production in sustainability science.

PubMed

Thorén, Henrik; Breian, Line

2016-04-01

The concept of Mode 2 has often been seen as especially applicable to fields addressing grand challenges, such as climate change. Being a relatively new field-interdisciplinary in its approach, and focused on addressing such issues-sustainability science would appear to be a case in point. The aim of this paper is twofold: 1) to explore the perceived relation between Mode 2 and sustainability science, and 2) to advance the discussion of Mode 2 from a philosophical perspective. To address these questions we focus on three characteristic features of Mode 2: the notion of a distinct, but evolving framework; boundary crossing; and a problem solving capacity "on the move". We report the results of a survey carried out amongst leading sustainability scientists. The survey gives insight into the scientists' perception of Mode 2, their perception of their own field of sustainability science and the relation between the two. The free text answers reveal a tension within the field of sustainability science: with developments both towards Mode 1 and Mode 2 science. We conclude that the implementation of inter- and trans-disciplinarity is challenged by institutional and conceptual factors alike. Copyright © 2015 Elsevier Ltd. All rights reserved.

Helicobacter pylori purine nucleoside phosphorylase shows new distribution patterns of open and closed active site conformations and unusual biochemical features.

PubMed

Narczyk, Marta; Bertoša, Branimir; Papa, Lucija; Vuković, Vedran; Leščić Ašler, Ivana; Wielgus-Kutrowska, Beata; Bzowska, Agnieszka; Luić, Marija; Štefanić, Zoran

2018-04-01

Even with decades of research, purine nucleoside phosphorylases (PNPs) are enzymes whose mechanism is yet to be fully understood. This is especially true in the case of hexameric PNPs, and is probably, in part, due to their complex oligomeric nature and a whole spectrum of active site conformations related to interactions with different ligands. Here we report an extensive structural characterization of the apo forms of hexameric PNP from Helicobacter pylori (HpPNP), as well as its complexes with phosphate (P i ) and an inhibitor, formycin A (FA), together with kinetic, binding, docking and molecular dynamics studies. X-ray structures show previously unseen distributions of open and closed active sites. Microscale thermophoresis results indicate that a two-site model describes P i binding, while a three-site model is needed to characterize FA binding, irrespective of P i presence. The latter may be related to the newly found nonstandard mode of FA binding. The ternary complex of the enzyme with P i and FA shows, however, that P i binding stabilizes the standard mode of FA binding. Surprisingly, HpPNP has low affinity towards the natural substrate adenosine. Molecular dynamics simulations show that P i moves out of most active sites, in accordance with its weak binding. Conformational changes between nonstandard and standard binding modes of nucleoside are observed during the simulations. Altogether, these findings show some unique features of HpPNP and provide new insights into the functioning of the active sites, with implications for understanding the complex mechanism of catalysis of this enzyme. The atomic coordinates and structure factors have been deposited in the Protein Data Bank: with accession codes 6F52 (HpPNPapo_1), 6F5A (HpPNPapo_2), 6F5I (HpPNPapo_3), 5LU0 (HpPNP_PO4), 6F4W (HpPNP_FA) and 6F4X (HpPNP_PO4_FA). Purine nucleoside orthophosphate ribosyl transferase, EC2.4.2.1, UniProtID: P56463. © 2018 Federation of European Biochemical Societies.

Science highlights from MAVEN/IUVS after two years in Mars Orbit

NASA Astrophysics Data System (ADS)

Schneider, N. M.; Deighan, J.; Stiepen, A.; Jain, S.; Lefèvre, F.; Stevens, M. H.; Gröller, H.; Yelle, R. V.; Lo, D.; Evans, J. S.; Stewart, I. F.; Chaffin, M.; Crismani, M. M. J.; Mayyasi, M.; McClintock, W. E.; Holsclaw, G.; Clarke, J. T.; Montmessin, F.; Jakosky, B. M.

2016-12-01

The broad capabilities of the Imaging UltraViolet Spectrograph on the MAVEN mission are enabling new science ranging from Mars' lower atmosphere up though the escaping corona. After two years in Mars orbit, the instrument has yielded insights on present-day processes at Mars including dayglow, nightglow, aurora, meteor showers, clouds, and solar-planetary interactions. In this presentation we will highlight several new discoveries in the mesosphere and below. First, spatial mapping of nitric oxide nightglow reveals regions of atmospheric downwelling necessitating substantial changes to global atmospheric circulation models. Second, a new high-spatial-resolution UV imaging mode allows detection of clouds from nadir to limb and their local time evolution, as well as unprecedented determinations of Mars' low-altitude ozone. Finally, IUVS has obtained hundreds of stellar occultation profiles probing atmospheric structure, composition, waves and tides.

Effect of optical damage resistant dopants on the dielectric properties of LiNbO3: Insight from broadband impedance spectroscopy and Raman scattering

NASA Astrophysics Data System (ADS)

Cochard, Charlotte; Guennou, Mael; Spielmann, Thiemo; van Hoof, Niels; Halpin, Alexei; Granzow, Torsten

2018-04-01

Optical damage limits the application range of congruent LiNbO3. This problem is commonly overcome by adding optical-damage-resistant cations. Here, the influence of doping with optical-damage-resistant Mg and Zn on the ionic and piezoelectric contributions to the dielectric permittivity is investigated in a broad frequency range (1 mHz-2 THz). It is shown that the two dopants have radically different influences on the variation of ionic permittivity with doping, in spite of their similarities with respect to the crystallographic structure. Raman spectroscopy reveals that the difference in permittivity can be traced to the effect of Mg and Zn doping on the susceptibility of the phonon modes. Both observations point to differences in the defect incorporation mechanisms.

Decentralized supply chain network design: monopoly, duopoly and oligopoly competitions under uncertainty

NASA Astrophysics Data System (ADS)

Seyedhosseini, Seyed Mohammad; Fahimi, Kaveh; Makui, Ahmad

2017-12-01

This paper presents the competitive supply chain network design problem in which n decentralized supply chains simultaneously enter the market with no existing rival chain, shape their networks and set wholesale and retail prices in competitive mode. The customer demand is elastic and price dependent, customer utility function is based on the Hoteling model and the chains produce identical or highly substitutable products. We construct a solution algorithm based on bi-level programming and possibility theory. In the proposed bi-level model, the inner part sets the prices based on simultaneous extra- and Stackleberg intra- chains competitions, and the outer part shapes the networks in cooperative competitions. Finally, we use a real-word study to discuss the effect of the different structures of the competitors on the equilibrium solution. Moreover, sensitivity analyses are conducted and managerial insights are offered.

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

PubMed

Pérez-Pérez, María-Jesús; Priego, Eva-María; Bueno, Oskía; Martins, Maria Solange; Canela, María-Dolores; Liekens, Sandra

2016-10-13

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

The versatility of boron in biological target engagement

NASA Astrophysics Data System (ADS)

Diaz, Diego B.; Yudin, Andrei K.

2017-08-01

Boron-containing molecules have been extensively used for the purposes of chemical sensing, biological probe development and drug discovery. Due to boron's empty p orbital, it can coordinate to heteroatoms such as oxygen and nitrogen. This reversible covalent mode of interaction has led to the use of boron as bait for nucleophilic residues in disease-associated proteins, culminating in the approval of new therapeutics that work by covalent mechanisms. Our analysis of a wide range of covalent inhibitors with electrophilic groups suggests that boron is a unique electrophile in its chameleonic ability to engage protein targets. Here we review boron's interactions with a range of protein side-chain residues and reveal that boron's properties are nuanced and arise from its uncommon coordination preferences. These mechanistic and structural insights should serve as a guide for the development of selective boron-based bioactive molecules.

Photonic crystal resonances for sensing and imaging

NASA Astrophysics Data System (ADS)

Pitruzzello, Giampaolo; Krauss, Thomas F.

2018-07-01

This review provides an insight into the recent developments of photonic crystal (PhC)-based devices for sensing and imaging, with a particular emphasis on biosensors. We focus on two main classes of devices, namely sensors based on PhC cavities and those on guided mode resonances (GMRs). This distinction is able to capture the richness of possibilities that PhCs are able to offer in this space. We present recent examples highlighting applications where PhCs can offer new capabilities, open up new applications or enable improved performance, with a clear emphasis on the different types of structures and photonic functions. We provide a critical comparison between cavity-based devices and GMR devices by highlighting strengths and weaknesses. We also compare PhC technologies and their sensing mechanism to surface plasmon resonance, microring resonators and integrated interferometric sensors.

Scaling of mode shapes from operational modal analysis using harmonic forces

NASA Astrophysics Data System (ADS)

Brandt, A.; Berardengo, M.; Manzoni, S.; Cigada, A.

2017-10-01

This paper presents a new method for scaling mode shapes obtained by means of operational modal analysis. The method is capable of scaling mode shapes on any structure, also structures with closely coupled modes, and the method can be used in the presence of ambient vibration from traffic or wind loads, etc. Harmonic excitation can be relatively easily accomplished by using general-purpose actuators, also for force levels necessary for driving large structures such as bridges and highrise buildings. The signal processing necessary for mode shape scaling by the proposed method is simple and the method can easily be implemented in most measurement systems capable of generating a sine wave output. The tests necessary to scale the modes are short compared to typical operational modal analysis test time. The proposed method is thus easy to apply and inexpensive relative to some other methods for scaling mode shapes that are available in literature. Although it is not necessary per se, we propose to excite the structure at, or close to, the eigenfrequencies of the modes to be scaled, since this provides better signal-to-noise ratio in the response sensors, thus permitting the use of smaller actuators. An extensive experimental activity on a real structure was carried out and the results reported demonstrate the feasibility and accuracy of the proposed method. Since the method utilizes harmonic excitation for the mode shape scaling, we propose to call the method OMAH.

Single-mode annular chirally-coupled core fibers for fiber lasers

NASA Astrophysics Data System (ADS)

Zhang, Haitao; Hao, He; He, Linlu; Gong, Mali

2018-03-01

Chirally-coupled core (CCC) fiber can transmit single fundamental mode and effectively suppresses higher-order mode (HOM) propagation, thus improve the beam quality. However, the manufacture of CCC fiber is complicated due to its small side core. To decrease the manufacture difficulty in China, a novel fiber structure is presented, defined as annular chirally-coupled core (ACCC) fiber, replacing the small side core by a larger side annulus. In this paper, we designed the fiber parameters of this new structure, and demonstrated that the new structure has a similar property of single mode with traditional CCC fiber. Helical coordinate system was introduced into the finite element method (FEM) to analyze the mode field in the fiber, and the beam propagation method (BPM) was employed to analyze the influence of the fiber parameters on the mode loss. Based on the result above, the fiber structure was optimized for efficient single-mode transmission, in which the core diameter is 35 μm with beam quality M2 value of 1.04 and an optical to optical conversion efficiency of 84%. In this fiber, fundamental mode propagates in an acceptable loss, while the HOMs decay rapidly.

Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

DOE PAGES

Nikolaienko, Roman M.; Hammel, Michal; Dubreuil, Véronique; ...

2016-08-18

Protein-tyrosine phosphatase receptor type G (RPTPγ/PTPRG) interacts in vitro with contactin-3-6 (CNTN3-6), a group of glycophosphatidylinositol-anchored cell adhesion molecules involved in the wiring of the nervous system. In addition to PTPRG, CNTNs associate with multiple transmembrane proteins and signal inside the cell via cis-binding partners to alleviate the absence of an intracellular region. Here, we use comprehensive biochemical and structural analyses to demonstrate that PTPRG·CNTN3-6 complexes share similar binding affinities and a conserved arrangement. Furthermore, as a first step to identifying PTPRG·CNTN complexes in vivo, we found that PTPRG and CNTN3 associate in the outer segments of mouse rod photoreceptormore » cells. In particular, PTPRG and CNTN3 form cis-complexes at the surface of photoreceptors yet interact in trans when expressed on the surfaces of apposing cells. Further structural analyses suggest that all CNTN ectodomains adopt a bent conformation and might lie parallel to the cell surface to accommodate these cis and trans binding modes. Taken together, these studies identify a PTPRG·CNTN complex in vivo and provide novel insights into PTPRG- and CNTN-mediated signaling.« less