Interdomain flexibility and pH-induced conformational changes of AcrA revealed by molecular dynamics simulations.

PubMed

Wang, Beibei; Weng, Jingwei; Fan, Kangnian; Wang, Wenning

2012-03-15

The membrane fusion protein (MFP) AcrA is proposed to link the inner membrane transporter AcrB and outer membrane protein TolC, forming the tripartite AcrAB-TolC efflux pump, and was shown to be functionally indispensible. Structural and EPR studies showed that AcrA has high conformational flexibility and exhibited pH-induced conformational change. In this study, we built the complete structure of AcrA through homology modeling and performed atomistic simulations of AcrA at different pH values. It was shown that the conformational flexibility of AcrA originates from the motions of α-hairpin and MP domains. The conformational dynamics of AcrA is sensitive to specific point mutations and pH values. In agreement with the EPR experiments, the interdomain motions were restrained upon lowering pH from 7.0 to 5.0 in the simulations. It was found that the protonation/deprotonation of His285 underlies the pH-regulated conformational dynamics of AcrA by disturbing the local hydrogen bond interactions, suggesting that the changes of pH in the periplasm accompanying the drug efflux could act as a signal to trigger the action of AcrA, which undergoes reversible conformational rearrangement. © 2012 American Chemical Society

Structural Refinement of Proteins by Restrained Molecular Dynamics Simulations with Non-interacting Molecular Fragments.

PubMed

Shen, Rong; Han, Wei; Fiorin, Giacomo; Islam, Shahidul M; Schulten, Klaus; Roux, Benoît

2015-10-01

The knowledge of multiple conformational states is a prerequisite to understand the function of membrane transport proteins. Unfortunately, the determination of detailed atomic structures for all these functionally important conformational states with conventional high-resolution approaches is often difficult and unsuccessful. In some cases, biophysical and biochemical approaches can provide important complementary structural information that can be exploited with the help of advanced computational methods to derive structural models of specific conformational states. In particular, functional and spectroscopic measurements in combination with site-directed mutations constitute one important source of information to obtain these mixed-resolution structural models. A very common problem with this strategy, however, is the difficulty to simultaneously integrate all the information from multiple independent experiments involving different mutations or chemical labels to derive a unique structural model consistent with the data. To resolve this issue, a novel restrained molecular dynamics structural refinement method is developed to simultaneously incorporate multiple experimentally determined constraints (e.g., engineered metal bridges or spin-labels), each treated as an individual molecular fragment with all atomic details. The internal structure of each of the molecular fragments is treated realistically, while there is no interaction between different molecular fragments to avoid unphysical steric clashes. The information from all the molecular fragments is exploited simultaneously to constrain the backbone to refine a three-dimensional model of the conformational state of the protein. The method is illustrated by refining the structure of the voltage-sensing domain (VSD) of the Kv1.2 potassium channel in the resting state and by exploring the distance histograms between spin-labels attached to T4 lysozyme. The resulting VSD structures are in good agreement with the consensus model of the resting state VSD and the spin-spin distance histograms from ESR/DEER experiments on T4 lysozyme are accurately reproduced.

Antibacterial Activity Affected by the Conformational Flexibility in Glycine-Lysine Based α-Helical Antimicrobial Peptides.

PubMed

Rončević, Tomislav; Vukičević, Damir; Ilić, Nada; Krce, Lucija; Gajski, Goran; Tonkić, Marija; Goić-Barišić, Ivana; Zoranić, Larisa; Sonavane, Yogesh; Benincasa, Monica; Juretić, Davor; Maravić, Ana; Tossi, Alessandro

2018-04-12

Antimicrobial peptides often show broad-spectrum activity due to a mechanism based on bacterial membrane disruption, which also reduces development of permanent resistance, a desirable characteristic in view of the escalating multidrug resistance problem. Host cell toxicity however requires design of artificial variants of natural AMPs to increase selectivity and reduce side effects. Kiadins were designed using rules obtained from natural peptides active against E. coli and a validated computational algorithm based on a training set of such peptides, followed by rational conformational alterations. In vitro activity, tested against ESKAPE strains (ATCC and clinical isolates), revealed a varied activity spectrum and cytotoxicity that only in part correlated with conformational flexibility. Peptides with a higher proportion of Gly were generally less potent and caused less bacterial membrane alteration, as observed by flow cytometry and AFM, which correlate to structural characteristics as observed by circular dichroism spectroscopy and predicted by molecular dynamics calculations.

Structural constraints-based evaluation of immunogenic avirulent toxins from Clostridium botulinum C2 and C3 toxins as subunit vaccines.

PubMed

Prisilla, A; Prathiviraj, R; Sasikala, R; Chellapandi, P

2016-10-01

Clostridium botulinum (group-III) is an anaerobic bacterium producing C2 and C3 toxins in addition to botulinum neurotoxins in avian and mammalian cells. C2 and C3 toxins are members of bacterial ADP-ribosyltransferase superfamily, which modify the eukaryotic cell surface proteins by ADP-ribosylation reaction. Herein, the mutant proteins with lack of catalytic and pore forming function derived from C2 (C2I and C2II) and C3 toxins were computationally evaluated to understand their structure-function integrity. We have chosen many structural constraints including local structural environment, folding process, backbone conformation, conformational dynamic sub-space, NAD-binding specificity and antigenic determinants for screening of suitable avirulent toxins. A total of 20 avirulent mutants were identified out of 23 mutants, which were experimentally produced by site-directed mutagenesis. No changes in secondary structural elements in particular to α-helices and β-sheets and also in fold rate of all-β classes. Structural stability was maintained by reordered hydrophobic and hydrogen bonding patterns. Molecular dynamic studies suggested that coupled mutations may restrain the binding affinity to NAD(+) or protein substrate upon structural destabilization. Avirulent toxins of this study have stable energetic backbone conformation with a common blue print of folding process. Molecular docking studies revealed that avirulent mutants formed more favorable hydrogen bonding with the side-chain of amino acids near to conserved NAD-binding core, despite of restraining NAD-binding specificity. Thus, structural constraints in the avirulent toxins would determine their immunogenic nature for the prioritization of protein-based subunit vaccine/immunogens to avian and veterinary animals infected with C. botulinum. Copyright © 2016 Elsevier B.V. All rights reserved.

Acyclic peptides incorporating the d-Phe-2-Abz turn motif: Investigations on antimicrobial activity and propensity to adopt β-hairpin conformations.

PubMed

Cameron, Alan J; Varnava, Kyriakos G; Edwards, Patrick J B; Harjes, Elena; Sarojini, Vijayalekshmi

2018-06-14

Three linear peptides incorporating d-Phe-2-Abz as the turn motif are reported. Peptide 1, a hydrophobic β-hairpin, served as a proof of principle for the design strategy with both NMR and CD spectra strongly suggesting a β-hairpin conformation. Peptides 2 and 3, designed as amphipathic antimicrobials, exhibited broad spectrum antimicrobial activity, with potency in the nanomolar range against Staphylococcus aureus. Both compounds possess a high degree of selectivity, proving non-haemolytic at concentrations 500 to 800 times higher than their respective minimal inhibitory concentrations (MICs) against S. aureus. Peptide 2 induced cell membrane and cell wall disintegration in both S. aureus and Pseudomonas aeruginosa as observed by transmission electron microscopy. Peptide 2 also demonstrated moderate antifungal activity against Candida albicans with an MIC of 50 μM. Synergism was observed with sub-MIC levels of amphotericin B (AmB), leading to nanomolar MICs against C. albicans for peptide 2. Based on circular dichroism spectra, both peptides 2 and 3 appear to exist as a mixture of conformers with the β-hairpin as a minor conformer in aqueous solution, and a slight increase in hairpin population in 50% trifluoroethanol, which was more pronounced for peptide 3. NMR spectra of peptide 2 in a 1:1 CD 3 CN/H 2 O mixture and 30 mM deuterated sodium dodecyl sulfate showed evidence of an extended backbone conformation of the β-strand residues. However, inter-strand rotating frame Overhauser effects (ROE) could not be detected and a loosely defined divergent hairpin structure resulted from ROE structure calculation in CD 3 CN/H 2 O. The loosely defined hairpin conformation is most likely a result of the electrostatic repulsions between cationic strand residues which also probably contribute towards maintaining low haemolytic activity. Copyright © 2018 European Peptide Society and John Wiley & Sons, Ltd.

Accurate calculation of conformational free energy differences in explicit water: the confinement-solvation free energy approach.

PubMed

Esque, Jeremy; Cecchini, Marco

2015-04-23

The calculation of the free energy of conformation is key to understanding the function of biomolecules and has attracted significant interest in recent years. Here, we present an improvement of the confinement method that was designed for use in the context of explicit solvent MD simulations. The development involves an additional step in which the solvation free energy of the harmonically restrained conformers is accurately determined by multistage free energy perturbation simulations. As a test-case application, the newly introduced confinement/solvation free energy (CSF) approach was used to compute differences in free energy between conformers of the alanine dipeptide in explicit water. The results are in excellent agreement with reference calculations based on both converged molecular dynamics and umbrella sampling. To illustrate the general applicability of the method, conformational equilibria of met-enkephalin (5 aa) and deca-alanine (10 aa) in solution were also analyzed. In both cases, smoothly converged free-energy results were obtained in agreement with equilibrium sampling or literature calculations. These results demonstrate that the CSF method may provide conformational free-energy differences of biomolecules with small statistical errors (below 0.5 kcal/mol) and at a moderate computational cost even with a full representation of the solvent.

Opposing Biological Functions of Tryptophan Catabolizing Enzymes During Intracellular Infection

PubMed Central

Divanovic, Senad; Sawtell, Nancy M.; Trompette, Aurelien; Warning, Jamie I.; Dias, Alexandra; Cooper, Andrea M.; Yap, George S.; Arditi, Moshe; Shimada, Kenichi; DuHadaway, James B.; Prendergast, George C.; Basaraba, Randall J.; Mellor, Andrew L.; Munn, David H.; Aliberti, Julio

2012-01-01

Recent studies have underscored physiological and pathophysiological roles for the tryptophan-degrading enzyme indolamine 2,3-dioxygenase (IDO) in immune counterregulation. However, IDO was first recognized as an antimicrobial effector, restricting tryptophan availability to Toxoplasma gondii and other pathogens in vitro. The biological relevance of these findings came under question when infectious phenotypes were not forthcoming in IDO-deficient mice. The recent discovery of an IDO homolog, IDO-2, suggested that the issue deserved reexamination. IDO inhibition during murine toxoplasmosis led to 100% mortality, with increased parasite burdens and no evident effects on the immune response. Similar studies revealed a counterregulatory role for IDO during leishmaniasis (restraining effector immune responses and parasite clearance), and no evident role for IDO in herpes simplex virus type 1 (HSV-1) infection. Thus, IDO plays biologically important roles in the host response to diverse intracellular infections, but the dominant nature of this role—antimicrobial or immunoregulatory—is pathogen-specific. PMID:21990421

Characterizing highly dynamic conformational states: The transcription bubble in RNAP-promoter open complex as an example

NASA Astrophysics Data System (ADS)

Lerner, Eitan; Ingargiola, Antonino; Weiss, Shimon

2018-03-01

Bio-macromolecules carry out complicated functions through structural changes. To understand their mechanism of action, the structure of each step has to be characterized. While classical structural biology techniques allow the characterization of a few "structural snapshots" along the enzymatic cycle (usually of stable conformations), they do not cover all (and often fast interconverting) structures in the ensemble, where each may play an important functional role. Recently, several groups have demonstrated that structures of different conformations in solution could be solved by measuring multiple distances between different pairs of residues using single-molecule Förster resonance energy transfer (smFRET) and using them as constrains for hybrid/integrative structural modeling. However, this approach is limited in cases where the conformational dynamics is faster than the technique's temporal resolution. In this study, we combine existing tools that elucidate sub-millisecond conformational dynamics together with hybrid/integrative structural modeling to study the conformational states of the transcription bubble in the bacterial RNA polymerase-promoter open complex (RPo). We measured microsecond alternating laser excitation-smFRET of differently labeled lacCONS promoter dsDNA constructs. We used a combination of burst variance analysis, photon-by-photon hidden Markov modeling, and the FRET-restrained positioning and screening approach to identify two conformational states for RPo. The experimentally derived distances of one conformational state match the known crystal structure of bacterial RPo. The experimentally derived distances of the other conformational state have characteristics of a scrunched RPo. These findings support the hypothesis that sub-millisecond dynamics in the transcription bubble are responsible for transcription start site selection.

Structure and dynamics of double helical DNA in torsion angle hyperspace: a molecular mechanics approach.

PubMed

Borkar, Aditi; Ghosh, Indira; Bhattacharyya, Dhananjay

2010-04-01

Analysis of the conformational space populated by the torsion angles and the correlation between the conformational energy and the sequence of DNA are important for fully understanding DNA structure and function. Presence of seven variable torsion angles about single covalent bonds in DNA main chain puts a big challenge for such analysis. We have carried out restrained energy minimization studies for four representative dinucleosides, namely d(ApA):d(TpT), d(CpG):d(CpG), d(GpC):d(GpC) and d(CpA):d(TpG) to determine the energy hyperspace of DNA in context to the values of the torsion angles and the structural properties of the DNA conformations populating the favorable regions of this energy hyperspace. The torsion angles were manipulated by constraining their values at the reference points and then performing energy minimization. The energy minima obtained on the potential energy contour plots mostly correspond to the conformations populated in crystal structures of DNA. Some novel favorable conformations that are not present in crystal structure data are also found. The plots also suggest few low energy routes for conformational transitions or the associated energy barrier heights. Analyses of base pairing and stacking possibility reveal structural changes accompanying these transitions as well as the flexibility of different base steps towards variations in different torsion angles.

Conformation of glycomimetics in the free and protein-bound state: structural and binding features of the C-glycosyl analogue of the core trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man.

PubMed

Mikkelsen, Lise Munch; Hernáiz, María José; Martín-Pastor, M; Skrydstrup, Troels; Jiménez-Barbero, Jesús

2002-12-18

The conformational properties of the C-glycosyl analogue of the core trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man in solution have been carefully analyzed by a combination of NMR spectroscopy and time-averaged restrained molecular dynamics. It has been found that both the alpha-1,3- and the alpha-1,6-glycosidic linkages show a major conformational averaging. Unusual Phi ca. 60 degrees orientations for both Phi torsion angles are found. Moreover, a major conformational distinction between the natural compound and the glycomimetic affects to the behavior of the omega(16) torsion angle around the alpha-1 --> 6-linkage. Despite this increased flexibility, the C-glycosyl analogue is recognized by three mannose binding lectins, as shown by NMR (line broadening, TR-NOE, and STD) and surface plasmon resonance (SPR) methods. Moreover, a process of conformational selection takes place, so that these lectins probably bind the glycomimetic similarly to the way they recognize the natural analogue. Depending upon the architecture and extension of the binding site of the lectin, loss or gain of binding affinity with respect to the natural analogue is found.

Development of potent anti-infective agents from Silurana tropicalis: conformational analysis of the amphipathic, alpha-helical antimicrobial peptide XT-7 and its non-haemolytic analogue [G4K]XT-7.

PubMed

Subasinghage, Anusha P; Conlon, J Michael; Hewage, Chandralal M

2010-04-01

Peptide XT-7 (GLLGP(5)LLKIA(10)AKVGS(15)NLL.NH(2)) is a cationic, leucine-rich peptide, first isolated from skin secretions of the frog, Silurana tropicalis (Pipidae). The peptide shows potent, broad-spectrum antimicrobial activity but its therapeutic potential is limited by haemolytic activity (LC(50)=140 microM). The analogue [G4K]XT-7, however, retains potent antimicrobial activity but is non-haemolytic (LC(50)>500 microM). In order to elucidate the molecular basis for this difference in properties, the three dimensional structures of XT-7 and the analogue have been investigated by proton NMR spectroscopy and molecular modelling. In aqueous solution, both peptides lack secondary structure. In a 2,2,2-trifluoroethanol (TFE-d(3))-H(2)O mixed solvent system, XT-7 is characterised by a right handed alpha-helical conformation between residues Leu(3) and Leu(17) whereas [G4K]XT-7 adopts a more restricted alpha-helical conformation between residues Leu(6) and Leu(17). A similar conformation for XT-7 in 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) micellular media was observed with a helical segment between Leu(3) and Leu(17). However, differences in side chain orientations restricting the hydrophilic residues to a smaller patch resulted in an increased hydrophobic surface relative to the conformation in TFE-H(2)O. Molecular modelling of the structures obtained in our study demonstrates the amphipathic character of the helical segments. It is proposed that the marked decrease in haemolytic activity produced by the substitution Gly(4)-->Lys in XT-7 arises from a decrease in both helicity and hydrophobicity. These studies may facilitate the development of potent but non-toxic anti-infective agents based upon the structure of XT-7. Copyright 2009 Elsevier B.V. All rights reserved.

Complement Factor H and Simian Virus 40 bind the GM1 ganglioside in distinct conformations.

PubMed

Blaum, Bärbel S; Frank, Martin; Walker, Ross C; Neu, Ursula; Stehle, Thilo

2016-05-01

Mammalian cell surfaces are decorated with a variety of glycan chains that orchestrate development and defense and are exploited by pathogens for cellular attachment and entry. While glycosidic linkages are, in principle, flexible, the conformational space that a given glycan can sample is subject to spatial and electrostatic restrictions imposed by its overall chemical structure. Here, we show how the glycan moiety of the GM1 ganglioside, a branched, monosialylated pentasaccharide that serves as a ligand for various proteins, undergoes differential conformational selection in its interactions with different lectins. Using STD NMR and X-ray crystallography, we found that the innate immune regulator complement Factor H (FH) binds a previously not reported GM1 conformation that is not compatible with the GM1-binding sites of other structurally characterized GM1-binding lectins such as the Simian Virus 40 (SV40) capsid. Molecular dynamics simulations of the free glycan in explicit solvent on the 10 μs timescale reveal that the FH-bound conformation nevertheless corresponds to a minimum in the Gibbs free energy plot. In contrast to the GM1 conformation recognized by SV40, the FH-bound GM1 conformation is associated with poor NOE restraints, explaining how it escaped(1)H-(1)H NOE-restrained modeling in the past and highlighting the necessity for ensemble representations of glycan structures. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Synthesis and conformational analysis by 1H NMR and restrained molecular dynamics simulations of the cyclic decapeptide [Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly

NASA Astrophysics Data System (ADS)

Buono, Ronald A.; Kucharczyk, Nathalie; Neuenschwander, Magrit; Kemmink, Johan; Hwang, Lih-Yueh; Fauchère, Jean-Luc; Venanzi, Carol A.

1996-06-01

The design of enzyme mimics with therapeutic and industrial applications has interested both experimental and computational chemists for several decades. Recent advances in the computational methodology of restrained molecular dynamics, used in conjunction with data obtained from two-dimensional 1H NMR spectroscopy, make it a promising method to study peptide and protein structure and function. Several issues, however, need to be addressed in order to assess the validity of this method for its explanatory and predictive value. Among the issues addressed in this study are: the accuracy and generizability of the GROMOS peptide molecular mechanics force field; the effect of inclusion of solvent on the simulations; and the effect of different types of restraining algorithms on the computational results. The decapeptide Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly, which corresponds to the sequence of ACTH1-10, has been synthesized, cyclized, and studied by two-dimensional 1H NMR spectroscopy. Restrained molecular dynamics (RMD) and time-averaged restrained molecular dynamics (TARMD) simulations were carried out on four different distance-geometry starting structures in order to determine and contrast the behavior of cyclic ACTH1-10 in vacuum and in solution. For the RMD simulations, the structures did not fit the NOE data well, even at high values of the restraining potential. The TARMD simulation method, however, was able to give structures that fit the NOE data at high values of the restraining potential. In both cases, inclusion of explicit solvent molecules in the simulation had little effect on the quality of the fit, although it was found to dampen the motion of the cyclic peptide. For both simulation techniques, the number and size of the NOE violations increased as the restraining potential approached zero. This is due, presumably, to inadequacies in the force field. Additional TARMD vacuum-phase simulations, run with a larger memory length or with a larger sampling size (16 additional distance-geometry structures), yielded no significantly different results. The computed data were then analyzed to help explain the sparse NOE data and poor chymotryptic activity of the cyclic peptide. Cyclic ACTH1-10, which contains the functional moieties of the catalytic triad of chymotrypsin, was evaluated as a potential mimic of chymotrypsin by measurement of the rate of hydrolysis of esters of L-and d-phenylalanine. The poor rate of hydrolysis is attributed to the flexibility of the decapeptide, the motion of the side chains, which result in the absence of long-range NOEs, the small size of the macrocycle relative to that of the substrate, and the inappropriate orientation of the Gly, His, and Ser residues. The results demonstrate the utility of this method in computer-aided molecular design of cyclic peptides and suggest structural modifications for future work based on a larger and more rigid peptide framework.

Conformation, orientation, and adsorption kinetics of dermaseptin B2 onto synthetic supports at aqueous/solid interface.

PubMed

Noinville, S; Bruston, F; El Amri, C; Baron, D; Nicolas, P

2003-08-01

The antimicrobial activity of cationic amphipathic peptides is due mainly to the adsorption of peptides onto target membranes, which can be modulated by such physicochemical parameters as charge and hydrophobicity. We investigated the structure of dermaseptin B2 (Drs B2) at the aqueous/synthetic solid support interface and its adsorption kinetics using attenuated total reflection Fourier transform infrared spectroscopy and surface plasmon resonance. We determined the conformation and affinity of Drs B2 adsorbed onto negatively charged (silica or dextran) and hydrophobic supports. Synthetic supports of differing hydrophobicity were obtained by modifying silica or gold with omega-functionalized alkylsilanes (bromo, vinyl, phenyl, methyl) or alkylthiols. The peptide molecules adsorbed onto negatively charged supports mostly had a beta-type conformation. In contrast, a monolayer of Drs B2, mainly in the alpha-helical conformation, was adsorbed irreversibly onto the hydrophobic synthetic supports. The conformational changes during formation of the adsorbed monolayer were monitored by two-dimensional Fourier transform infrared spectroscopy correlation; they showed the influence of peptide-peptide interactions on alpha-helix folding on the most hydrophobic support. The orientation of the alpha-helical Drs B2 with respect to the hydrophobic support was determined by polarized attenuated total reflection; it was around 15 +/- 5 degrees. This orientation was confirmed and illustrated by a molecular dynamics study. These combined data demonstrate that specific chemical environments influence the structure of Drs B2, which could explain the many functions of antimicrobial peptides.

[Antimicrobial susceptibility testing in clinically relevant non-fermenting gram-negative bacilli: recommendations from the Antimicrobial Agents Subcommittee of the Sociedad Argentina de Bacteriología, Micología y Parasitología Clínicas, Asociación Argentina de Microbiología].

PubMed

Radice, Marcela; Marín, Marcelo; Giovanakis, Marta; Vay, Carlos; Almuzara, Marisa; Limansky, Adriana; Casellas, José M; Famiglietti, Angela; Quinteros, Mirta; Bantar, Carlos; Galas, Marcelo; Kovensky Pupko, Jaime; Nicola, Federico; Pasterán, Fernando; Soloaga, Rolando; Gutkind, Gabriel

2011-01-01

This document contains the recommendations for antimicrobial susceptibility testing of the clinically relevant non-fermenting gram-negative bacilli (NFGNB), adopted after conforming those from international committees to the experience of the Antimicrobial Agents Subcommittee members and invited experts. This document includes an update on NFGNB classification and description, as well as some specific descriptions regarding natural or frequent antimicrobial resistance and a brief account of associated resistance mechanisms. These recommendations not only suggest the antimicrobial drugs to be evaluated in each case, but also provide an optimization of the disk diffusion layout and a selection of results to be reported. Finally, this document also includes a summary of the different methodological approaches that may be used for detection and confirmation of emerging b-lactamases, such as class A and B carbapenemases.

Rational design of anti-microbial peptides with enhanced activity and low cytotoxicity based on the structure of the arginine/histidine-rich peptide, chensinin-1.

PubMed

Shang, D; Sun, Y; Wang, C; Ma, L; Li, J; Wang, X

2012-09-01

To understand the structure-activity relationship of chensinin-1, a anti-microbial peptide (AMP) with an unusual structure, and to develop novel AMPs as therapeutic agents. A series of chensinin-1 analogues were designed and synthesized by one to three replacement of glycines with leucines at the hydrophilic face of chensinin-1 or rearrangement of some of the residues in its sequence. Circular dichroism spectroscopy showed that the analogues adopted α-helical-type conformations in 50% trifluoroethanol/water but adopted β-strand-type conformations in 30 mmol l(-1) sodium dodecyl sulphate. The anti-microbial activities of the peptides against Gram-positive bacteria increased 5- to 30-fold, and these increases paralleled the increases in the peptides' hydrophobicities. Their haemolytic activities also increased. Amphipathicities had little influence on the bactericidal activity of chensinin-1. All peptides caused leakage of calcein entrapped in negatively charged liposomes although with different efficiencies. The peptides did not induce leakage of calcein from uncharged liposomes. Peptide adopted an aperiodic structure can improve the anti-microbial potency by increasing peptide hydrophobicity. Its target is bacteria plasma membrane. Chensinin-1 can act as a new lead molecule for the study of AMPs with atypical structures. © 2012 The Authors Journal of Applied Microbiology © 2012 The Society for Applied Microbiology.

Pegylation of Antimicrobial Peptides Maintains the Active Peptide Conformation, Model Membrane Interactions, and Antimicrobial Activity while Improving Lung Tissue Biocompatibility following Airway Delivery

PubMed Central

Morris, Christopher J.; Beck, Konrad; Fox, Marc A.; Ulaeto, David; Clark, Graeme C.

2012-01-01

Antimicrobial peptides (AMPs) have therapeutic potential, particularly for localized infections such as those of the lung. Here we show that airway administration of a pegylated AMP minimizes lung tissue toxicity while nevertheless maintaining antimicrobial activity. CaLL, a potent synthetic AMP (KWKLFKKIFKRIVQRIKDFLR) comprising fragments of LL-37 and cecropin A peptides, was N-terminally pegylated (PEG-CaLL). PEG-CaLL derivatives retained significant antimicrobial activity (50% inhibitory concentrations [IC50s] 2- to 3-fold higher than those of CaLL) against bacterial lung pathogens even in the presence of lung lining fluid. Circular dichroism and fluorescence spectroscopy confirmed that conformational changes associated with the binding of CaLL to model microbial membranes were not disrupted by pegylation. Pegylation of CaLL reduced AMP-elicited cell toxicity as measured using in vitro lung epithelial primary cell cultures. Further, in a fully intact ex vivo isolated perfused rat lung (IPRL) model, airway-administered PEG-CaLL did not result in disruption of the pulmonary epithelial barrier, whereas CaLL caused an immediate loss of membrane integrity leading to pulmonary edema. All AMPs (CaLL, PEG-CaLL, LL-37, cecropin A) delivered to the lung by airway administration showed limited (<3%) pulmonary absorption in the IPRL with extensive AMP accumulation in lung tissue itself, a characteristic anticipated to be beneficial for the treatment of pulmonary infections. We conclude that pegylation may present a means of improving the lung biocompatibility of AMPs designed for the treatment of pulmonary infections. PMID:22430978

Structural Refinement of Membrane Proteins by Restrained Molecular Dynamics and Solvent Accessibility Data

PubMed Central

Sompornpisut, Pornthep; Roux, Benoît; Perozo, Eduardo

2008-01-01

We present an approach for incorporating solvent accessibility data from electron paramagnetic resonance experiments in the structural refinement of membrane proteins through restrained molecular dynamics simulations. The restraints have been parameterized from oxygen (ΠO2) and nickel-ethylenediaminediacetic acid (ΠNiEdda) collision frequencies, as indicators of lipid or aqueous exposed spin-label sites. These are enforced through interactions between a pseudoatom representation of the covalently attached Nitroxide spin-label and virtual “solvent” particles corresponding to O2 and NiEdda in the surrounding environment. Interactions were computed using an empirical potential function, where the parameters have been optimized to account for the different accessibilities of the spin-label pseudoatoms to the surrounding environment. This approach, “pseudoatom-driven solvent accessibility refinement”, was validated by refolding distorted conformations of the Streptomyces lividans potassium channel (KcsA), corresponding to a range of 2–30 Å root mean-square deviations away from the native structure. Molecular dynamics simulations based on up to 58 electron paramagnetic resonance restraints derived from spin-label mutants were able to converge toward the native structure within 1–3 Å root mean-square deviations with minimal computational cost. The use of energy-based ranking and structure similarity clustering as selection criteria helped in the convergence and identification of correctly folded structures from a large number of simulations. This approach can be applied to a variety of integral membrane protein systems, regardless of oligomeric state, and should be particularly useful in calculating conformational changes from a known reference crystal structure. PMID:18676641

Crystal structures of HIV-1 nonnucleoside reverse transcriptase inhibitors: N-benzyl-4-methyl-benzimidazoles

NASA Astrophysics Data System (ADS)

Ziółkowska, Natasza E.; Michejda, Christopher J.; Bujacz, Grzegorz D.

2009-07-01

HIV-1 nonnucleoside reverse transcriptase inhibitors are potentially specific and effective drugs in AIDS therapy. The presence of two aromatic systems with an angled orientation in the molecule of the inhibitor is crucial for interactions with HIV-1 RT. The inhibitor drives like a wedge into the cluster of aromatic residues of RT HIV-1 and restrains the enzyme in a conformation that blocks the chemical step of nucleotide incorporation. Structural studies provide useful information for designing new, more active inhibitors. The crystal structures of four NNRTIs are presented here. The investigated compounds are derivatives of N-benzyl-4-methyl-benzimidazole with various aliphatic and aromatic substituents at carbon 2 positions and a 2,6-dihalogeno-substituted N-benzyl moiety. Structural data reported here show that the conformation of the investigated compounds is relatively rigid. Such feature is important for the nonnucleoside inhibitor binding to HIV-1 reverse transcriptase.

Antimicrobial preservative use in parenteral products: past and present.

PubMed

Meyer, Brian K; Ni, Alex; Hu, Binghua; Shi, Li

2007-12-01

The following review provides a comprehensive summary of antimicrobial preservatives that are commonly used in licensed parenteral products to date. The information reviewed includes the general properties of the preservatives, the doses and frequency of their use, the classes of the preserved products (peptide, protein, vaccine, and small molecule products), the interactions with other formulation components, and the criteria commonly used for their selection in parental product formulations. It was revealed that phenol and benzyl alcohol are the two most common antimicrobial preservatives used in peptide and protein products, while phenoxyethanol is the most frequently used preservative in vaccines. Benzyl alcohol or a combination of methylparaben and propylparaben are generally found in small molecule parenteral formulations. The key criteria for antimicrobial preservative selection are the preservative's dose, antimicrobial functionality, and effect on the active ingredient. Additionally, the use of spectroscopic techniques (circular dicroism (CD) and fluorescence) and differential scanning calorimetry (DSC) were identified as common techniques used in evaluating an antimicrobial preservative for its impact on the conformational stability of peptide, protein, and vaccine antigens. The future use of preservatives is also discussed, including antimicrobial agents such as peptides, and regulatory requirements for antimicrobial effectiveness testing. (c) 2007 Wiley-Liss, Inc.

Bactericidal and antibiofilm activity of bactenecin-derivative peptides against the food-pathogen Listeria monocytogenes: New perspectives for food processing industry.

PubMed

Palmieri, Gianna; Balestrieri, Marco; Capuano, Federico; Proroga, Yolande T R; Pomilio, Francesco; Centorame, Patrizia; Riccio, Alessia; Marrone, Raffaele; Anastasio, Aniello

2018-08-20

Antimicrobial peptides have received great attention for their potential benefits to extend the shelf-life of food-products. Innate defense regulator peptide-1018 (IDR-1018) represents a promising candidate for such applications, due to its broad-spectrum antimicrobial activity, although food-isolated pathogens have been poorly investigated. Herein, we describe the design and the structural-functional characterization of a new 1018-derivative peptide named 1018-K6, in which the alanine in position 6 was replaced with a lysine. Spectroscopic analysis revealed a noticeable switch from β-sheet to helical conformations of 1018-K6 respect to IDR-1018, with a faster folding kinetic and increased structural stability. Moreover, 1018-K6 evidenced a significant antibiofilm/bactericidal efficiency specifically against Listeria monocytogenes isolates from food-products and food-processing environments, belonging to serotype 4b involved in the majority of human-listeriosis cases, with EC 50 values two- five-fold lower than those measured for IDR-1018. Therefore, a single amino-acid substitution in IDR-1018 sequence produced severe changes in peptide conformation and antimicrobial performances. Published by Elsevier B.V.

A Molecular Dynamics-Quantum Mechanics Theoretical Study of DNA-Mediated Charge Transport in Hydrated Ionic Liquids.

PubMed

Meng, Zhenyu; Kubar, Tomas; Mu, Yuguang; Shao, Fangwei

2018-05-08

Charge transport (CT) through biomolecules is of high significance in the research fields of biology, nanotechnology, and molecular devices. Inspired by our previous work that showed the binding of ionic liquid (IL) facilitated charge transport in duplex DNA, in silico simulation is a useful means to understand the microscopic mechanism of the facilitation phenomenon. Here molecular dynamics simulations (MD) of duplex DNA in water and hydrated ionic liquids were employed to explore the helical parameters. Principal component analysis was further applied to capture the subtle conformational changes of helical DNA upon different environmental impacts. Sequentially, CT rates were calculated by a QM/MM simulation of the flickering resonance model based upon MD trajectories. Herein, MD simulation illustrated that the binding of ionic liquids can restrain dynamic conformation and lower the on-site energy of the DNA base. Confined movement among the adjacent base pairs was highly related to the increase of electronic coupling among base pairs, which may lead DNA to a CT facilitated state. Sequentially combining MD and QM/MM analysis, the rational correlations among the binding modes, the conformational changes, and CT rates illustrated the facilitation effects from hydrated IL on DNA CT and supported a conformational-gating mechanism.

Unusual structural transition of antimicrobial VP1 peptide.

PubMed

Shanmugam, Ganesh; Phambu, Nsoki; Polavarapu, Prasad L

2011-05-01

VP1 peptide, an active domain of m-calpain enzyme with antimicrobial activity is found to undergo an unusual conformational transition in trifluoroethanol (TFE) solvent. The nature of, and time dependent variations in, circular dichroism associated with the amide I vibrations, suggest that VP1 undergoes self-aggregation forming anti-parallel β-sheet structure in TFE. Transmission electron micrograph (TEM) images revealed that β-sheet aggregates formed by VP1 possess fibril-like assemblies. Copyright © 2011 Elsevier B.V. All rights reserved.

Selective killing of Helicobacter pylori with pH-responsive helix–coil conformation transitionable antimicrobial polypeptides

PubMed Central

Xiong, Menghua; Bao, Yan; Xu, Xin; Wang, Hua; Han, Zhiyuan; Wang, Zhiyu; Liu, Yeqing; Huang, Songyin; Song, Ziyuan; Chen, Jinjing; Peek, Richard M.; Yin, Lichen; Chen, Lin-Feng; Cheng, Jianjun

2017-01-01

Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues. PMID:29133389

Structures and mechanisms in clay nanopore trapping of structurally-different fluoroquinolone antimicrobials.

PubMed

Okaikue-Woodi, Fanny E K; Kelch, Sabrina E; Schmidt, Michael P; Enid Martinez, Carmen; Youngman, Randall E; Aristilde, Ludmilla

2018-03-01

Smectite clay nanoparticles are implicated in the retention of antimicrobials within soils and sediments; these clays are also inspected as drug carriers in physiological systems. Cation exchange is considered the primary adsorption mechanism of antimicrobials within smectite nanopores. However, a dual role of acid-base chemistry and adsorptive structures is speculated by recent studies. Using the prototypical smectite clay montmorillonite, we employed a combination of X-ray diffraction (XRD), nuclear magnetic resonance, attenuated total reflectance-Fourier transform infrared spectroscopy, and molecular dynamics simulations to investigate the interlayer nanopore trapping of two structurally-different fluoroquinolone (FQ) antimicrobials with similar acid-base chemistry: ciprofloxacin (a first-generation FQ) and moxifloxacin (a third-generation FQ). Greater sorption at pH 5.0 than at pH 7.0 for both FQs was consistent with cation-exchange of positively-charged species. However, the clay exhibited a near twofold higher sorption capacity for moxifloxacin than for ciprofloxacin. This difference was shown by the XRD data to be accompanied by enhanced trapping of moxifloxacin within the clay interlayers. Using the XRD-determined nanopore sizes, we performed molecular dynamics simulations of thermodynamically-favorable model adsorbates, which revealed that ciprofloxacin was adsorbed parallel to the clay surface but moxifloxacin adopted a tilted conformation across the nanopore. These conformations resulted in more slowly-exchanged than quickly-exchanged Na complexes with ciprofloxacin compared with moxifloxacin. These different Na populations were also captured by 23 Na nuclear magnetic resonance. Furthermore, the simulated adsorbates uncovered different complexation interactions that were corroborated by infrared spectroscopy. Therefore, beyond acid-base chemistry, our findings imply that distinct adsorbate structures control antimicrobial trapping within clay nanopores, which can promote persistence in environmental matrices and stable delivery in biological systems. Copyright © 2017 Elsevier Inc. All rights reserved.

Self-assembled cationic amphiphiles as antimicrobial peptides mimics: Role of hydrophobicity, linkage type, and assembly state.

PubMed

Zhang, Yingyue; Algburi, Ammar; Wang, Ning; Kholodovych, Vladyslav; Oh, Drym O; Chikindas, Michael; Uhrich, Kathryn E

2017-02-01

Inspired by high promise using naturally occurring antimicrobial peptides (AMPs) to treat infections caused by antimicrobial-resistant bacteria, cationic amphiphiles (CAms) were strategically designed as synthetic mimics to overcome associated limitations, including high manufacture cost and low metabolic stability. CAms with facially amphiphilic conformation were expected to demonstrate membrane-lytic properties and thus reduce tendency of resistance development. By systematically tuning the hydrophobicity, CAms with optimized compositions exhibited potent broad-spectrum antimicrobial activity (with minimum inhibitory concentrations in low μg/mL range) as well as negligible hemolytic activity. Electron microscope images revealed the morphological and ultrastructure changes of bacterial membranes induced by CAm treatment and validated their membrane-disrupting mechanism. Additionally, an all-atom molecular dynamics simulation was employed to understand the CAm-membrane interaction on molecular level. This study shows that these CAms can serve as viable scaffolds for designing next generation of AMP mimics as antimicrobial alternatives to combat drug-resistant pathogens. Copyright © 2016 Elsevier Inc. All rights reserved.

Theoretical and NMR conformational studies of β-proline oligopeptides with alternating chirality of pyrrolidine units

NASA Astrophysics Data System (ADS)

Mantsyzov, Alexey B.; Savelyev, Oleg Y.; Ivantcova, Polina M.; Bräse, Stefan; Kudryavtsev, Konstantin V.; Polshakov, Vladimir I.

2018-03-01

Synthetic β-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of β-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z/E isomerism of β-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of β-proline oligopeptides. Preferences in structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied β-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the β-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating β-proline pentapeptide, the presence of an E configuration for at least of one β-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of β-peptide bonds forming a wave-like extended structure.

Theoretical and NMR Conformational Studies of β-Proline Oligopeptides With Alternating Chirality of Pyrrolidine Units.

PubMed

Mantsyzov, Alexey B; Savelyev, Oleg Y; Ivantcova, Polina M; Bräse, Stefan; Kudryavtsev, Konstantin V; Polshakov, Vladimir I

2018-01-01

Synthetic β-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of β-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z / E isomerism of β-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of β-proline oligopeptides. Preferences in their structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied β-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the β-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating β-proline pentapeptide, the presence of an E configuration for at least of one β-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of β-peptide bonds forming a wave-like extended structure.

Correlating the Effects of Antimicrobial Preservatives on Conformational Stability, Aggregation Propensity, and Backbone Flexibility of an IgG1 mAb.

PubMed

Arora, Jayant; Joshi, Sangeeta B; Middaugh, C Russell; Weis, David D; Volkin, David B

2017-06-01

Multidose formulations of biotherapeutics, which offer better dosage management and reduced production costs, require the addition of antimicrobial preservatives (APs). APs have been shown, however, to decrease protein stability in solution and cause protein aggregation. In this report, the effect of 4 APs, m-cresol, phenol, phenoxyethanol, and benzyl alcohol on conformational stability, aggregation propensity, and backbone flexibility of an IgG1 mAb, mAb-4, is investigated. Compared with no preservative control, each of the APs decreased the conformational stability of mAb-4 as measured by differential scanning calorimetry and extrinsic fluorescence spectroscopy. The addition of APs resulted in increased monomer loss and aggregate accumulation at 50°C over 28 days, as monitored by size-exclusion chromatography. The extent of conformational destabilization and protein aggregation of mAb-4 induced by APs followed their calculated octanol-water partition coefficients. Increases in backbone flexibility, as measured by hydrogen exchange, of a region located in the C H 2 domain of the mAb (heavy chain 237-254) in the presence of APs also correlated with hydrophobicity. Based on these results, the destabilizing effect of APs on mAb-4 correlates with the increased hydrophobicity of the APs and their ability to enhance the local backbone flexibility of an aggregation hot spot within the C H 2 domain of the mAb. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Potential Energy Surface-Based Automatic Deduction of Conformational Transition Networks and Its Application on Quantum Mechanical Landscapes of d-Glucose Conformers.

PubMed

Satoh, Hiroko; Oda, Tomohiro; Nakakoji, Kumiyo; Uno, Takeaki; Tanaka, Hiroaki; Iwata, Satoru; Ohno, Koichi

2016-11-08

This paper describes our approach that is built upon the potential energy surface (PES)-based conformational analysis. This approach automatically deduces a conformational transition network, called a conformational reaction route map (r-map), by using the Scaled Hypersphere Search of the Anharmonic Downward Distortion Following method (SHS-ADDF). The PES-based conformational search has been achieved by using large ADDF, which makes it possible to trace only low transition state (TS) barriers while restraining bond lengths and structures with high free energy. It automatically performs sampling the minima and TS structures by simply taking into account the mathematical feature of PES without requiring any a priori specification of variable internal coordinates. An obtained r-map is composed of equilibrium (EQ) conformers connected by reaction routes via TS conformers, where all of the reaction routes are already confirmed during the process of the deduction using the intrinsic reaction coordinate (IRC) method. The postcalculation analysis of the deduced r-map is interactively carried out using the RMapViewer software we have developed. This paper presents computational details of the PES-based conformational analysis and its application to d-glucose. The calculations have been performed for an isolated glucose molecule in the gas phase at the RHF/6-31G level. The obtained conformational r-map for α-d-glucose is composed of 201 EQ and 435 TS conformers and that for β-d-glucose is composed of 202 EQ and 371 TS conformers. For the postcalculation analysis of the conformational r-maps by using the RMapViewer software program we have found multiple minimum energy paths (MEPs) between global minima of 1 C 4 and 4 C 1 chair conformations. The analysis using RMapViewer allows us to confirm the thermodynamic and kinetic predominance of 4 C 1 conformations; that is, the potential energy of the global minimum of 4 C 1 is lower than that of 1 C 4 (thermodynamic predominance) and that the highest energy of those of all the TS structures along a route from 4 C 1 to 1 C 4 is lower than that of 1 C 4 to 4 C 1 (kinetic predominance).

The conformational preferences of γ-lactam and its role in constraining peptide structure

NASA Astrophysics Data System (ADS)

Paul, P. K. C.; Burney, P. A.; Campbell, M. M.; Osguthorpe, D. J.

1990-09-01

The conformational constraints imposed by γ-lactams in peptides have been studied using valence force field energy calculations and flexible geometry maps. It has been found that while cyclisation restrains the Ψ of the lactam, non-bonded interactions contribute to the constraints on ϕ of the lactam. The γ-lactam also affects the (ϕ,Ψ) of the residue after it in a peptide sequence. For an l-lactam, the ring geometry restricts Ψ to about-120°, and ϕ has two minima, the lowest energy around-140° and a higher minimum (5 kcal/mol higher) at 60°, making an l-γ-lactam more favourably accommodated in a near extended conformation than in position 2 of a type II' β-turn. The energy of the ϕ˜+60° minimum can be lowered substantially until it is more favoured than the-140° minimum by progressive substitution of bulkier groups on the amide N of the l-γ-lactam. The (ϕ,Ψ) maps of the residue succeeding a γ-lactam show subtle differences from those of standard N-methylated residues. The dependence of the constraints on the chirality of γ-lactams and N-substituted γ-lactams, in terms of the formation of secondary structures like β-turns is discussed and the comparison of the theoretical conformations with experimental results is highlighted.

Antimicrobial Peptide Potency is Facilitated by Greater Conformational Flexibility when Binding to Gram-negative Bacterial Inner Membranes

NASA Astrophysics Data System (ADS)

Amos, Sarah-Beth T. A.; Vermeer, Louic S.; Ferguson, Philip M.; Kozlowska, Justyna; Davy, Matthew; Bui, Tam T.; Drake, Alex F.; Lorenz, Christian D.; Mason, A. James

2016-11-01

The interaction of antimicrobial peptides (AMPs) with the inner membrane of Gram-negative bacteria is a key determinant of their abilities to exert diverse bactericidal effects. Here we present a molecular level understanding of the initial target membrane interaction for two cationic α-helical AMPs that share structural similarities but have a ten-fold difference in antibacterial potency towards Gram-negative bacteria. The binding and insertion from solution of pleurocidin or magainin 2 to membranes representing the inner membrane of Gram-negative bacteria, comprising a mixture of 128 anionic and 384 zwitterionic lipids, is monitored over 100 ns in all atom molecular dynamics simulations. The effects of the membrane interaction on both the peptide and lipid constituents are considered and compared with new and published experimental data obtained in the steady state. While both magainin 2 and pleurocidin are capable of disrupting bacterial membranes, the greater potency of pleurocidin is linked to its ability to penetrate within the bacterial cell. We show that pleurocidin displays much greater conformational flexibility when compared with magainin 2, resists self-association at the membrane surface and penetrates further into the hydrophobic core of the lipid bilayer. Conformational flexibility is therefore revealed as a key feature required of apparently α-helical cationic AMPs for enhanced antibacterial potency.

Diversity, Antimicrobial Action and Structure-Activity Relationship of Buffalo Cathelicidins

PubMed Central

Brahma, Biswajit; Patra, Mahesh Chandra; Karri, Satyanagalakshmi; Chopra, Meenu; Mishra, Purusottam; De, Bidhan Chandra; Kumar, Sushil; Mahanty, Sourav; Thakur, Kiran; Poluri, Krishna Mohan; Datta, Tirtha Kumar; De, Sachinandan

2015-01-01

Cathelicidins are an ancient class of antimicrobial peptides (AMPs) with broad spectrum bactericidal activities. In this study, we investigated the diversity and biological activity of cathelicidins of buffalo, a species known for its disease resistance. A series of new homologs of cathelicidin4 (CATHL4), which were structurally diverse in their antimicrobial domain, was identified in buffalo. AMPs of newly identified buffalo CATHL4s (buCATHL4s) displayed potent antimicrobial activity against selected Gram positive (G+) and Gram negative (G-) bacteria. These peptides were prompt to disrupt the membrane integrity of bacteria and induced specific changes such as blebing, budding, and pore like structure formation on bacterial membrane. The peptides assumed different secondary structure conformations in aqueous and membrane-mimicking environments. Simulation studies suggested that the amphipathic design of buCATHL4 was crucial for water permeation following membrane disruption. A great diversity, broad-spectrum antimicrobial action, and ability to induce an inflammatory response indicated the pleiotropic role of cathelicidins in innate immunity of buffalo. This study suggests short buffalo cathelicidin peptides with potent bactericidal properties and low cytotoxicity have potential translational applications for the development of novel antibiotics and antimicrobial peptidomimetics. PMID:26675301

Biofilms from Klebsiella pneumoniae: Matrix Polysaccharide Structure and Interactions with Antimicrobial Peptides.

PubMed

Benincasa, Monica; Lagatolla, Cristina; Dolzani, Lucilla; Milan, Annalisa; Pacor, Sabrina; Liut, Gianfranco; Tossi, Alessandro; Cescutti, Paola; Rizzo, Roberto

2016-08-10

Biofilm matrices of two Klebsiella pneumoniae clinical isolates, KpTs101 and KpTs113, were investigated for their polysaccharide composition and protective effects against antimicrobial peptides. Both strains were good biofilm producers, with KpTs113 forming flocs with very low adhesive properties to supports. Matrix exopolysaccharides were isolated and their monosaccharide composition and glycosidic linkage types were defined. KpTs101 polysaccharide is neutral and composed only of galactose, in both pyranose and furanose ring configurations. Conversely, KpTs113 polysaccharide is anionic due to glucuronic acid units, and also contains glucose and mannose residues. The susceptibility of the two strains to two bovine cathelicidin antimicrobial peptides, BMAP-27 and Bac7(1-35), was assessed using both planktonic cultures and biofilms. Biofilm matrices exerted a relevant protection against both antimicrobials, which act with quite different mechanisms. Similar protection was also detected when antimicrobial peptides were tested against planktonic bacteria in the presence of the polysaccharides extracted from KpTs101 and KpTs113 biofilms, suggesting sequestering adduct formation with antimicrobials. Circular dichroism experiments on BMAP-27 in the presence of increasing amounts of either polysaccharide confirmed their ability to interact with the peptide and induce an α-helical conformation.

Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations

PubMed Central

Lapelosa, Mauro; Gallicchio, Emilio; Levy, Ronald M.

2011-01-01

The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallographic data, which was not used to restrain ligand orientations. The BEDAM method is based on λ -hopping Hamiltonian parallel Replica Exchange (HREM) molecular dynamics conformational sampling, the OPLS-AA/AGBNP2 effective potential, and multi-state free energy estimators (MBAR). Achieving converged and accurate results depends on all of these elements of the calculation. Convergence of the binding free energy is tied to the level of convergence of binding energy distributions at critical intermediate states where bound and unbound states are at equilibrium, and where the rate of binding/unbinding conformational transitions is maximal. This finding mirrors similar observations in the context of order/disorder transitions as for example in protein folding. Insights concerning the physical mechanism of ligand binding and unbinding are obtained. Convergence for the largest FK506 ligand is achieved only after imposing strict conformational restraints, which however require accurate prior structural knowledge of the structure of the complex. The analytical AGBNP2 model is found to underestimate the magnitude of the hydrophobic driving force towards binding in these systems characterized by loosely packed protein-ligand binding interfaces. Rescoring of the binding energies using a numerical surface area model corrects this deficiency. This study illustrates the complex interplay between energy models, exploration of conformational space, and free energy estimators needed to obtain robust estimates from binding free energy calculations. PMID:22368530

A flexible docking scheme to explore the binding selectivity of PDZ domains.

PubMed

Gerek, Z Nevin; Ozkan, S Banu

2010-05-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 A. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

A flexible docking scheme to explore the binding selectivity of PDZ domains

PubMed Central

Gerek, Z Nevin; Ozkan, S Banu

2010-01-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using RosettaLigand, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately. PMID:20196074

IL-10 inhibits while calcitriol reestablishes placental antimicrobial peptides gene expression.

PubMed

Olmos-Ortiz, Andrea; Noyola-Martínez, Nancy; Barrera, David; Zaga-Clavellina, Verónica; Avila, Euclides; Halhali, Ali; Biruete, Benjamín; Larrea, Fernando; Díaz, Lorenza

2015-04-01

IL-10 and calcitriol help to achieve a successful pregnancy by suppressing active maternal immunity; however, these factors exert opposite effects upon microbial infections. In the skin and immune cells, IL-10 downregulates β-defensins while calcitriol induces cathelicidin gene expression in various tissues including placenta. Though, the regulation of human placental β-defensins by IL-10 and calcitriol has not been studied. Therefore, we explored the regulation of these antimicrobial peptides expression in cultured placental cells by calcitriol and IL-10 alone and combined. Real time PCR showed that calcitriol stimulated, while IL-10 inhibited, β-defensins and cathelicidin gene expression (P<0.05). In coincubations studies, calcitriol was able to maintain antimicrobial peptides gene expression above control values, overriding IL-10 inhibitory effects. Calcitriol downregulated endogenous IL-10 secretion. Interestingly, calcitriol and TNF-α cooperatively enhanced β-defensins, while TNF-α reduced basal and calcitriol-stimulated cathelicidin gene expression. In summary, calcitriol and IL-10 exerted opposite effects on antimicrobial peptides expression in the human placenta, suggesting that unbalanced production of IL-10 and calcitriol could be deleterious to innate immune responses during gestation. Our results suggest that calcitriol enhancement of placental defenses involves two mechanisms: (1) downregulation of IL-10 secretion and (2) direct upregulation of β-defensins and cathelicidin gene expression. Considering that IL-10 and calcitriol differentially regulate the innate immune response in the placenta, in the case of an infection, calcitriol might restrict IL-10 permissive actions towards microbial invasion while restrains inflammation, allowing for pregnancy to continue in quiescence. These results strongly advice maternal vitamin D sufficiency during pregnancy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Computational study of solution behavior of magainin 2 monomers.

PubMed

Petkov, P; Marinova, R; Kochev, V; Ilieva, N; Lilkova, E; Litov, L

2018-03-27

Antimicrobial peptides (AMPs) play crucial role as mediators of the primary host defense against microbial invasion. They are considered a promising alternative to antibiotics for multidrug resistant bacterial strains. For complete understanding of the antimicrobial defense mechanism, a detailed knowledge of the dynamics of peptide-membrane interactions, including atomistic studies on AMPs geometry and both peptide and membrane structural changes during the whole process is a prerequisite. We aim at clarifying the conformation dynamics of small linear AMPs in solution as a first step of in silico protocol for establishing a correspondence between certain amino-acid sequence motifs, secondary-structure elements, conformational dynamics in solution and the intensity and mode of interaction with the bacterial membrane. To this end, we use molecular dynamics simulations augmented by well-tempered metadynamics to study the free-energy landscape of two AMPs with close primary structure and different antibacterial activity - the native magainin 2 (MG2) and an analog (MG2m, with substitutions F5Y and F16W) in aqueous solution. We observe that upon solvation, the initial α-helical structures change differently. The native form remains structured, with three shorter α-helical motifs, connected by random coils, while the synthetic analog tends predominantly to a disordered conformation. Our results indicate the importance of the side-chains at positions 5 and 16 for maintaining the solvated peptide conformation. They also provide a modeling background for recent experimental observations, relating the higher α-helical content in solution (peptide pre-folding) in the case of small linear AMPs to a lower antibacterial activity.

Conformational dynamics of proanthocyanidins: physical and computational approaches

Treesearch

Fred L. Tobiason; Richard W. Hemingway; T. Hatano

1998-01-01

The interaction of plant polyphenols with proteins accounts for a good part of their commercial (e.g., leather manufacture) and biological (e.g., antimicrobial activity) significance. The interplay between observations of physical data such as crystal structure, NMR analyses, and time-resolved fluorescence with results of computational chemistry approaches has been...

Triclosan Computational Conformational Chemistry Analysis for Antimicrobial Properties in Polymers.

PubMed

Petersen, Richard C

2015-03-01

Triclosan is a diphenyl ether antimicrobial that has been analyzed by computational conformational chemistry for an understanding of Mechanomolecular Theory. Subsequent energy profile analysis combined with easily seen three-dimensional chemistry structure models for the nonpolar molecule Triclosan show how single bond rotations can alternate rapidly at a polar and nonpolar interface. Bond rotations for the center ether oxygen atom of the two aromatic rings then expose or hide nonbonding lone-pair electrons for the oxygen atom depending on the polar nature of the immediate local molecular environment. Rapid bond movements can subsequently produce fluctuations as vibration energy. Consequently, related mechanical molecular movements calculated as energy relationships by forces acting through different bond positions can help improve on current Mechanomolecular Theory. A previous controversy reported as a discrepancy in literature contends for a possible bacterial resistance from Triclosan antimicrobial. However, findings in clinical settings have not reported a single case for Triclosan bacterial resistance in over 40 years that has been documented carefully in government reports. As a result, Triclosan is recommended whenever there is a health benefit consistent with a number of approvals for use of Triclosan in healthcare devices. Since Triclosan is the most researched antimicrobial ever, literature meta analysis with computational chemistry can best describe new molecular conditions that were previously impossible by conventional chemistry methods. Triclosan vibrational energy can now explain the molecular disruption of bacterial membranes. Further, Triclosan mechanomolecular movements help illustrate use in polymer matrix composites as an antimicrobial with two new additive properties as a toughening agent to improve matrix fracture toughness from microcracking and a hydrophobic wetting agent to help incorporate strengthening fibers. Interrelated Mechanomolecular Theory by oxygen atom bond rotations or a nitrogen-type pyramidal inversion can be shown to produce energy at a polar and nonpolar boundary condition to better make clear membrane transport of other molecules, cell recognition/signaling/defense and enzyme molecular "mixing" action.

[Comparative effectiveness of antimicrobial action of antiseptics against pathogens of chronic purulent otitis media].

PubMed

Paliĭ, G K; Barilo, A S; Chesnokova, A A

1992-12-01

Comparable antimicrobial and disinfecting action of decamethoxine and silver preparations on pathogens of chronic purulent otitis media (CPOM) was studied. The clinical isolates of staphylococci proved to be most sensitive to decamethoxine whose MBcC conformed to 16.5 micrograms/ml. The antimicrobial action on Proteus spp. and Pseudomonas aeruginosa was less pronounced. The required concentrations for bactericidal action on these pathogens were 69 and 93.5 micrograms/ml, respectively. The antimicrobial activity of the silver preparations such as poviargol, collargol and protargol was low. Depending on the microbial species, the bactericidal effect of the silver preparations was 12-235 times lower than that of decamethoxin. It was also shown that decamethoxin had a high disinfecting action on CPOM pathogens. It was noted that decamethoxin had a marked ability to increase the bactericidal action of poviargol (by 2-14 times) and its disinfecting action (by 2 times) on Proteus spp., E. coli and Ps. aeruginosa.

Structure-activity relationships of an antimicrobial peptide plantaricin s from two-peptide class IIb bacteriocins.

PubMed

Soliman, Wael; Wang, Liru; Bhattacharjee, Subir; Kaur, Kamaljit

2011-04-14

Class IIb bacteriocins are ribosomally synthesized antimicrobial peptides comprising two different peptides synergistically acting in equal amounts for optimal potency. In this study, we demonstrate for the first time potent (nanomolar) antimicrobial activity of a representative class IIb bacteriocin, plantaricin S (Pls), against four pathogenic gram-positive bacteria, including Listeria monocytogenes. The structure-activity relationships for Pls were studied using activity assays, circular dichroism (CD), and molecular dynamics (MD) simulations. The two Pls peptides and five Pls derived fragments were synthesized. The CD spectra of the Pls and selected fragments revealed helical conformations in aqueous 2,2,2-trifluoroethanol. The MD simulations showed that when the two Pls peptides are in antiparallel orientation, the helical regions interact and align, mediated by strong attraction between conserved GxxxG/AxxxA motifs. The results strongly correlate with the antimicrobial activity suggesting that helix-helix alignment of the two Pls peptides and interaction between the conserved motifs are crucial for interaction with the target cell membrane.

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions.

PubMed

Bian, Jifeng; Kang, Hae-Eun; Telling, Glenn C

2014-04-22

Quinacrine's ability to reduce levels of pathogenic prion protein (PrP(Sc)) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP(Sc) accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP(Sc) deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP(Sc) conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

PubMed Central

Bian, Jifeng; Kang, Hae-Eun; Telling, Glenn C.

2014-01-01

Quinacrine’s ability to reduce levels of pathogenic prion protein (PrPSc) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrPSc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrPSc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrPSc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds. PMID:24711410

GalaxyGPCRloop: Template-Based and Ab Initio Structure Sampling of the Extracellular Loops of G-Protein-Coupled Receptors.

PubMed

Won, Jonghun; Lee, Gyu Rie; Park, Hahnbeom; Seok, Chaok

2018-06-07

The second extracellular loops (ECL2s) of G-protein-coupled receptors (GPCRs) are often involved in GPCR functions, and their structures have important implications in drug discovery. However, structure prediction of ECL2 is difficult because of its long length and the structural diversity among different GPCRs. In this study, a new ECL2 conformational sampling method involving both template-based and ab initio sampling was developed. Inspired by the observation of similar ECL2 structures of closely related GPCRs, a template-based sampling method employing loop structure templates selected from the structure database was developed. A new metric for evaluating similarity of the target loop to templates was introduced for template selection. An ab initio loop sampling method was also developed to treat cases without highly similar templates. The ab initio method is based on the previously developed fragment assembly and loop closure method. A new sampling component that takes advantage of secondary structure prediction was added. In addition, a conserved disulfide bridge restraining ECL2 conformation was predicted and analytically incorporated into sampling, reducing the effective dimension of the conformational search space. The sampling method was combined with an existing energy function for comparison with previously reported loop structure prediction methods, and the benchmark test demonstrated outstanding performance.

Binding free energy and counterion release for adsorption of the antimicrobial peptide lactoferricin B on a POPG membrane.

PubMed

Tolokh, Igor S; Vivcharuk, Victor; Tomberli, Bruno; Gray, C G

2009-09-01

Molecular dynamics (MD) simulations are used to study the interaction of an anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with a POPG bilayer is employed as a model system for studying the details of membrane adsorption selectivity of cationic antimicrobial peptides. Seventy eight 4 ns MD production run trajectories of the equilibrated system, with six restrained orientations of LFCinB at 13 different separations from the POPG membrane, are generated to determine the free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the profile for this relatively large system, a variant of constrained MD and thermodynamic integration is used. A simplified method for relating the free energy profile to the LFCinB-POPG membrane binding constant is employed to predict a free energy of adsorption of -5.4+/-1.3 kcal/mol and a corresponding maximum adsorption binding force of about 58 pN. We analyze the results using Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions and polarized water from the region between the charged membrane and peptide, as the two approach each other. We contrast these results with those found earlier for adsorption of LFCinB on the mammalianlike palmitoyl-oleoyl-phosphatidylcholine membrane.

Microsecond molecular dynamics simulations provide insight into the ATP-competitive inhibitor-induced allosteric protection of Akt kinase phosphorylation.

PubMed

Mou, Linkai; Cui, Tongwei; Liu, Weiguang; Zhang, Hong; Cai, Zhanxiu; Lu, Shaoyong; Gao, Guojun

2017-05-01

Akt is a serine/threonine protein kinase, a critical mediator of growth factor-induced survival in key cellular pathways. Allosteric signaling between protein intramolecular domains requires long-range communication mediated by hotspot residues, often triggered by ligand binding. Here, based on extensive 3 μs explicit solvent molecular dynamics (MD) simulations of Akt1 kinase domain in the unbound (apo) and ATP-competitive inhibitor, GDC-0068-bound states, we propose a molecular mechanism for allosteric regulation of Akt1 kinase phosphorylation by GDC-0068 binding to the ATP-binding site. MD simulations revealed that the apo Akt1 is flexible with two disengaged N- and C-lobes, equilibrated between the open and closed conformations. GDC-0068 occupancy of the ATP-binding site shifts the conformational equilibrium of Akt1 from the open conformation toward the closed conformation and stabilizes the closed state. This effect enables allosteric signal propagation from the GDC-0068 to the phosphorylated T308 (pT308) in the activation loop and restrains phosphatase access to pT308, thereby protecting the pT308 in the GDC-0068-bound Akt1. Importantly, functional hotspots involved in the allosteric communication from the GDC-0068 to the pT308 are identified. Our analysis of GDC-0068-induced allosteric protection of Akt kinase phosphorylation yields important new insights into the molecular mechanism of allosteric regulation of Akt kinase activity. © 2016 John Wiley & Sons A/S.

Mutational scanning of the human serotonin transporter reveals fast translocating serotonin transporter mutants.

PubMed

Kristensen, Anders S; Larsen, Mads B; Johnsen, Laust B; Wiborg, Ove

2004-03-01

The serotonin transporter (SERT) belongs to a family of sodium-chloride-dependent transporters responsible for uptake of amino acids and biogenic amines from the extracellular space. SERT represents a major pharmacological target in the treatment of several clinical conditions, including depression and anxiety. In the present study we have undertaken a mutational scanning of human SERT in order to identify residues that are responsible for individual differences among related monoamine transporters. One mutant, G100A, was inactive in transport. However, ligand binding affinity was similar to wild-type, suggesting that G100A amongst different possible SERT conformations is restrained to a binding conformation. We suggest that the main role of glycine-100 is to confer structural flexibility during substrate translocation. For the two single mutants, T178A and F263C, uptake rates and K(m) values were both several-fold higher than wild-type while binding affinities and inhibitory potencies decreased considerably for several drugs. Ion dependency increased and only at hyperosmotic concentrations were K(m) values partly restored. For the double mutant, T178A/F263C, shifts in uptake kinetics and ligand affinities, as well as ion dependencies, were drastic. Effects were synergistic compared to the corresponding single mutants. In conclusion, we suggest that mutating threonine-178 to an alanine and phenylalanine-263 to a cysteine mainly alter the overall uptake kinetics of SERT by affecting the conformational equilibrium of different transporter conformations.

Virtual screening of a milk peptide database for the identification of food-derived antimicrobial peptides.

PubMed

Liu, Yufang; Eichler, Jutta; Pischetsrieder, Monika

2015-11-01

Milk provides a wide range of bioactive substances, such as antimicrobial peptides and proteins. Our study aimed to identify novel antimicrobial peptides naturally present in milk. The components of an endogenous bovine milk peptide database were virtually screened for charge, amphipathy, and predicted secondary structure. Thus, 23 of 248 screened peptides were identified as candidates for antimicrobial effects. After commercial synthesis, their antimicrobial activities were determined against Escherichia coli NEB5α, E. coli ATCC25922, and Bacillus subtilis ATCC6051. In the tested concentration range (<2 mM), bacteriostatic activity of 14 peptides was detected including nine peptides inhibiting both Gram-positive and Gram-negative bacteria. The most effective fragment was TKLTEEEKNRLNFLKKISQRYQKFΑLPQYLK corresponding to αS2 -casein151-181 , with minimum inhibitory concentration (MIC) of 4.0 μM against B. subtilis ATCC6051, and minimum inhibitory concentrations of 16.2 μM against both E. coli strains. Circular dichroism spectroscopy revealed conformational changes of most active peptides in a membrane-mimic environment, transitioning from an unordered to α-helical structure. Screening of food peptide databases by prediction tools is an efficient method to identify novel antimicrobial food-derived peptides. Milk-derived antimicrobial peptides may have potential use as functional food ingredients and help to understand the molecular mechanisms of anti-infective milk effects. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antimicrobial peptides: a review of how peptide structure impacts antimicrobial activity

NASA Astrophysics Data System (ADS)

Soares, Jason W.; Mello, Charlene M.

2004-03-01

Antimicrobial peptides (AMPs) have been discovered in insects, mammals, reptiles, and plants to protect against microbial infection. Many of these peptides have been isolated and studied exhaustively to decipher the molecular mechanisms that impart protection against infectious bacteria, fungi, and viruses. Unfortunately, the molecular mechanisms are still being debated within the scientific community but valuable clues have been obtained through structure/function relationship studies1. Biophysical studies have revealed that cecropins, isolated from insects and pigs, exhibit random structure in solution but undergo a conformational change to an amphipathic α-helix upon interaction with a membrane surface2. The lack of secondary structure in solution results in an extremely durable peptide able to survive exposure to high temperatures, organic solvents and incorporation into fibers and films without compromising antibacterial activity. Studies to better understand the antimicrobial action of cecropins and other AMPs have provided insight into the importance of peptide sequence and structure in antimicrobial activities. Therefore, enhancing our knowledge of how peptide structure imparts function may result in customized peptide sequences tailored for specific applications such as targeted cell delivery systems, novel antibiotics and food preservation additives. This review will summarize the current state of knowledge with respect to cell binding and antimicrobial activity of AMPs focusing primarily upon cecropins.

Biofilms from Klebsiella pneumoniae: Matrix Polysaccharide Structure and Interactions with Antimicrobial Peptides

PubMed Central

Benincasa, Monica; Lagatolla, Cristina; Dolzani, Lucilla; Milan, Annalisa; Pacor, Sabrina; Liut, Gianfranco; Tossi, Alessandro; Cescutti, Paola; Rizzo, Roberto

2016-01-01

Biofilm matrices of two Klebsiella pneumoniae clinical isolates, KpTs101 and KpTs113, were investigated for their polysaccharide composition and protective effects against antimicrobial peptides. Both strains were good biofilm producers, with KpTs113 forming flocs with very low adhesive properties to supports. Matrix exopolysaccharides were isolated and their monosaccharide composition and glycosidic linkage types were defined. KpTs101 polysaccharide is neutral and composed only of galactose, in both pyranose and furanose ring configurations. Conversely, KpTs113 polysaccharide is anionic due to glucuronic acid units, and also contains glucose and mannose residues. The susceptibility of the two strains to two bovine cathelicidin antimicrobial peptides, BMAP-27 and Bac7(1–35), was assessed using both planktonic cultures and biofilms. Biofilm matrices exerted a relevant protection against both antimicrobials, which act with quite different mechanisms. Similar protection was also detected when antimicrobial peptides were tested against planktonic bacteria in the presence of the polysaccharides extracted from KpTs101 and KpTs113 biofilms, suggesting sequestering adduct formation with antimicrobials. Circular dichroism experiments on BMAP-27 in the presence of increasing amounts of either polysaccharide confirmed their ability to interact with the peptide and induce an α-helical conformation. PMID:27681920

Conformational dynamics of cancer-associated MyD88-TIR domain mutant L252P (L265P) allosterically tilts the landscape toward homo-dimerization

PubMed Central

Zhan, Chendi; Qi, Ruxi; Wei, Guanghong; Guven-Maiorov, Emine; Nussinov, Ruth; Ma, Buyong

2016-01-01

MyD88 is an essential adaptor protein, which mediates the signaling of the toll-like and interleukin-1 receptors’ superfamily. The MyD88 L252P (L265P) mutation has been identified in diffuse large B-cell lymphoma. The identification of this mutation has been a major advance in the diagnosis of patients with aldenstrom macroglobulinemia and related lymphoid neoplasms. Here we used computational methods to characterize the conformational effects of the mutation. Our molecular dynamics simulations revealed that the mutation allosterically quenched the global conformational dynamics of the toll/IL-1R (TIR) domain, and readjusted its salt bridges and dynamic community network. Specifically, the mutation changed the orientation and reduced the fluctuation of α-helix 3, possibly through eliminating/weakening ~8 salt bridges and enhancing the salt bridge D225-K258. Using the energy landscape of the TIR domains of MyD88, we identified two dynamic conformational basins, which correspond to the binding sites used in homo- and hetero-oligomerization, respectively. Our results indicate that the mutation stabilizes the core of the homo-dimer interface of the MyD88-TIR domain, and increases the population of homo-dimer-compatible conformational states in MyD88 family proteins. However, the dampened motion restricts its ability to heterodimerize with other TIR domains, thereby curtailing physiological signaling. In conclusion, the L252P both shifts the landscape toward homo-dimerization and restrains the dynamics of the MyD88-TIR domain, which disfavors its hetero-dimerization with other TIR domains. We further put these observations within the framework of MyD88-mediated cell signaling. PMID:27503954

Solution structure of a DNA decamer containing the antiviral drug ganciclovir: combined use of NMR, restrained molecular dynamics, and full relaxation matrix refinement.

PubMed

Foti, M; Marshalko, S; Schurter, E; Kumar, S; Beardsley, G P; Schweitzer, B I

1997-05-06

The nucleoside analog 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir, DHPG) is an antiviral drug that is used in the treatment of a variety of herpes viruses in immunocompromised patients and in a gene therapy protocol that has shown promising activity for the treatment of cancer. To probe the structural effects of ganciclovir when incorporated into DNA, we determined and compared the solution structure of a modified ganciclovir-containing decamer duplex [d(CTG)(ganciclovir)d(ATCCAG)]2 and a control duplex d[(CTGGATCCAG)]2 using nuclear magnetic resonance techniques. 1H and 31P resonances in both duplexes were assigned using a combination of 2-D 1H and 31P NMR experiments. Proton-proton distances determined from NOESY data and dihedral angles determined from DQF-COSY data were used in restrained molecular dynamics simulations starting from canonical A- and B-form DNA models. Both the control and ganciclovir sets of simulations converged to B-type structures. These structures were subjected to full relaxation matrix refinement to produce final structures that were in excellent agreement with the observed NOE intensities. Examination of the final ganciclovir-containing structures reveals that the base of the ganciclovir residue is hydrogen bonded to its complementary dC and is stacked in the helix; in fact, the base of ganciclovir exhibits increased stacking with the 5' base relative to the control. Interestingly, some of the most significant distortions in the structures occur 3' to the lesion site, including a noticeable kink in the sugar-phosphate backbone at this position. Further examination reveals that the backbone conformation, sugar pucker, and glycosidic torsion angle of the residue 3' to the lesion site all indicate an A-type conformation at this position. A possible correlation of these structural findings with results obtained from earlier biochemical studies will be discussed.

Relative Packing Groups in Template-Based Structure Prediction: Cooperative Effects of True Positive Constraints

PubMed Central

Day, Ryan; Qu, Xiaotao; Swanson, Rosemarie; Bohannan, Zach; Bliss, Robert

2011-01-01

Abstract Most current template-based structure prediction methods concentrate on finding the correct backbone conformation and then packing sidechains within that backbone. Our packing-based method derives distance constraints from conserved relative packing groups (RPGs). In our refinement approach, the RPGs provide a level of resolution that restrains global topology while allowing conformational sampling. In this study, we test our template-based structure prediction method using 51 prediction units from CASP7 experiments. RPG-based constraints are able to substantially improve approximately two-thirds of starting templates. Upon deeper investigation, we find that true positive spatial constraints, especially those non-local in sequence, derived from the RPGs were important to building nearer native models. Surprisingly, the fraction of incorrect or false positive constraints does not strongly influence the quality of the final candidate. This result indicates that our RPG-based true positive constraints sample the self-consistent, cooperative interactions of the native structure. The lack of such reinforcing cooperativity explains the weaker effect of false positive constraints. Generally, these findings are encouraging indications that RPGs will improve template-based structure prediction. PMID:21210729

Exploring the free-energy landscape of a short peptide using an average force

NASA Astrophysics Data System (ADS)

Chipot, Christophe; Hénin, Jérôme

2005-12-01

The reversible folding of deca-alanine is chosen as a test case for characterizing a method that uses an adaptive biasing force (ABF) to escape from the minima and overcome the barriers of the free-energy landscape. This approach relies on the continuous estimation of a biasing force that yields a Hamiltonian in which no average force is exerted along the ordering parameter ξ. Optimizing the parameters that control how the ABF is applied, the method is shown to be extremely effective when a nonequivocal ordering parameter can be defined to explore the folding pathway of the peptide. Starting from a β-turn motif and restraining ξ to a region of the conformational space that extends from the α-helical state to an ensemble of extended structures, the ABF scheme is successful in folding the peptide chain into a compact α helix. Sampling of this conformation is, however, marginal when the range of ξ values embraces arrangements of greater compactness, hence demonstrating the inherent limitations of free-energy methods when ambiguous ordering parameters are utilized.

DNA conformational change induced by the bacteriophage phi 29 connector.

PubMed Central

Valpuesta, J M; Serrano, M; Donate, L E; Herranz, L; Carrascosa, J L

1992-01-01

Translocation of viral DNA inwards and outwards of the capsid of double-stranded DNA bacteriophages occurs through the connector, a key viral structure that is known to interact with DNA. It is shown here that phage phi 29 connector binds both linear and circular double-stranded DNA. However, DNA-mediated protection of phi 29 connectors against Staphylococcus aureus endoprotease V8 digestion suggests that binding to linear DNA is more stable than to circular DNA. Endoprotease V8-protection assays also suggest that the length of the linear DNA required to produce a stable phi 29 connector-DNA interaction is, at least, twice longer than the phi 29 connector channel. This result is confirmed by experiments of phi 29 connector-protection of DNA against DNase I digestion. Furthermore, DNA circularization assays indicate that phi 29 connectors restrain negative supercoiling when bound to linear DNA. This DNA conformational change is not observed upon binding to circular DNA and it could reflect the existence of some left-handed DNA coiling or DNA untwisting inside of the phi 29 connector channel. Images PMID:1454519

New natural product -an efficient antimicrobial applications of new newly synthesized pyrimidine derivatives by the electrochemical oxidation of hydroxyl phenol in the presence of 2-mercapto-6-(trifluoromethyl) pyrimidine-4-ol as nucleophile.

PubMed

Khan, Zia Ul Haq; Khan, Amjad; Wan, Pingyu; Khan, Arif Ullah; Tahir, Kamran; Muhammad, Nawshad; Khan, Faheem Ullah; Shah, Hidayat Ullah; Khan, Zia Ullah

2018-05-01

Some new pyrimidine derivatives have been synthesised by electrochemical oxidation of catechol (1a) in the existence of 2-mercapto-6-(trifluoromethyl) pyrimidine-4-ol (3) as a nucleophile in aqueous solution using Cyclic Voltammetric and Controlled Potential Coulometry. The catechol has been oxidised to o-quinone through electrochemical method and participative in Michael addition reaction, leading to the development of some new pyrimidine derivatives. The products were achieved in good yield with high pureness. The mechanism of the reaction has been conformed from the Cyclic Voltammetric data and Controlled Potential Coulometry. After purification, the compounds were characterised using modern techniques. The synthesised materials were screened for antimicrobial actions using Gram positive and Gram negative strain of bacteria. These new synthesised pyrimidine derivatives showed very good antimicrobial activity.

Adaptive ingredients against food spoilage in Japanese cuisine.

PubMed

Ohtsubo, Yohsuke

2009-12-01

Billing and Sherman proposed the antimicrobial hypothesis to explain the worldwide spice use pattern. The present study explored whether two antimicrobial ingredients (i.e. spices and vinegar) are used in ways consistent with the antimicrobial hypothesis. Four specific predictions were tested: meat-based recipes would call for more spices/vinegar than vegetable-based recipes; summer recipes would call for more spices/vinegar than winter recipes; recipes in hotter regions would call for more spices/vinegar; and recipes including unheated ingredients would call for more spices/vinegar. Spice/vinegar use patterns were compiled from two types of traditional Japanese cookbooks. Dataset I included recipes provided by elderly Japanese housewives. Dataset II included recipes provided by experts in traditional Japanese foods. The analyses of Dataset I revealed that the vinegar use pattern conformed to the predictions. In contrast, analyses of Dataset II generally supported the predictions in terms of spices, but not vinegar.

β-Boomerang Antimicrobial and Antiendotoxic Peptides: Lipidation and Disulfide Bond Effects on Activity and Structure.

PubMed

Mohanram, Harini; Bhattacharjya, Surajit

2014-04-21

Drug-resistant Gram-negative bacterial pathogens and endotoxin- or lipopolysaccharide (LPS)-mediated inflammations are among some of the most  prominent health issues globally. Antimicrobial peptides (AMPs) are eminent molecules that can kill drug-resistant strains and neutralize LPS toxicity. LPS, the outer layer of the outer membrane of Gram-negative bacteria safeguards cell integrity against hydrophobic compounds, including antibiotics and AMPs. Apart from maintaining structural integrity, LPS, when released into the blood stream, also induces inflammatory pathways leading to septic shock. In previous works, we have reported the de novo design of a set of 12-amino acid long cationic/hydrophobic peptides for LPS binding and activity. These peptides adopt β-boomerang like conformations in complex with LPS. Structure-activity studies demonstrated some critical features of the β-boomerang scaffold that may be utilized for the further development of potent analogs. In this work, β-boomerang lipopeptides were designed and structure-activity correlation studies were carried out. These lipopeptides were homo-dimerized through a disulfide bridge to stabilize conformations and for improved activity. The designed peptides exhibited potent antibacterial activity and efficiently neutralized LPS toxicity under in vitro assays. NMR structure of C4YI13C in aqueous solution demonstrated the conserved folding of the lipopeptide with a boomerang aromatic lock stabilized with disulfide bond at the C-terminus and acylation at the N-terminus. These lipo-peptides displaying bacterial sterilization and low hemolytic activity may be useful for future applications as antimicrobial and antiendotoxin molecules.

High-disinhibition restrained eaters are disinhibited by self-regulatory depletion in the food-related inhibitory control.

PubMed

Zhou, Yizhou; Gao, Xiao; Chen, Hong; Kong, Fanchang

2017-08-01

Restrained eating for weight control and loss is becoming highly prevalent in many affluent societies, while most of the restrained eaters are rather unsuccessful in the long term. According to the strength model of self-control, the disinhibition effect of restrained eaters may occur after the depletion of self-control resources. However, no work has examined the direct impact of self-control resources on inhibitory control ability of restrained eaters. This study investigated the influences of self-control resources on the food-related inhibitory control among high-restraint/low-disinhibition restrained eaters, high-restraint/high-disinhibition restrained eaters and unrestrained eaters using stop signal task. Results reveal that there's no difference of food-related inhibitory control between three groups when the self-control resources are non-depleted, while high-restraint/high-disinhibition restrained eaters showing a decrease of food-related inhibitory control after ego-depletion. This disinhibition effect only seems to occur in samples of restrained eaters with a high tendency toward overeating. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Rigidity-Enhanced Antimicrobial Activity: A Case for Linear Cationic α-Helical Peptide HP(2–20) and Its Four Analogues

PubMed Central

Liu, Li; Fang, Ying; Huang, Qingsheng; Wu, Jianhua

2011-01-01

Linear cationic α-helical antimicrobial peptides are referred to as one of the most likely substitutes for common antibiotics, due to their relatively simple structures (≤40 residues) and various antimicrobial activities against a wide range of pathogens. Of those, HP(2–20) was isolated from Helicobacter pylori ribosomal protein. To reveal a mechanical determinant that may mediate the antimicrobial activities, we examined the mechanical properties and structural stabilities of HP(2–20) and its four analogues of same chain length by steered molecular dynamics simulation. The results indicated the following: the resistance of H-bonds to the tensile extension mediated the early extensive stage; with the loss of H-bonds, the tensile force was dispensed to prompt the conformational phase transition; and Young's moduli (N/m2) of the peptides were about 4∼8×109. These mechanical features were sensitive to the variation of the residue compositions. Furthermore, we found that the antimicrobial activity is rigidity-enhanced, that is, a harder peptide has stronger antimicrobial activity. It suggests that the molecular spring constant may be used to seek a new structure-activity relationship for different α-helical peptide groups. This exciting result was reasonably explained by a possible mechanical mechanism that regulates both the membrane pore formation and the peptide insertion. PMID:21283643

Conformational dynamics of dry lamellar crystals of sugar based lipids: an atomistic simulation study.

PubMed

ManickamAchari, Vijayan; Bryce, Richard A; Hashim, Rauzah

2014-01-01

The rational design of a glycolipid application (e.g. drug delivery) with a tailored property depends on the detailed understanding of its structure and dynamics. Because of the complexity of sugar stereochemistry, we have undertaken a simulation study on the conformational dynamics of a set of synthetic glycosides with different sugar groups and chain design, namely dodecyl β-maltoside, dodecyl β-cellobioside, dodecyl β-isomaltoside and a C12C10 branched β-maltoside under anhydrous conditions. We examined the chain structure in detail, including the chain packing, gauche/trans conformations and chain tilting. In addition, we also investigated the rotational dynamics of the headgroup and alkyl chains. Monoalkylated glycosides possess a small amount of gauche conformers (∼20%) in the hydrophobic region of the lamellar crystal (LC) phase. In contrast, the branched chain glycolipid in the fluid Lα phase has a high gauche population of up to ∼40%. Rotational diffusion analysis reveals that the carbons closest to the headgroup have the highest correlation times. Furthermore, its value depends on sugar type, where the rotational dynamics of an isomaltose was found to be 11-15% and more restrained near the sugar, possibly due to the chain disorder and partial inter-digitation compared to the other monoalkylated lipids. Intriguingly, the present simulation demonstrates the chain from the branched glycolipid bilayer has the ability to enter into the hydrophilic region. This interesting feature of the anhydrous glycolipid bilayer simulation appears to arise from a combination of lipid crowding and the amphoteric nature of the sugar headgroups.

The structures of non-CG-repeat Z-DNAs co-crystallized with the Z-DNA-binding domain, hZ alpha(ADAR1).

PubMed

Ha, Sung Chul; Choi, Jongkeun; Hwang, Hye-Yeon; Rich, Alexander; Kim, Yang-Gyun; Kim, Kyeong Kyu

2009-02-01

The Z-DNA conformation preferentially occurs at alternating purine-pyrimidine repeats, and is specifically recognized by Z alpha domains identified in several Z-DNA-binding proteins. The binding of Z alpha to foreign or chromosomal DNA in various sequence contexts is known to influence various biological functions, including the DNA-mediated innate immune response and transcriptional modulation of gene expression. For these reasons, understanding its binding mode and the conformational diversity of Z alpha bound Z-DNAs is of considerable importance. However, structural studies of Z alpha bound Z-DNA have been mostly limited to standard CG-repeat DNAs. Here, we have solved the crystal structures of three representative non-CG repeat DNAs, d(CACGTG)(2), d(CGTACG)(2) and d(CGGCCG)(2) complexed to hZ alpha(ADAR1) and compared those structures with that of hZ alpha(ADAR1)/d(CGCGCG)(2) and the Z alpha-free Z-DNAs. hZ alpha(ADAR1) bound to each of the three Z-DNAs showed a well conserved binding mode with very limited structural deviation irrespective of the DNA sequence, although varying numbers of residues were in contact with Z-DNA. Z-DNAs display less structural alterations in the Z alpha-bound state than in their free form, thereby suggesting that conformational diversities of Z-DNAs are restrained by the binding pocket of Z alpha. These data suggest that Z-DNAs are recognized by Z alpha through common conformational features regardless of the sequence and structural alterations.

Computational conformational antimicrobial analysis developing mechanomolecular theory for polymer biomaterials in materials science and engineering

NASA Astrophysics Data System (ADS)

Petersen, Richard C.

2014-03-01

Single-bond rotations or pyramidal inversions tend to either hide or expose relative energies that exist for atoms with nonbonding lone-pair electrons. Availability of lone-pair electrons depends on overall molecular electron distributions and differences in the immediate polarity of the surrounding pico/nanoenvironment. Stereochemistry three-dimensional aspects of molecules provide insight into conformations through single-bond rotations with associated lone-pair electrons on oxygen atoms in addition to pyramidal inversions with nitrogen atoms. When electrons are protected, potential energy is sheltered toward an energy minimum value to compatibilize molecularly with nonpolar environments. When electrons are exposed, maximum energy is available toward polar environment interactions. Computational conformational analysis software calculated energy profiles that exist during specific oxygen ether single-bond rotations with easy-to-visualize three-dimensional models for the trichlorinated bisaromatic ether triclosan antimicrobial polymer additive. As shown, fluctuating alternating bond rotations can produce complex interactions between molecules to provide entanglement strength for polymer toughness or alternatively disrupt weak secondary bonds of attraction to lower resin viscosity for new additive properties with nonpolar triclosan as a hydrophobic toughening/wetting agent. Further, bond rotations involving lone-pair electrons by a molecule at a nonpolar-hydrocarbon-membrane/polar-biologic-fluid interface might become sufficiently unstable to provide free mechanomolecular energies to disrupt weaker microbial membranes, for membrane transport of molecules into cells, provide cell signaling/recognition/defense and also generate enzyme mixing to speed reactions.

Assessment of antimicrobial and wound healing effects of Brevinin-2Ta against the bacterium Klebsiella pneumoniae in dermally-wounded rats

PubMed Central

Liu, Siqin; Long, Qilin; Xu, Yang; Wang, Jun; Xu, Zhongwei; Wang, Lei; Zhou, Mei; Wu, Yuxin; Chen, Tianbao; Shaw, Chris

2017-01-01

Antimicrobial peptides (AMPs) are regarded as promising alternatives for antibiotics due to their inherent capacity to prevent microbial drug resistance. Amphibians are rich source of bioactive molecules, which provide numerous AMPs with various structures as drug candidates. Here, we isolated and identified a novel AMP Brevinin-2Ta (B-2Ta) from the skin secretion of the European frog, Pelophylax kl. esculentus. In vitro studies revealed that it showed broad antimicrobial activities against S. aureus, E. coli and C. albicans with low cytotoxicity to erythrocytes. Furthermore, we examined the anti-inflammation effect in vivo by using Klebsiella pneumoniae-infected Sprague-Dawley (SD) rats. The wound closure outcomes revealed that B-2Ta effectively restrained the bacterial infection at a dose of 10 times minimal inhibitory concentration (MIC) during the 14 days of the wound healing process. Ultra-structure analyses showed that B-2Ta caused structural damage to the microorganism, and bacterial culture found that the number of microbes was significantly reduced by the end of treatment. Immunohistochemistry for the inflammatory marker IL-10 and the endothelial cell marker CD31 suggested positive effects on inflammatory status and epithelial migration and angiogenesis following treatment of the infected granulation tissues with B-2Ta. These results exhibited the continuous phase of inflammation reduction and wound healing acceleration in the B-2Ta-modulated re-epithelialisation of K. pneumoniae infected rats. Taken together, these data demonstrated that B-2Ta has great potential to be developed as antibacterial agents in clinic. PMID:29340060

Binding free energy and counterion release for adsorption of the antimicrobial peptide lactoferricin B on a POPG membrane

NASA Astrophysics Data System (ADS)

Tolokh, Igor S.; Vivcharuk, Victor; Tomberli, Bruno; Gray, C. G.

2009-09-01

Molecular dynamics (MD) simulations are used to study the interaction of an anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with a POPG bilayer is employed as a model system for studying the details of membrane adsorption selectivity of cationic antimicrobial peptides. Seventy eight 4 ns MD production run trajectories of the equilibrated system, with six restrained orientations of LFCinB at 13 different separations from the POPG membrane, are generated to determine the free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the profile for this relatively large system, a variant of constrained MD and thermodynamic integration is used. A simplified method for relating the free energy profile to the LFCinB-POPG membrane binding constant is employed to predict a free energy of adsorption of -5.4±1.3kcal/mol and a corresponding maximum adsorption binding force of about 58 pN. We analyze the results using Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions and polarized water from the region between the charged membrane and peptide, as the two approach each other. We contrast these results with those found earlier for adsorption of LFCinB on the mammalianlike palmitoyl-oleoyl-phosphatidylcholine membrane.

Electron Microscopic Visualization of Protein Assemblies on Flattened DNA Origami.

PubMed

Mallik, Leena; Dhakal, Soma; Nichols, Joseph; Mahoney, Jacob; Dosey, Anne M; Jiang, Shuoxing; Sunahara, Roger K; Skiniotis, Georgios; Walter, Nils G

2015-07-28

DNA provides an ideal substrate for the engineering of versatile nanostructures due to its reliable Watson-Crick base pairing and well-characterized conformation. One of the most promising applications of DNA nanostructures arises from the site-directed spatial arrangement with nanometer precision of guest components such as proteins, metal nanoparticles, and small molecules. Two-dimensional DNA origami architectures, in particular, offer a simple design, high yield of assembly, and large surface area for use as a nanoplatform. However, such single-layer DNA origami were recently found to be structurally polymorphous due to their high flexibility, leading to the development of conformationally restrained multilayered origami that lack some of the advantages of the single-layer designs. Here we monitored single-layer DNA origami by transmission electron microscopy (EM) and discovered that their conformational heterogeneity is dramatically reduced in the presence of a low concentration of dimethyl sulfoxide, allowing for an efficient flattening onto the carbon support of an EM grid. We further demonstrated that streptavidin and a biotinylated target protein (cocaine esterase, CocE) can be captured at predesignated sites on these flattened origami while maintaining their functional integrity. Our demonstration that protein assemblies can be constructed with high spatial precision (within ∼2 nm of their predicted position on the platforms) by using strategically flattened single-layer origami paves the way for exploiting well-defined guest molecule assemblies for biochemistry and nanotechnology applications.

Antimicrobial Peptides: Insights into Membrane Permeabilization, Lipopolysaccharide Fragmentation and Application in Plant Disease Control.

PubMed

Datta, Aritreyee; Ghosh, Anirban; Airoldi, Cristina; Sperandeo, Paola; Mroue, Kamal H; Jiménez-Barbero, Jesús; Kundu, Pallob; Ramamoorthy, Ayyalusamy; Bhunia, Anirban

2015-07-06

The recent increase in multidrug resistance against bacterial infections has become a major concern to human health and global food security. Synthetic antimicrobial peptides (AMPs) have recently received substantial attention as potential alternatives to conventional antibiotics because of their potent broad-spectrum antimicrobial activity. These peptides have also been implicated in plant disease control for replacing conventional treatment methods that are polluting and hazardous to the environment and to human health. Here, we report de novo design and antimicrobial studies of VG16, a 16-residue active fragment of Dengue virus fusion peptide. Our results reveal that VG16KRKP, a non-toxic and non-hemolytic analogue of VG16, shows significant antimicrobial activity against Gram-negative E. coli and plant pathogens X. oryzae and X. campestris, as well as against human fungal pathogens C. albicans and C. grubii. VG16KRKP is also capable of inhibiting bacterial disease progression in plants. The solution-NMR structure of VG16KRKP in lipopolysaccharide features a folded conformation with a centrally located turn-type structure stabilized by aromatic-aromatic packing interactions with extended N- and C-termini. The de novo design of VG16KRKP provides valuable insights into the development of more potent antibacterial and antiendotoxic peptides for the treatment of human and plant infections.

A folding-dependent mechanism of antimicrobial peptide resistance to degradation unveiled by solution structure of distinctin

PubMed Central

Raimondo, Domenico; Andreotti, Giuseppina; Saint, Nathalie; Amodeo, Pietro; Renzone, Giovanni; Sanseverino, Marina; Zocchi, Ivana; Molle, Gerard; Motta, Andrea; Scaloni, Andrea

2005-01-01

Many bioactive peptides, presenting an unstructured conformation in aqueous solution, are made resistant to degradation by posttranslational modifications. Here, we describe how molecular oligomerization in aqueous solution can generate a still unknown transport form for amphipathic peptides, which is more compact and resistant to proteases than forms related to any possible monomer. This phenomenon emerged from 3D structure, function, and degradation properties of distinctin, a heterodimeric antimicrobial compound consisting of two peptide chains linked by a disulfide bond. After homodimerization in water, this peptide exhibited a fold consisting of a symmetrical full-parallel four-helix bundle, with a well secluded hydrophobic core and exposed basic residues. This fold significantly stabilizes distinctin against proteases compared with other linear amphipathic peptides, without affecting its antimicrobial, hemolytic, and ion-channel formation properties after membrane interaction. This full-parallel helical orientation represents a perfect compromise between formation of a stable structure in water and requirement of a drastic structural rearrangement in membranes to elicit antimicrobial potential. Thus, distinctin can be claimed as a prototype of a previously unrecognized class of antimicrobial derivatives. These results suggest a critical revision of the role of peptide oligomerization whenever solubility or resistance to proteases is known to affect biological properties. PMID:15840728

The relevance of restrained eating behavior for circadian eating patterns in adolescents

PubMed Central

Alexy, Ute; Diederichs, Tanja; Buyken, Anette E.; Roßbach, Sarah

2018-01-01

Background Restrained Eating, i.e. the tendency to restrict dietary intake to control body-weight, often emerges during adolescence and may result in changes in circadian eating patterns. Objective The objective of the present investigation was to determine the cross-sectional relevance of restrained eating for characteristics of circadian eating pattern in adolescents and whether changes in restrained eating are accompanied by concurrent changes in circadian eating pattern over the course of adolescence. Methods Two questionnaires assessing restrained eating (Score 0–30) with parallel 3-day weighed dietary records from two different time points were available from 209 (♂:101, ♀:108) 11–18 year old adolescents of the DONALD study. Mixed linear regression models were used to analyze whether restrained eating was associated with eating occasion frequency, snack frequency and morning and evening energy intake [in % of daily energy intake, %E]. Linear regression models were used to examine whether changes in restrained eating were associated with changes in the mentioned variables. Results Among girls, greater restrained eating was cross-sectionally associated with higher morning energy intake (p = 0.03). Further, there was a tendency towards lower evening energy intake with higher levels of restrained eating for the whole sample (p = 0.06). No cross-sectional associations were found with eating occasion or snack frequency. Each one-point increase in restrained eating during adolescence was related to a concurrent decrease in eating occasion frequency by 0.04 (95% CI -0.08; -0.01, p = 0.02) and in evening energy intake by 0.36%E (95% CI -0.70; -0.03, p = 0.04). A tendency towards decreasing snack frequency with increasing restrained eating was observed (β = -0.03, 95% CI -0.07; 0.00, p = 0.07). No association was found between changes in restrained eating and concurrent changes in morning energy intake. Conclusion We found indications for cross-sectional and prospective associations between restrained eating and chronobiological aspects of food intake in adolescents. Our results suggest that restrained eating should be considered a relevant determinant of circadian eating patterns. PMID:29791516

A shrimp C-type lectin inhibits proliferation of the hemolymph microbiota by maintaining the expression of antimicrobial peptides.

PubMed

Wang, Xian-Wei; Xu, Ji-Dong; Zhao, Xiao-Fan; Vasta, Gerardo Raul; Wang, Jin-Xing

2014-04-25

Some aquatic invertebrates such as shrimp contain low albeit stable numbers of bacteria in the circulating hemolymph. The proliferation of this hemolymph microbiota in such a nutrient-rich environment is tightly controlled in healthy animals, but the mechanisms responsible had remained elusive. In the present study, we report a C-type lectin (MjHeCL) from the kuruma shrimp (Marsupenaeus japonicus) that participates in restraining the hemolymph microbiota. Although the expression of MjHeCL did not seem to be modulated by bacterial challenge, the down-regulation of its expression by RNA interference led to proliferation of the hemolymph microbiota, ultimately resulting in shrimp death. This phenotype was rescued by the injection of recombinant MjHeCL, which restored the healthy status of the knockdown shrimp. A mechanistic analysis revealed that MjHeCL inhibited bacterial proliferation by modulating the expression of antimicrobial peptides. The key function of MjHeCL in the shrimp immune homeostasis might be related to its broader recognition spectrum of the hemolymph microbiota components than other lectins. Our study demonstrates the role of MjHeCL in maintaining the healthy status of shrimp and provides new insight into the biological significance of C-type lectins, a diversified and abundant lectin family in invertebrate species.

Structure and Mechanism of ArnA: Conformational Change Implies Ordered Dehydrogenase Mechanism in Key Enzyme for Polymyxin Resistance

PubMed Central

Gatzeva-Topalova, Petia Z.; May, Andrew P.; Sousa, Marcelo C.

2010-01-01

Summary The modification of lipid A with 4-amino-4-deoxy-L-arabinose (Ara4N) allows gram-negative bacteria to resist the antimicrobial activity of cationic antimicrobial peptides and antibiotics such as polymyxin. ArnA is the first enzyme specific to the lipid A-Ara4N pathway. It contains two functionally and physically separable domains: a dehydrogenase domain (ArnA_DH) catalyzing the NAD+-dependent oxidative decarboxylation of UDP-Glucuronic acid (UDP-GlcA), and a transformylase domain that formylates UDP-Ara4N. Here, we describe the crystal structure of the full-length bifunctional ArnA with UDP-GlcA and ATP bound to the dehydrogenase domain. Binding of UDP-GlcA triggers a 17 Å conformational change in ArnA_DH that opens the NAD+ binding site while trapping UDP-GlcA. We propose an ordered mechanism of substrate binding and product release. Mutation of residues R619 and S433 demonstrates their importance in catalysis and suggests that R619 functions as a general acid in catalysis. The proposed mechanism for ArnA_DH has important implications for the design of selective inhibitors. PMID:15939024

Nanomaterials for alternative antibacterial therapy

PubMed Central

Hemeg, Hassan A

2017-01-01

Despite an array of cogent antibiotics, bacterial infections, notably those produced by nosocomial pathogens, still remain a leading factor of morbidity and mortality around the globe. They target the severely ill, hospitalized and immunocompromised patients with incapacitated immune system, who are prone to infections. The choice of antimicrobial therapy is largely empirical and not devoid of toxicity, hypersensitivity, teratogenicity and/or mutagenicity. The emergence of multidrug-resistant bacteria further intensifies the clinical predicament as it directly impacts public health due to diminished potency of current antibiotics. In addition, there is an escalating concern with respect to biofilm-associated infections that are refractory to the presently available antimicrobial armory, leaving almost no therapeutic option. Hence, there is a dire need to develop alternate antibacterial agents. The past decade has witnessed a substantial upsurge in the global use of nanomedicines as innovative tools for combating the high rates of antimicrobial resistance. Antibacterial activity of metal and metal oxide nanoparticles (NPs) has been extensively reported. The microbes are eliminated either by microbicidal effects of the NPs, such as release of free metal ions culminating in cell membrane damage, DNA interactions or free radical generation, or by microbiostatic effects coupled with killing potentiated by the host’s immune system. This review encompasses the magnitude of multidrug resistance in nosocomial infections, bacterial evasion of the host immune system, mechanisms used by bacteria to develop drug resistance and the use of nanomaterials based on metals to overcome these challenges. The diverse annihilative effects of conventional and biogenic metal NPs for antibacterial activity are also discussed. The use of polymer-based nanomaterials and nanocomposites, alone or functionalized with ligands, antibodies or antibiotics, as alternative antimicrobial agents for treating severe bacterial infections is also discussed. Combinatorial therapy with metallic NPs, as adjunct to the existing antibiotics, may aid to restrain the mounting menace of bacterial resistance and nosocomial threat. PMID:29184409

D-amino acid substitution enhances the stability of antimicrobial peptide polybia-CP.

PubMed

Jia, Fengjing; Wang, Jiayi; Peng, Jinxiu; Zhao, Ping; Kong, Ziqing; Wang, Kairong; Yan, Wenjin; Wang, Rui

2017-10-01

With the increasing emergence of resistant microbes toward conventional antimicrobial agents, there is an urgent need for the development of antimicrobial agents with novel action mode. Antimicrobial peptides (AMPs) are believed to be one kind of ideal alternatives. However, AMPs can be easily degraded by protease, which limited their therapeutic use. In the present study, D-amino acid substitution strategy was employed to enhance the stability of polybia-CP. We investigated the stability of peptides against the degradation of trypsin and chymotrypsin by determining the antimicrobial activity or determining the HPLC profile of peptides after incubation with proteases. Our results showed that both the all D-amino acid derivative (D-CP) and partial D-lysine substitution derivative (D-lys-CP) have an improved stability against trypsin and chymotrypsin. Although D-CP takes left-hand α-helical conformation and D-lys-CP loses some α-helical content, both of the D-amino acid-substituted derivatives maintain their parental peptides' membrane active action mode. In addition, D-lys-CP showed a slight weaker antimicrobial activity than polybia-CP, but the hemolytic activity decreased greatly. These results suggest that D-CP and D-lys-CP can offer strategy to improve the property of AMPs and may be leading compounds for the development of novel antimicrobial agents. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Restrained eaters show altered brain response to food odor.

PubMed

Kemmotsu, Nobuko; Murphy, Claire

2006-02-28

Do restrained and unrestrained eaters differ in their brain response to food odor? We addressed this question by examining restrained eaters' brain response to food (chocolate) and non-food (geraniol, floral) odors, both when odor was attended to and when ignored. Using olfactory event-related potentials (OERPs), we found that restrained eaters and controls responded similarly to the non-food odor; however, unlike controls, restrained eaters showed no increase in brain response to the food odor when they focused attention on it. Rather, restrained eaters showed attenuated OERP amplitudes to the food odor in both attended and ignored conditions, suggesting that the brain's response to attended food odor was abnormally suppressed.

β-Boomerang Antimicrobial and Antiendotoxic Peptides: Lipidation and Disulfide Bond Effects on Activity and Structure

PubMed Central

Mohanram, Harini; Bhattacharjya, Surajit

2014-01-01

Drug-resistant Gram-negative bacterial pathogens and endotoxin- or lipopolysaccharide (LPS)-mediated inflammations are among some of the most prominent health issues globally. Antimicrobial peptides (AMPs) are eminent molecules that can kill drug-resistant strains and neutralize LPS toxicity. LPS, the outer layer of the outer membrane of Gram-negative bacteria safeguards cell integrity against hydrophobic compounds, including antibiotics and AMPs. Apart from maintaining structural integrity, LPS, when released into the blood stream, also induces inflammatory pathways leading to septic shock. In previous works, we have reported the de novo design of a set of 12-amino acid long cationic/hydrophobic peptides for LPS binding and activity. These peptides adopt β-boomerang like conformations in complex with LPS. Structure-activity studies demonstrated some critical features of the β-boomerang scaffold that may be utilized for the further development of potent analogs. In this work, β-boomerang lipopeptides were designed and structure-activity correlation studies were carried out. These lipopeptides were homo-dimerized through a disulfide bridge to stabilize conformations and for improved activity. The designed peptides exhibited potent antibacterial activity and efficiently neutralized LPS toxicity under in vitro assays. NMR structure of C4YI13C in aqueous solution demonstrated the conserved folding of the lipopeptide with a boomerang aromatic lock stabilized with disulfide bond at the C-terminus and acylation at the N-terminus. These lipo-peptides displaying bacterial sterilization and low hemolytic activity may be useful for future applications as antimicrobial and antiendotoxin molecules. PMID:24756162

Temporal attention for visual food stimuli in restrained eaters.

PubMed

Neimeijer, Renate A M; de Jong, Peter J; Roefs, Anne

2013-05-01

Although restrained eaters try to limit their food intake, they often fail and indulge in exactly those foods that they want to avoid. A possible explanation is a temporal attentional bias for food cues. It could be that for these people food stimuli are processed relatively efficiently and require less attentional resources to enter awareness. Once a food stimulus has captured attention, it may be preferentially processed and granted prioritized access to limited cognitive resources. This might help explain why restrained eaters often fail in their attempts to restrict their food intake. A Rapid Serial Visual Presentation task consisting of dual and single target trials with food and neutral pictures as targets and/or distractors was administered to restrained (n=40) and unrestrained (n=40) eaters to study temporal attentional bias. Results indicated that (1) food cues did not diminish the attentional blink in restrained eaters when presented as second target; (2) specifically restrained eaters showed an interference effect of identifying food targets on the identification of preceding neutral targets; (3) for both restrained and unrestrained eaters, food cues enhanced the attentional blink; (4) specifically in restrained eaters, food distractors elicited an attention blink in the single target trials. In restrained eaters, food cues get prioritized access to limited cognitive resources, even if this processing priority interferes with their current goals. This temporal attentional bias for food stimuli might help explain why restrained eaters typically have difficulties maintaining their diet rules. Copyright © 2012 Elsevier Ltd. All rights reserved.

Being restrained: a study of power and powerlessness.

PubMed

Johnson, M E

1998-01-01

Previous research about the use of restraints has mainly sought generalizations regarding (a) who is likely to be restrained, (b) the frequency of the use of restraints, and (c) the behavior that precipitates the application of restraining devices. Therefore, there has been a paucity of research that attempts to understand the impact of restraint on the restrained person. The purpose of this study was to understand the meaning of the experience of being restrained for 10 psychiatric patients who had been restrained in leather restraints. Participants were interviewed in unstructured interviews. The taped interviews were transcribed and analyzed by means of a modification of an eight-stage interpretive process, grounded in Heideggerian phenomenology. In this article the theme of power is reported and discussed.

Restrained eating and self-esteem in premenopausal and postmenopausal women.

PubMed

Drobnjak, Suzana; Atsiz, Semra; Ditzen, Beate; Tuschen-Caffier, Brunna; Ehlert, Ulrike

2014-01-01

There has been limited research about disordered eating in middle-aged women, and to date, few data exist about restrained eating behavior in postmenopausal women. Therefore, the aim of this study was to examine eating behavior with a specific focus on menopause as an associated factor in restrained eating. Beyond this, we were interested in how postmenopausal status and self-esteem would interact to determine eating patterns in women in middle age. We conducted an online survey in women aged between 40 and 66. Eating behavior was assessed with the Eating Disorder Examination-Questionnaire (EDE-Q) in premenopausal (N = 318) and postmenopausal women (N = 250). All participants rated their self-esteem using the Rosenberg Self-Esteem Scale (RSE) and reported their weight, height, waist circumference, and hip circumference. 15.7% of all participants showed clinically meaningful scores on restrained eating. Postmenopausal women showed significantly higher scores on the EDE-Q subscale of restrained eating as compared to premenopausal women, but when controlling for body mass index, however, this finding was no longer significant. Further exploratory analyses suggest that particularly low or high self-esteem levels are associated with restrained eating. Self-esteem might serve as a mediator between menopausal status and restrained eating, however results of these additional analyses were inconsistent. Restrained eating may appear in middle-aged women. Particularly in postmenopausal women, restrained eating might be associated with lower and higher self-esteem.

Harmonic Fourier beads method for studying rare events on rugged energy surfaces.

PubMed

Khavrutskii, Ilja V; Arora, Karunesh; Brooks, Charles L

2006-11-07

We present a robust, distributable method for computing minimum free energy paths of large molecular systems with rugged energy landscapes. The method, which we call harmonic Fourier beads (HFB), exploits the Fourier representation of a path in an appropriate coordinate space and proceeds iteratively by evolving a discrete set of harmonically restrained path points-beads-to generate positions for the next path. The HFB method does not require explicit knowledge of the free energy to locate the path. To compute the free energy profile along the final path we employ an umbrella sampling method in two generalized dimensions. The proposed HFB method is anticipated to aid the study of rare events in biomolecular systems. Its utility is demonstrated with an application to conformational isomerization of the alanine dipeptide in gas phase.

Crystal structure of Halobacterium salinarum halorhodopsin with a partially depopulated primary chloride-binding site.

PubMed

Schreiner, Madeleine; Schlesinger, Ramona; Heberle, Joachim; Niemann, Hartmut H

2016-09-01

The transmembrane pump halorhodopsin in halophilic archaea translocates chloride ions from the extracellular to the cytoplasmic side upon illumination. In the ground state a tightly bound chloride ion occupies the primary chloride-binding site (CBS I) close to the protonated Schiff base that links the retinal chromophore to the protein. The light-triggered trans-cis isomerization of retinal causes structural changes in the protein associated with movement of the chloride ion. In reverse, chemical depletion of CBS I in Natronomonas pharaonis halorhodopsin (NpHR) through deprotonation of the Schiff base results in conformational changes of the protein: a state thought to mimic late stages of the photocycle. Here, crystals of Halobacterium salinarum halorhodopsin (HsHR) were soaked at high pH to provoke deprotonation of the Schiff base and loss of chloride. The crystals changed colour from purple to yellow and the occupancy of CBS I was reduced from 1 to about 0.5. In contrast to NpHR, this chloride depletion did not cause substantial conformational changes in the protein. Nevertheless, two observations indicate that chloride depletion could eventually result in structural changes similar to those found in NpHR. Firstly, the partially chloride-depleted form of HsHR has increased normalized B factors in the region of helix C that is close to CBS I and changes its conformation in NpHR. Secondly, prolonged soaking of HsHR crystals at high pH resulted in loss of diffraction. In conclusion, the conformation of the chloride-free protein may not be compatible with this crystal form of HsHR despite a packing arrangement that hardly restrains helices E and F that presumably move during ion transport.

Mechanical coupling in myosin V: a simulation study

PubMed Central

Ovchinnikov, Victor; Trout, Bernhardt L.

2009-01-01

Myosin motor function depends on the interaction between different domains that transmit information from one part of the molecule to another. The inter-domain coupling in myosin V is studied with Restrained Targeted Molecular Dynamics (RTMD) using an all-atom representation in explicit solvent. To elucidate the origin of the conformational change due to the binding of ATP, targeting forces are applied to small sets of atoms (the forcing sets, FS) in the direction of their displacement from the rigor conformation, which has a closed actin-binding cleft, to the post-rigor conformation, in which the cleft is open. The ‘minimal’ FS that results in extensive structural changes in the overall myosin conformation is comprised of the ATP, Switch 1, and the nearby HF, HG and HH helices. Addition of switch 2 to the forcing set is required to achieve a complete opening of the actin-binding cleft. The RTMD simulations reveal the mechanical coupling pathways between (i) the nucleotide-binding pocket (NBP) and the actin-binding cleft, (ii) the NBP and the converter, and (iii) the actin-binding cleft and the converter. Closing of the NBP due to ATP binding is tightly coupled to the opening of the cleft, and leads to the rupture of a key hydrogen bond (F441N/A684O) between switch 2 and the SH1 helix. The actin-binding cleft may mediate the rupture of this bond via a connection between the HW helix, the Relay helix, and Switch 2. The findings are consistent with experimental studies and a recent normal mode analysis. The present method is expected to be useful more generally in studies of inter-domain coupling in proteins. PMID:19853615

NMR spectroscopy and molecular modelling studies of nitrosylcobalamin: further evidence that the deprotonated, base-off form is important for nitrosylcobalamin in solution†

PubMed Central

Hassanin, Hanaa A.; Hannibal, Luciana; Jacobsen, Donald W.; Brown, Kenneth L.

2009-01-01

The structure of nitrosylcobalamin (NOCbl) in solution has been studied by NMR spectroscopy and the 1H and 13C NMR spectra have been assigned. 13C and 31P NMR chemical shifts, the UV-vis spectrum of NOCbl and the observed pK base-off value of ~5.1 for NOCbl provide evidence that a significant fraction of NOCbl is present in the base-off, 5,6-dimethylbenzimidazole (DMB) deprotonated, form in solution. NOE-restrained molecular mechanics modelling of base-on NOCbl gave annealed structures with minor conformational differences in the flexible side chains and the nucleotide loop position compared with the X-ray structure. A molecular dynamics simulation at 300 K showed that DMB remains in close proximity to the α face of the corrin in the base-off form of NOCbl. Simulated annealing calculations produced two major conformations of base-off NOCbl. In the first, the DMB is perpendicular to the corrin and its B3 nitrogen is about 3.1 Å away from and pointing directly at the metal ion; in the second the DMB is parallel to and tucked beneath the D ring of the corrin. PMID:19122899

Computational prediction of atomic structures of helical membrane proteins aided by EM maps.

PubMed

Kovacs, Julio A; Yeager, Mark; Abagyan, Ruben

2007-09-15

Integral membrane proteins pose a major challenge for protein-structure prediction because only approximately 100 high-resolution structures are available currently, thereby impeding the development of rules or empirical potentials to predict the packing of transmembrane alpha-helices. However, when an intermediate-resolution electron microscopy (EM) map is available, it can be used to provide restraints which, in combination with a suitable computational protocol, make structure prediction feasible. In this work we present such a protocol, which proceeds in three stages: 1), generation of an ensemble of alpha-helices by flexible fitting into each of the density rods in the low-resolution EM map, spanning a range of rotational angles around the main helical axes and translational shifts along the density rods; 2), fast optimization of side chains and scoring of the resulting conformations; and 3), refinement of the lowest-scoring conformations with internal coordinate mechanics, by optimizing the van der Waals, electrostatics, hydrogen bonding, torsional, and solvation energy contributions. In addition, our method implements a penalty term through a so-called tethering map, derived from the EM map, which restrains the positions of the alpha-helices. The protocol was validated on three test cases: GpA, KcsA, and MscL.

Genetic and environmental influences on restrained eating behavior

PubMed Central

Schur, Ellen; Noonan, Carolyn; Polivy, Janet; Goldberg, Jack; Buchwald, Dedra

2009-01-01

Objective We examined the relative contributions of genetic and environmental influences to restrained eating. Methods Restrained eating was assessed by the Restraint Scale in a survey mailed to all twins enrolled in the University of Washington Twin Registry. We used structural equation modeling to estimate genetic and non-genetic contributions to restrained eating. Results 1,196 monozygotic, 456 same-sex dizygotic twins, and 447 opposite-sex twins were included in analyses. Restraint Scale scores were more closely correlated in monozygotic twins (rmale = 0.55, rfemale = 0.55) than in same-sex dizygotic twins (rmale = 0.31, rfemale = 0.19). Based on structural equation modeling, the estimated heritability for restrained eating, adjusted for BMI and sex, was 43% (95% confidence interval 35–50%). There was little evidence for common environmental effects. Conclusion These results indicate an inherited component to restrained eating. Genes could influence restrained eating directly or through inherited mediators such as personality factors or tendencies to gain weight. PMID:19658171

Parallel pathways and free-energy landscapes for enzymatic hydride transfer probed by hydrostatic pressure.

PubMed

Pudney, Christopher R; McGrory, Tom; Lafite, Pierre; Pang, Jiayun; Hay, Sam; Leys, David; Sutcliffe, Michael J; Scrutton, Nigel S

2009-05-25

Mutation of an active-site residue in morphinone reductase leads to a conformationally rich landscape that enhances the rate of hydride transfer from NADH to FMN at standard pressure (1 bar). Increasing the pressure causes interconversion between different conformational substates in the mutant enzyme. While high pressure reduces the donor-acceptor distance in the wild-type enzyme, increased conformational freedom "dampens" its effect in the mutant.We show that hydride transfer from NADH to FMN catalysed by the N189A mutant of morphinone reductase occurs along parallel "chemical" pathways in a conformationally rich free-energy landscape. We have developed experimental kinetic and spectroscopic tools by using hydrostatic pressure to explore this free-energy landscape. The crystal structure of the N189A mutant enzyme in complex with the unreactive coenzyme analogue NADH(4) indicates that the nicotinamide moiety of the analogue is conformationally less restrained than the corresponding structure of the wild-type NADH(4) complex. This increased degree of conformational freedom in the N189A enzyme gives rise to the concept of multiple reactive configurations (MRCs), and we show that the relative population of these states across the free-energy landscape can be perturbed experimentally as a function of pressure. Specifically, the amplitudes of individual kinetic phases that were observed in stopped-flow studies of the hydride transfer reaction are sensitive to pressure; this indicates that pressure drives an altered distribution across the energy landscape. We show by absorbance spectroscopy that the loss of charge-transfer character of the enzyme-coenzyme complex is attributed to the altered population of MRCs on the landscape. The existence of a conformationally rich landscape in the N189A mutant is supported by molecular dynamics simulations at low and high pressure. The work provides firm experimental and computational support for the existence of parallel pathways arising from multiple conformational states of the enzyme-coenzyme complex. Hydrostatic pressure is a powerful and general probe of multidimensional energy landscapes that can be used to analyse experimentally parallel pathways for enzyme-catalysed reactions. We suggest that this is especially the case following directed mutation of a protein, which can lead to increased population of reactant states that are essentially inaccessible in the free-energy landscape of wild-type enzyme.

Stress-induced release of GUT peptides in young women classified as restrained or unrestrained eaters.

PubMed

Hilterscheid, Esther; Laessle, Reinhold

2015-12-01

Basal release of GUT peptides has been found to be altered in restrained eaters. Stress-induced secretion, however, has not yet been described, but could be a biological basis of overeating that exposes restrained eaters to a higher risk of becoming obese. The aim of the present study was to compare restrained and unrestrained eaters with respect to stress-induced release of the GUT peptides ghrelin and PYY. 46 young women were studied. Blood sampling for peptides was done before and after the Trier Social Stress Test. Ghrelin secretion after stress was significantly elevated in the restrained eaters, whereas no significant differences were detected for PYY. Stress-induced release of GUT peptides can be interpreted as a cause as well as a consequence of restrained eating.

Biofunctionalization of titanium with bacitracin immobilization shows potential for anti-bacteria, osteogenesis and reduction of macrophage inflammation.

PubMed

Nie, Bin'en; Ao, Haiyong; Zhou, Jianliang; Tang, Tingting; Yue, Bing

2016-09-01

Titanium has been widely used in the orthopedic and dental fields, however, the inert nature of Ti makes it unsuitable for application in promoting bone cell growth，osteogenic differentiation and antibacterial ability. The aims of the current study were to investigate the antimicrobial activity and biofunction of the polypeptide antibiotic bacitracin, and obtain a multi-biofunctional titanium implant by covalently-immobilizing titanium with the bacitracin. The results showed that the bacitracin possessed low minimum inhibitory concentration (MIC) to both Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA), with the non-cytotoxicity concentration up to 500μg/mL to human bone marrow mesenchymal stem cells (hBMSCs), furthermore, the bacitracin could improve the osteogenic differentiation of hBMSCs. The results of Scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS) indicated that bacitracin had been covalently immobilized on the surface of titanium. Immobilized bacitracin could improve the hydrophilic of immobilized titanium. The results of antimicrobial assay demonstrated that the covalently-immobilized bacitracin also had excellent antimicrobial property, and the bacitracin immobilized titanium could inhibit bacterial adhesion and colonization. The results of cell biology experiments proved that the bacitracin immobilized titanium could improve hBMSCs' adhesion, proliferation and osteogenic differentiation. We also found that the macrophages were difficult to spread or activate on the surface of bacitracin immobilized titanium, and the secretion of inflammatory factors had been inhibited. In conclusion, the novel bacitracin immobilized titanium has multi-biofunctions including outstanding antibacterial properties, excellent cell biology performance, and restraining inflammation, which has exciting application prospect. Copyright © 2016 Elsevier B.V. All rights reserved.

Handling and restraint.

PubMed

Donovan, John; Brown, Patricia

2006-07-01

For the safety of the handler and the animal, proper methods for handling and restraining laboratory animals should be followed. Improper handling can result in increased stress and injury to the animal. In addition, the handler risks injury from bite wounds or scratches inflicted when the animal becomes fearful or anxious. By using sure, direct movements with a determined attitude, the animal can be easily handled and restrained. Animals can be restrained either manually or in a plastic restrainer. The protocols in this unit describe handling and manual restraint of mice, rats, hamsters, and rabbits. Alternate protocols describe restraint using the plastic restrainer.

Handling and restraint.

PubMed

Donovan, John; Brown, Patricia

2004-09-01

For the safety of the handler and the animal, proper methods for handling and restraining laboratory animals should be followed. Improper handling can result in increased stress and injury to the animal. In addition, the handler risks injury from bite wounds or scratches inflicted when the animal becomes fearful or anxious. By using sure, direct movements with a determined attitude, the animal can be easily handled and restrained. Animals can be restrained either manually or in a plastic restrainer. The protocols in this unit describe handling and manual restraint of mice, rats, hamsters, and rabbits. Alternate protocols describe restraint using the plastic restrainer.

Coupling of protein surface hydrophobicity change to ATP hydrolysis by myosin motor domain.

PubMed Central

Suzuki, M; Shigematsu, J; Fukunishi, Y; Harada, Y; Yanagida, T; Kodama, T

1997-01-01

Dielectric spectroscopy with microwaves in the frequency range between 0.2 and 20 GHz was used to study the hydration of myosin subfragment 1 (S1). The data were analyzed by a method recently devised, which can resolve the total amount of water restrained by proteins into two components, one with a rotational relaxation frequency (fc) in the gigahertz region (weakly restrained water) and the other with lower fc (strongly restrained water). The weight ratio of total restrained water to S1 protein thus obtained (0.35), equivalent to 2100 water molecules per S1 molecule, is not much different from the values (0.3-0.4) for other proteins. The weakly restrained component accounts for about two-thirds of the total restrained water, which is in accord with the number of water molecules estimated from the solvent-accessible surface area of alkyl groups on the surface of the atomic model of S1. The number of strongly restrained water molecules coincides with the number of solvent-accessible charged or polar atoms. The dynamic behavior of the S1-restrained water during the ATP hydrolysis was also examined in a time-resolved mode. The result indicates that when S1 changes from the S1.ADP state into the S1.ADP.P1 state (ADP release followed by ATP binding and cleavage), about 9% of the weakly restrained waters are released, which are restrained again on slow P1 release. By contrast, there is no net mobilization of strongly restrained component. The observed changes in S1 hydration are quantitatively consistent with the accompanying large entropy and heat capacity changes estimated by calorimetry (Kodama, 1985), indicating that the protein surface hydrophobicity change plays a crucial role in the enthalpy-entropy compensation effects observed in the steps of S1 ATP hydrolysis. Images FIGURE 4 PMID:8994589

Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor

DOE PAGES

Tischer, Alexander; Campbell, James C.; Machha, Venkata R.; ...

2015-12-16

Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limitedmore » proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The better stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His 1322 across the β2-β3 hairpin in the GPIbα binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIbα binding interface of normal VWF enhances the probability of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure.« less

Simulation of Reversible Protein–Protein Binding and Calculation of Binding Free Energies Using Perturbed Distance Restraints

PubMed Central

2017-01-01

Virtually all biological processes depend on the interaction between proteins at some point. The correct prediction of biomolecular binding free-energies has many interesting applications in both basic and applied pharmaceutical research. While recent advances in the field of molecular dynamics (MD) simulations have proven the feasibility of the calculation of protein–protein binding free energies, the large conformational freedom of proteins and complex free energy landscapes of binding processes make such calculations a difficult task. Moreover, convergence and reversibility of resulting free-energy values remain poorly described. In this work, an easy-to-use, yet robust approach for the calculation of standard-state protein–protein binding free energies using perturbed distance restraints is described. In the binding process the conformations of the proteins were restrained, as suggested earlier. Two approaches to avoid end-state problems upon release of the conformational restraints were compared. The method was evaluated by practical application to a small model complex of ubiquitin and the very flexible ubiquitin-binding domain of human DNA polymerase ι (UBM2). All computed free energy differences were closely monitored for convergence, and the calculated binding free energies had a mean unsigned deviation of only 1.4 or 2.5 kJ·mol–1 from experimental values. Statistical error estimates were in the order of thermal noise. We conclude that the presented method has promising potential for broad applicability to quantitatively describe protein–protein and various other kinds of complex formation. PMID:28898077

Mechanism of phospho-ubiquitin induced PARKIN activation

PubMed Central

Wauer, Tobias; Simicek, Michal; Schubert, Alexander; Komander, David

2016-01-01

Summary The E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1 (encoded by PARK6) are mutated in autosomal recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy1–3. PINK1 is stabilised on the outside of depolarised mitochondria, and phosphorylates poly-ubiquitin (polyUb)4–8 as well as the PARKIN Ub-like (Ubl) domain9,10. These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism4–12. Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in AR-JP patients. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilisation of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory13 but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens new avenues to identify small molecule PARKIN activators. PMID:26161729

Strategies for transformation of naturally-occurring amphibian antimicrobial peptides into therapeutically valuable anti-infective agents.

PubMed

Conlon, J Michael; Al-Ghaferi, Nadia; Abraham, Bency; Leprince, Jérôme

2007-08-01

The emergence of strains of pathogenic microorganisms with resistance to commonly used antibiotics has necessitated a search for novel types of antimicrobial agents. Many frog species produce amphipathic alpha-helical peptides with broad spectrum antimicrobial activity in the skin but their therapeutic potential is limited by varying degrees of cytolytic activity towards eukaryotic cells. Methods for development of such peptides into anti-infective drugs are illustrated by the example of temporin-1DRa (HFLGTLVNLAK KIL.NH(2)). Studies with model alpha-helical peptides have shown that increase in cationicity promotes antimicrobial activity whereas increases in hydrophobicity, helicity and amphipathicity promote hemolytic activity and loss of selectivity for microorganisms. Analogs of temporin-1DRa in which each amino acid is replaced by L-lysine and D-lysine were synthesized and their cytolytic activities tested against a range of microorganisms and human erythrocytes. Small changes in structure produced marked changes in conformation, as determined by retention time on reversed-phase HPLC, and in biological activity. However, peptides containing the substitutions (Val(7) -->L-Lys), (Thr(5)-->D-Lys) and (Asn(8)-->D-Lys) retained the high solubility and potent, broad spectrum antimicrobial activity of the naturally occurring peptide but were appreciably (up to 10-fold) less hemolytic. In contrast, analogs in which Leu(9) and Ile(13) were replaced by the more hydrophobic cyclohexylglycine residue showed slightly increased antimicrobial potencies (up to 2-fold) but a 4-fold increase in hemolytic activity. The data suggest a strategy of selective increases in cationicity concomitant with decreases in helicity and hydrophobicity in the transformation of naturally-occurring antimicrobial peptides into non-toxic therapeutic agents.

The importance of being kinked: role of Pro residues in the selectivity of the helical antimicrobial peptide P5.

PubMed

Bobone, Sara; Bocchinfuso, Gianfranco; Park, Yoonkyung; Palleschi, Antonio; Hahm, Kyung-Soo; Stella, Lorenzo

2013-12-01

Antimicrobial peptides (AMPs) are promising compounds for developing new antibiotic drugs against drug-resistant bacteria. Many of them kill bacteria by perturbing their membranes but exhibit no significant toxicity towards eukaryotic cells. The identification of the features responsible for this selectivity is essential for their pharmacological development. AMPs exhibit few conserved features, but a statistical analysis of an AMP sequence database indicated that many α-helical AMPs surprisingly have a helix-breaking Pro residue in the middle of their sequence. To discriminate among the different possible hypotheses for the functional role of this feature, we designed an analogue of the antimicrobial peptide P5, in which the central Pro was deleted (analogue P5Del). Pro removal resulted in a dramatic increase of toxicity. This was explained by the observation that P5Del binds both charged and neutral membranes, whereas P5 has no appreciable affinity towards neutral bilayers. CD and simulative data provided a rationalization of this behavior. In solution P5, due to the presence of Pro, attains compact conformations, in which its apolar residues are partially shielded from the solvent, whereas P5Del is more helical. These structural differences reduce the hydrophobic driving force for association of P5 to neutral membranes, whereas its binding to anionic bilayers can still take place because of electrostatic attraction. After membrane binding, the Pro residue does not preclude the attainment of a membrane-active amphiphilic helical conformation. These findings shed light on the role of Pro residues in the selectivity of AMPs and provide hints for the design of new, highly selective compounds. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

In Silico Template Selection of Short Antimicrobial Peptide Viscotoxin for Improving Its Antimicrobial Efficiency in Development of Potential Therapeutic Drugs.

PubMed

Senthilkumar, B; Rajasekaran, R

2017-03-01

Rapid increase in antibiotic resistance has posed a worldwide threat, due to increased mortality, morbidity, and expenditure caused by antibiotic-resistant microbes. Recent development of the antimicrobial peptides like viscotoxin (Vt) has been successfully comprehended as a substitute for classical antibiotics. A structurally stable peptide, Vt can enhance antimicrobial property and can be used for various developmental purposes. Thus, structural stability among the antimicrobial peptides, Vt A1 (3C8P), A2 (1JMN), A3 (1ED0), B (1JMP), and C (1ORL) of Viscus album was computationally analyzed. In specific, the static confirmation of VtA3 showed high number of intramolecular interactions, along with an increase in hydrophobicity than others comparatively. Further, conformational sampling was used to analyze various geometrical parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, and ovality which also revealed the structural stability of VtA3. Moreover, the statistically validated contours of surface area, lipophilicity, and distance constraints of disulfide bonds also supported the priority of VtA3 with respect to stability. Finally, the functional activity of peptides was accessed by computing their free energy of membrane association and membrane interactions, which defined VtA3 as functionally stable. Currently, peptide-based antibiotics and nanoparticles have attracted the pharmaceutical industries for their potential therapeutic applications. Thereby, it is proposed that viscotoxin A3 (1ED0) could be used as a preeminent template for scaffolding potentially efficient antimicrobial peptide-based drugs and nanomaterials in future.

Re-building Trust after Physical Restraint During Involuntary Psychiatric Hospitalization.

PubMed

Khatib, Anwar; Ibrahim, Mahajne; Roe, David

2018-06-01

This study attempted to identify the elements which might best minimize the negative consequences of restriction of inpatients and rebuild therapeutic alliance and trust. Through in depth interviews with 15 psychiatric patients who had experience restrained during the last involuntary psychiatric hospitalization. Analysis of the data revealed three major themes with regard to trust between restrained patient and restraining staff members during restriction of the patient's freedom. Duration of Restriction, Contact with a Staff Member while Restrained, Supportive Interactions and Staff's Response to Restricted Patients' Needs were reported by patients as crucial in determining the way restrained is experienced and its later impact. Physical restraint in psychiatric hospitalizations generates many negative feelings and can even be traumatic. The patients interviewed help us learn how to provide more human and therapeutic interactions even in extreme situations of restrain which can be crucial to rebuild therapeutic alliance and trust. Copyright © 2018 Elsevier Inc. All rights reserved.

Atomic Force Microscopy Study of the Interactions of Indolicidin with Model Membranes and DNA.

PubMed

Fojan, Peter; Gurevich, Leonid

2017-01-01

The cell membrane is the first barrier and quite often the primary target that antimicrobial peptides (AMPs) have to destroy or penetrate to fulfill their mission. Upon penetrating through the membrane, the peptides can further attack intracellular targets, in particular DNA. Studying the interaction of an antimicrobial peptide with a cell membrane and DNA holds keys to understanding its killing mechanisms. Commonly, these interactions are studied by using optical or scanning electron microscopy and appropriately labeled peptides. However, labeling can significantly affect the hydrophobicity, conformation, and size of the peptide, hence altering the interaction significantly. Here, we describe the use of atomic force microscopy (AFM) for a label-free study of the interactions of peptides with model membranes under physiological conditions and DNA as a possible intracellular target.

Use of unnatural amino acids to probe structure-activity relationships and mode-of-action of antimicrobial peptides.

PubMed

Tossi, Alessandro; Scocchi, Marco; Zahariev, Sotir; Gennaro, Renato

2012-01-01

Endogenous antimicrobial peptides (AMPs) can have multimodal mechanisms of bacterial inactivation, such as membrane lysis, interference with cell wall biosynthesis or membrane-based protein machineries, or translocation through the membrane to intracellular targets. The controlled variation of side-chain characteristics in their amino acid residues can provide much useful information on structure-activity relationships and mode-of-action, and also lead to improved activities. The small size and relatively low complexity of AMPs make them amenable to solid-phase peptide synthesis, facilitating the use of nonproteinogenic amino acids and vastly increasing the accessible molecular diversity of side chains. Here, we describe how such residues can be used to modulate such key parameters as cationicity, hydrophobicity, steric factors conformational stability, and H-bonding.

The influence of air bags and restraining devices on extremity injuries in motor vehicle collisions.

PubMed

McGovern, M K; Murphy, R X; Okunski, W J; Wasser, T E

2000-05-01

The influence of air bags and other restraining devices on injury after motor vehicle collisions is not well defined. This study examined the relationship between the use of restraining devices and the incidence of extremity injuries in motor vehicle collisions. A retrospective analysis was performed on motor vehicle collision data submitted to the Pennsylvania Trauma Outcome Study database from 1990 through 1995. Criteria for submission included trauma patients who were admitted to the intensive care unit, who died during hospitalization, who were hospitalized for more than 72 hours, or who were transferred in or out of the receiving hospital. A total of 21,875 patients met these criteria. These patients were analyzed for the presence or absence of upper and lower extremity injuries and were compared based on their use of restraining devices. Restraining devices were categorized into four groups: air bag alone, air bag and seat belt, seat belt or carseat without air bag, and no restraining device. Statistical analysis was performed using the chi-squared test of association. For contingency tables with small expected frequencies, Fisher's exact test was used. Study participants included 11,688 men and 10,185 women with a mean age of 38 +/- 20 years. There were 16,033 drivers and 5,842 passengers. Air bags were deployed in 472 instances. In 297 of these cases, additional restraint was provided with a seat belt. In 6,632 cases, air bags were not deployed; however, patients were restrained with either a seat belt or a carseat. In 14,771 cases, patients were not restrained. When comparing restraining devices as a group vs. no restraint, there was a significant decrease in the incidence of upper (p = 0.018) and lower (p < 0.001) extremity injuries. Air bags, however, were associated with an increased incidence of both upper (p = 0.033) and lower (p = 0.002) extremity injuries when compared with no restraint or when compared among patients who were restrained. As a group, restraining devices decrease the incidence of upper and lower extremity trauma sustained by patients injured in motor vehicle collisions. Air bags, however, are associated with an increased incidence of upper and lower extremity injuries when compared with seat belts alone or when no restraining devices are used.

Interactive effects of emotional and restrained eating on responses to chocolate and affect.

PubMed

Macht, Michael; Mueller, Jochen

2007-12-01

To examine differences and interactions between emotional and restrained-eating healthy adults (56 women, 53 men) were classified into emotional or restrained eaters, and persons scoring high or low on both dimensions. Participants tasted different types of chocolate (with 30, 70, 85, or 99% cocoa content) and completed questionnaires on affect and attitudes towards chocolate. Emotional eaters reported increased craving for and increased consumption of chocolate, whereas restrained eaters experienced chocolate-related guilt. However, restrained eaters rated plain chocolate (70% and 85% cocoa) as more pleasant than other groups. Persons scoring high on both dimensions showed heightened negative affect and may be prone to disturbances of eating and affect.

Purification, characterization and application of a novel antimicrobial peptide from Andrias davidianus blood.

PubMed

Pei, J; Feng, Z; Ren, T; Sun, H; Han, H; Jin, W; Dang, J; Tao, Y

2018-01-01

The Andrias davidianus has been known as a traditional Chinese medicine for a long time. Its blood is considered as a waste or by-product of the meat production industry. Although there are reports on isolation of the antimicrobial peptides from different resources, there are no reports of their isolation from A. davidianus blood. In this work, an antimicrobial peptide, andricin B, was isolated from the blood of A. davidianus by an innovative method in which the magnetic liposome adsorption was combined with reversed-phase high-performance liquid chromatography. The structure, antimicrobial activity and safety of andricin B were further investigated. Amino acid sequence was determined by N-terminal sequencing and found to be Gly-Leu-Thr-Arg-Leu-Phe-Ser-Val-Ile-Lys. Circular dichroism (CD) spectra and prediction of three-dimensional structure by bioinformatics software suggested the presence of a well-defined random coil conformation. Andricin B was found to be active against all bacteria tested in this study as well as some fungi. The minimum inhibitory concentrations (MICs) were in the range 8-64 μg ml -1 . Moreover, the haemolytic testing also suggested that andricin B could be considered safe at the MICs. Finally, andricin B was shown to inhibit the growth of Staphylococcus aureus in the cooked meat of A. davidianus. This study shows that andricin B is a promising novel antimicrobial peptide that may provide further insights towards the development of new drugs. This is the pioneer study on screening and isolation of antimicrobial peptide from the blood of Andrias davidianus. Here, we have developed a novel method by combining magnetic liposomes adsorption with reversed-phase high-performance liquid chromatography to purify and screen the antimicrobial peptides. From this screen, we identified a novel antimicrobial peptide which we name as andricin B. Andricin B is unique as it checks the growth of both Gram-positive and Gram-negative bacteria as well as few fungal species. © 2017 The Society for Applied Microbiology.

Associations between Restrained Eating and the Size and Frequency of Overall Intake, Meal, Snack and Drink Occasions in the UK Adult National Diet and Nutrition Survey

PubMed Central

Olea López, Ana Lorena; Johnson, Laura

2016-01-01

Obesity is a global public health priority. Restrained eating is related to obesity and total energy intake but associations with the eating patterns are unclear. We examined the associations of restrained eating with the size and frequency of intake occasions among 1213 British adult (19–64 y) participants in a cross-sectional analysis of the UK National Diet and Nutrition Survey 2000. The Dutch Eating Behaviour Questionnaire assessed restrained eating. Overall intake occasions were all energy consumed in a 60 min period. A food-based classification separated intake occasions into meals, snacks, or drinks from seven-day weighed food diaries. Average daily frequency and size (kcal) of overall intake, meal, snack and drink occasions were calculated and associations with restrained eating were modelled using multiple linear regression including under-reporting of energy intake, age, gender, BMI, emotional eating, external eating and physical activity as covariates. Restrained eating was very weakly positively correlated with overall intake (r = 0.08, p<0.05) and meal frequency (r = 0.10, p<0.05) but not snack or drink frequency (r = 0.02 and -0.02 respectively). Adjusted regressions showed a one-point change in restrained eating was associated with 0.07 (95% CI 0.03, 0.11) more meal occasions/day and 0.13 (95% CI 0.01, 0.25) extra overall intake occasions/day. Overall intake occasion size was weakly negatively correlated with restrained eating regardless of type (r = -0.16 to -0.20, all p<0.0001). Adjusted regressions showed each one-point increase in restrained eating was associated with lower-energy meals (-15 kcal 95% CI -5.9, -24.2) and drinks (-4 kcal 95%CI -0.1, -8), but not snacks or overall intake occasions. Among a national sample of UK adults, greater restrained eating was associated with smaller and slightly more frequent eating, suggesting that restrained eaters restrict their energy intake by reducing meal/drink size rather than skipping snacks. PMID:27227409

Peptide:lipid ratio and membrane surface charge determine the mechanism of action of the antimicrobial peptide BP100. Conformational and functional studies.

PubMed

Manzini, Mariana C; Perez, Katia R; Riske, Karin A; Bozelli, José C; Santos, Talita L; da Silva, Marcia A; Saraiva, Greice K V; Politi, Mario J; Valente, Ana P; Almeida, Fábio C L; Chaimovich, Hernan; Rodrigues, Magali A; Bemquerer, Marcelo P; Schreier, Shirley; Cuccovia, Iolanda M

2014-07-01

The cecropin-melittin hybrid antimicrobial peptide BP100 (H-KKLFKKILKYL-NH2) is selective for Gram-negative bacteria, negatively charged membranes, and weakly hemolytic. We studied BP100 conformational and functional properties upon interaction with large unilamellar vesicles, LUVs, and giant unilamellar vesicles, GUVs, containing variable proportions of phosphatidylcholine (PC) and negatively charged phosphatidylglycerol (PG). CD and NMR spectra showed that upon binding to PG-containing LUVs BP100 acquires α-helical conformation, the helix spanning residues 3-11. Theoretical analyses indicated that the helix is amphipathic and surface-seeking. CD and dynamic light scattering data evinced peptide and/or vesicle aggregation, modulated by peptide:lipid ratio and PG content. BP100 decreased the absolute value of the zeta potential (ζ) of LUVs with low PG contents; for higher PG, binding was analyzed as an ion-exchange process. At high salt, BP100-induced LUVS leakage requires higher peptide concentration, indicating that both electrostatic and hydrophobic interactions contribute to peptide binding. While a gradual release took place at low peptide:lipid ratios, instantaneous loss occurred at high ratios, suggesting vesicle disruption. Optical microscopy of GUVs confirmed BP100-promoted disruption of negatively charged membranes. The mechanism of action of BP100 is determined by both peptide:lipid ratio and negatively charged lipid content. While gradual release results from membrane perturbation by a small number of peptide molecules giving rise to changes in acyl chain packing, lipid clustering (leading to membrane defects), and/or membrane thinning, membrane disruption results from a sequence of events - large-scale peptide and lipid clustering, giving rise to peptide-lipid patches that eventually would leave the membrane in a carpet-like mechanism. Copyright © 2014 Elsevier B.V. All rights reserved.

A critical evaluation of random copolymer mimesis of homogeneous antimicrobial peptides.

PubMed

Hu, Kan; Schmidt, Nathan W; Zhu, Rui; Jiang, Yunjiang; Lai, Ghee Hwee; Wei, Gang; Palermo, Edmund F; Kuroda, Kenichi; Wong, Gerard C L; Yang, Lihua

2013-01-01

Polymeric synthetic mimics of antimicrobial peptides (SMAMPs) have recently demonstrated similar antimicrobial activity as natural antimicrobial peptides (AMPs) from innate immunity. This is surprising, since polymeric SMAMPs are heterogeneous in terms of chemical structure (random sequence) and conformation (random coil), in contrast to defined amino acid sequence and intrinsic secondary structure. To understand this better, we compare AMPs with a 'minimal' mimic, a well characterized family of polydisperse cationic methacrylate-based random copolymer SMAMPs. Specifically, we focus on a comparison between the quantifiable membrane curvature generating capacity, charge density, and hydrophobicity of the polymeric SMAMPs and AMPs. Synchrotron small angle x-ray scattering (SAXS) results indicate that typical AMPs and these methacrylate SMAMPs generate similar amounts of membrane negative Gaussian curvature (NGC), which is topologically necessary for a variety of membrane-destabilizing processes. Moreover, the curvature generating ability of SMAMPs is more tolerant of changes in the lipid composition than that of natural AMPs with similar chemical groups, consistent with the lower specificity of SMAMPs. We find that, although the amount of NGC generated by these SMAMPs and AMPs are similar, the SMAMPs require significantly higher levels of hydrophobicity and cationic charge to achieve the same level of membrane deformation. We propose an explanation for these differences, which has implications for new synthetic strategies aimed at improved mimesis of AMPs.

Apparatus for restraining and transporting dies

DOEpatents

Allison, James W.; LaBarre, Timothy L.

1994-01-01

Apparatus for restraining and transporting dies in punch press operations is provided. A floatation platen for supporting a die on the platen's upper surface has a plurality of recessed gas exhaust ports on the platen's lower surface. A source of pressurized gas delivers gas to a platen manifold, for delivery to orifices located in the gas exhaust ports. The flow of gas is controlled by a first valve adjacent the gas source and a second valve adjacent the manifold, with the second valve being used to control the gas flow during movement of the die. In this fashion, a die may be moved on a cushion of air from one workstation to a selected second workstation. A moveable hydraulically operated restraining fixture is also provided, for clamping the die in position during the compacting phase, and for releasing the die after completion of the compacting phase by releasing the hydraulic pressure on the restraining fixture. When pressure in the hydraulic cylinders on the restraining fixture is reversed, the restraining fixture will retract so that there is no contact between the die and the restraining fixture, thereby allowing the die to be removed from a first workstation and moved to a second selected workstation.

Age and Gender Effects on Injury Outcome for Restrained Occupants in Frontal Crashes: A Comparison of UK and US Data Bases

PubMed Central

Mackay, Murray; Hassan, Ahamedali M.

2000-01-01

Field accident data from NASS/CDS in the US and CCIS in the UK are compared. The UK sample is deliberately weighted to conform to the same AIS proportions (within AIS 2 – 6) as the weighted NASS data so that crash severity distributions can be compared for various selected outcomes. Age and gender have a significant effect on the deltaV distributions and median deltaV values. These differences are documented both for overall AIS 2 - 6, 3 - 6, and 4 - 6, and also for body regions of the head, neck, chest, abdomen and upper and lower extremities. Anomalies between the two samples are profound which raises doubts about the recording of belt use in NASS and the calculation of deltaV at lower crash severities. PMID:11558104

Conformational study of bovine lactoferricin in membrane-micking conditions by molecular dynamics simulation and circular dichroism.

PubMed

Daidone, Isabella; Magliano, Alessandro; Di Nola, Alfredo; Mignogna, Giuseppina; Clarkson, Matilda Manuela; Lizzi, Anna Rita; Oratore, Arduino; Mazza, Fernando

2011-04-01

Lactoferricins are potent antimicrobial peptides released by pepsin cleavage of Lactoferrins. Bovine Lactoferricin (LfcinB) has higher activity than the intact bovine Lactoferrin, and is the most active among the other Lactoferricins of human, murine and caprine origin. In the intact protein the fragment corresponding to LfcinB is in an helical conformation, while in water LfcinB adopts an amphipathic β-hairpin structure. However, whether any of these structural motifs is the antibacterial active conformation, i.e., the one interacting with bacterial membrane components, remains to be seen. Here we present Circular Dichroism (CD) spectra and Molecular Dynamics (MD) simulations indicating that in membrane-mimicking solvents the LfcinB adopts an amphipathic β-hairpin structure similar to that observed in water, but differing in the dynamic behavior of the side-chains of the two tryptophan residues. In the membrane-mimicking solvent these side-chains show a high propensity to point towards the hydrophobic environment, rather than being in the hydrophobic core as seen in water, while the backbone preserves the hairpin conformation as found in water. These results suggest that the tryptophans might act as anchors pulling the stable, solvent-invariant hairpin structure into the membrane.

Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages

PubMed Central

Shim, Do-Wan; Heo, Kang-Hyuck; Kim, Young-Kyu; Sim, Eun-Jeong; Kang, Tae-Bong; Choi, Jae-Wan; Sim, Dae-Won; Cheong, Sun-Hee; Lee, Seung-Hong; Bang, Jeong-Kyu; Won, Hyung-Sik; Lee, Kwang-Ho

2015-01-01

Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1β, IL-6, INF-β, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4)- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation. PMID:26017270

Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages.

PubMed

Shim, Do-Wan; Heo, Kang-Hyuck; Kim, Young-Kyu; Sim, Eun-Jeong; Kang, Tae-Bong; Choi, Jae-Wan; Sim, Dae-Won; Cheong, Sun-Hee; Lee, Seung-Hong; Bang, Jeong-Kyu; Won, Hyung-Sik; Lee, Kwang-Ho

2015-01-01

Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1β, IL-6, INF-β, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4)- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.

Comparison of oxygen saturation values obtained from fingers on physically restrained or unrestrained sides of the body.

PubMed

Korhan, Esra Akin; Yönt, Gülendam Hakverdioğlu; Khorshid, Leyla

2011-01-01

The aim of this study was to compare semiexperimentally the pulse oximetry values obtained from a finger on restrained or unrestrained sides of the body. The pulse oximeter provides a noninvasive measurement of the oxygen saturation of hemoglobin in arterial blood. One of the procedures most frequently applied to patients in intensive care units is the application of physical restraint. Circulation problems are the most important complication in patients who are physically restrained. Evaluation of oxygen saturation from body parts in which circulation is impeded or has deteriorated can cause false results. The research sample consisted of 30 hospitalized patients who participated in the study voluntarily and who were concordant with the inclusion criteria of the study. Patient information and patient follow-up forms were used for data collection. Pulse oximetry values were measured simultaneously using OxiMax Nellcor finger sensors from fingers on the restrained and unrestrained sides of the body. Numeric and percentile distributions were used in evaluating the sociodemographic properties of patients. A significant difference was found between the oxygen saturation values obtained from a finger of an arm that had been physically restrained and a finger of an arm that had not been physically restrained. The mean oxygen saturation value measured from a finger of an arm that had been physically restrained was found to be 93.40 (SD, 2.97), and the mean oxygen saturation value measured from a finger of an arm that had not been physically restrained was found to be 95.53 (SD, 2.38). The results of this study indicate that nurses should use a finger of an arm that is not physically restrained when evaluating oxygen saturation values to evaluate them correctly.

Seismic rehabilitation of skewed and curved bridges using a new generation of buckling restrained braces : research brief.

DOT National Transportation Integrated Search

2016-12-01

Damage to skewed and curved bridges during strong earthquakes is documented. This project investigates whether such damage could be mitigated by using buckling restrained braces. Nonlinear models show that using buckling restrained braces to mitigate...

Sex differences in the association between dietary restraint, insulin resistance and obesity.

PubMed

Jastreboff, Ania M; Gaiser, Edward C; Gu, Peihua; Sinha, Rajita

2014-04-01

Restrained food consumption may alter metabolic function and contribute to eventual weight gain; however, sex differences in these relationships have not been assessed. The objective of this study was to examine the relationship between restrained eating and insulin resistance and the influence of body mass index and sex on this relationship in a large community sample of both men and women. We hypothesized that restrained eating would be related to insulin resistance and this relationship would be influenced by sex and body mass index. In this cross-sectional, observational study, we studied 487 individuals from the community (men N = 222, women N = 265), who ranged from lean (body mass index 18.5-24.9 kg/m(2), N = 173), overweight (body mass index 25-29.9 kg/m(2), N = 159) to obese (body mass index >30 kg/m(2), N = 155) weight categories. We assessed restrained eating using the Dutch Eating Behavior Questionnaire and obtained fasting morning plasma insulin and glucose on all subjects. In men, but not in women, restrained eating was related to homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.0001). Furthermore, HOMA-IR was significantly higher in men who were high- versus low-restrained eaters (p = 0.0006). This study is the first to report sex differences with regard to the relationship between restrained eating and insulin resistance. Our results suggest that high restrained eating is associated with insulin resistance in men but not in women. Copyright © 2014 Elsevier Ltd. All rights reserved.

49 CFR 1103.22 - Restraining clients from improprieties.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 8 2010-10-01 2010-10-01 false Restraining clients from improprieties. 1103.22... Practitioner's Duties and Responsibilities Toward A Client § 1103.22 Restraining clients from improprieties. A practitioner should see that his clients act with the same restraint that the practitioner himself uses...

Triclosan antimicrobial polymers

PubMed Central

Petersen, Richard C.

2016-01-01

Triclosan antimicrobial molecular fluctuating energies of nonbonding electron pairs for the oxygen atom by ether bond rotations are reviewed with conformational computational chemistry analyses. Subsequent understanding of triclosan alternating ether bond rotations is able to help explain several material properties in Polymer Science. Unique bond rotation entanglements between triclosan and the polymer chains increase both the mechanical properties of polymer toughness and strength that are enhanced even better through secondary bonding relationships. Further, polymer blend compatibilization is considered due to similar molecular relationships and polarities. With compatibilization of triclosan in polymers a more uniform stability for nonpolar triclosan in the polymer solid state is retained by the antimicrobial for extremely low release with minimum solubility into aqueous solution. As a result, triclosan is projected for long extended lifetimes as an antimicrobial polymer additive. Further, triclosan rapid alternating ether bond rotations disrupt secondary bonding between chain monomers in the resin state to reduce viscosity and enhance polymer blending. Thus, triclosan is considered for a polymer additive with multiple properties to be an antimicrobial with additional benefits as a nonpolar toughening agent and a hydrophobic wetting agent. The triclosan material relationships with alternating ether bond rotations are described through a complete different form of medium by comparisons with known antimicrobial properties that upset bacterial cell membranes through rapid fluctuating mechanomolecular energies. Also, triclosan bond entanglements with secondary bonding can produce structural defects in weak bacterial lipid membranes requiring pliability that can then interfere with cell division. Regarding applications with polymers, triclosan can be incorporated by mixing into a resin system before cure, melt mixed with thermoplastic polymers that set on cooling into a solid or alternatively applied as a coating through several different methods with dissolving into an organic solvent and dried on by evaporation as a common means. PMID:27280150

Structural and biophysical characterization of an antimicrobial peptide chimera comprised of lactoferricin and lactoferrampin.

PubMed

Haney, Evan F; Nazmi, Kamran; Bolscher, Jan G M; Vogel, Hans J

2012-03-01

Lactoferricin and lactoferrampin are two antimicrobial peptides found in the N-terminal lobe of bovine lactoferrin with broad spectrum antimicrobial activity against a range of Gram-positive and Gram-negative bacteria as well as Candida albicans. A heterodimer comprised of lactoferrampin joined to a fragment of lactoferricin was recently reported in which these two peptides were joined at their C-termini through the two amino groups of a single Lys residue (Bolscher et al., 2009, Biochimie 91(1):123-132). This hybrid peptide, termed LFchimera, has significantly higher antimicrobial activity compared to the individual peptides or an equimolar mixture of the two. In this work, the underlying mechanism behind the increased antibacterial activity of LFchimera was investigated. Differential scanning calorimetry studies demonstrated that all the peptides influenced the thermotropic phase behaviour of anionic phospholipid suspensions. Calcein leakage and vesicle fusion experiments with anionic liposomes revealed that LFchimera had enhanced membrane perturbing properties compared to the individual peptides. Peptide structures were evaluated using circular dichroism and NMR spectroscopy to gain insight into the structural features of LFchimera that contribute to the increased antimicrobial activity. The NMR solution structure, determined in a miscible co-solvent mixture of chloroform, methanol and water, revealed that the Lys linkage increased the helical content in LFchimera compared to the individual peptides, but it did not fix the relative orientations of lactoferricin and lactoferrampin with respect to each other. The structure of LFchimera provides insight into the conformation of this peptide in a membranous environment and improves our understanding of its antimicrobial mechanism of action. Copyright © 2011 Elsevier B.V. All rights reserved.

On the role of water density fluctuations in the inhibition of a proton channel

PubMed Central

Gianti, Eleonora; Delemotte, Lucie; Klein, Michael L.; Carnevale, Vincenzo

2016-01-01

Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel’s most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel. PMID:27956641

Research on the honeycomb restrain layer application to the high power microwave dielectric window

NASA Astrophysics Data System (ADS)

Zhang, Qingyuan; Shao, Hao; Huang, Wenhua; Guo, Letian

2018-01-01

Dielectric window breakdown is an important problem of high power microwave radiation. A honeycomb layer can suppress the multipactor in two directions to restrain dielectric window breakdown. This paper studies the effect of the honeycomb restrain layer on improving the dielectric window power capability. It also studies the multipactor suppression mechanism by using the electromagnetic particle-in-cell software, gives the design method, and accomplishes the test experiment. The experimental results indicated that the honeycomb restrain layer can effectively improve the power capability twice.

Research on the honeycomb restrain layer application to the high power microwave dielectric window.

PubMed

Zhang, Qingyuan; Shao, Hao; Huang, Wenhua; Guo, Letian

2018-01-01

Dielectric window breakdown is an important problem of high power microwave radiation. A honeycomb layer can suppress the multipactor in two directions to restrain dielectric window breakdown. This paper studies the effect of the honeycomb restrain layer on improving the dielectric window power capability. It also studies the multipactor suppression mechanism by using the electromagnetic particle-in-cell software, gives the design method, and accomplishes the test experiment. The experimental results indicated that the honeycomb restrain layer can effectively improve the power capability twice.

Observed child restraint use in automobiles

PubMed Central

Williams, A.

1998-01-01

Visual observations were made on restraint use in occupants of 5050 automobiles containing at least one passenger less than 10 years of age, and short interviews were conducted with the drivers. Ninety three per cent of passengers less than 10 years old were not restrained. Eighty nine per cent of passengers 10 or older and 78% of the drivers were not restrained. Sixteen per cent of child motor vehicle restraint devices observed were not used, and 73% of those in use were not used correctly. Use of such devices declined sharply after age one. Although child passengers were more likely to be restrained if the driver was restrained, more than 75% of the children were not restrained when the driver was, even if the driver was the child's parent. PMID:9666374

Watching your weight? The relations between watching soaps and music television and body dissatisfaction and restrained eating in young girls.

PubMed

Anschutz, Doeschka; Engels, Rutger; Leeuwe, Jan Van; Strien, Tatjana van

2009-11-01

Although previous research showed that the thin ideal provided by the media affects body image and eating behaviour in young children, less is known about specific media contents that are related to body image and eating behaviour. This study tested the associations between watching soaps and music television and body dissatisfaction and restrained eating directly, and indirectly through thin ideal internalisation. We conducted a survey in class, in which 245 girls (aged 7-9) completed scales on their television watching behaviour, thin ideal internalisation, body dissatisfaction and restrained eating. Additionally, height and weight were measured. Watching soaps and music television often was associated with higher thin ideal internalisation, which in turn was associated with higher body dissatisfaction and restrained eating. Furthermore, a direct association between watching soaps and music television and restrained eating was found. If watching other types of children's programmes or maternal encouragement to be thin were included in the models, watching soaps and music television remained an important factor, especially with regard to restrained eating. Therefore, our results suggest that if young girls watch soaps and music television often, this is related to higher restrained eating and body dissatisfaction, directly or indirectly, through higher thin ideal internalisation.

Temperature dependent rapid annealing effect induces amorphous aggregation of human serum albumin.

PubMed

Ishtikhar, Mohd; Ali, Mohd Sajid; Atta, Ayman M; Al-Lohedan, Hammad; Badr, Gamal; Khan, Rizwan Hasan

2016-01-01

This study represents an analysis of the thermal aggregation of human serum albumin (HSA) induced by novel rosin modified compounds. The aggregation process causes conformational alterations in the secondary and tertiary structures of the proteins. The conversion of globular protein to amorphous aggregates was carried out by spectroscopic, calorimetric and microscopic techniques to investigate the factors that are responsible for the structural, conformational and morphological alteration in the protein. Our outcome results show that the aggregation of HSA was dependent on the hydrophobicity, charge and temperature, because the formation of amorphous aggregates occurs in the presence of a novel cationic rosin compound, quaternary amine of rosin diethylaminoethyl ester (QRMAE), at 40°C and pH 7.4 (but at 25°C on similar pH value, there was no evidence of aggregate formation). In addition, the parent compound of QRMAE, i.e., abietic acid, and other derivatives such as nonionic rosin compounds [(RMPEG-750) and (RMA-MPEG-750)] do not shows the aggregating property. This work provides precise and necessary information that aid in the understanding the effects of rosin derivative compounds on HSA. This study also restrains important information for athletes, health providers, pharmaceutical companies, industries, and soft drink-processing companies. Copyright © 2015 Elsevier B.V. All rights reserved.

Nuclear magnetic resonance and restrained molecular dynamics studies of the interaction of an epidermal growth factor-derived peptide with protein tyrosine phosphatase 1B.

PubMed

Glover, N R; Tracey, A S

1999-04-20

The epidermal growth factor-derived (EGFR988) fluorophosphonate peptide, DADE(F2Pmp)L, is a potent (30 pM) inhibitor of the protein tyrosine phosphatase PTP1B. Nuclear magnetic resonance (NMR) transferred nuclear Overhauser effect (nOe) experiments have been used to determine the conformation of DADE(F2Pmp)L while bound in the active site of PTP1B. When bound, the peptide adopts an extended beta-strand conformation. Molecular modeling and molecular dynamics simulations allowed the elucidation of the sources of many of the interactions leading to binding of this inhibitor. Electrostatic, hydrophobic, and hydrogen-bonding interactions were all found to contribute significantly to its binding. However, despite the overall tight binding of this inhibitor, the N-terminal and adjacent residue of the peptide were virtually unrestrained in their motion. The major contributions to binding arose from hydrophobic interactions at the leucine and at the aromatic center, hydrogen bonding to the pro-R fluorine of the fluorophosphonomethyl group, and electrostatic interactions involving the carboxylate functionalities of the aspartate and glutamate residues. These latter two residues were found to form tight contacts with surface recognition elements (arginine and lysine) situated near the active-site cleft.

Computational Prediction of Atomic Structures of Helical Membrane Proteins Aided by EM Maps

PubMed Central

Kovacs, Julio A.; Yeager, Mark; Abagyan, Ruben

2007-01-01

Integral membrane proteins pose a major challenge for protein-structure prediction because only ≈100 high-resolution structures are available currently, thereby impeding the development of rules or empirical potentials to predict the packing of transmembrane α-helices. However, when an intermediate-resolution electron microscopy (EM) map is available, it can be used to provide restraints which, in combination with a suitable computational protocol, make structure prediction feasible. In this work we present such a protocol, which proceeds in three stages: 1), generation of an ensemble of α-helices by flexible fitting into each of the density rods in the low-resolution EM map, spanning a range of rotational angles around the main helical axes and translational shifts along the density rods; 2), fast optimization of side chains and scoring of the resulting conformations; and 3), refinement of the lowest-scoring conformations with internal coordinate mechanics, by optimizing the van der Waals, electrostatics, hydrogen bonding, torsional, and solvation energy contributions. In addition, our method implements a penalty term through a so-called tethering map, derived from the EM map, which restrains the positions of the α-helices. The protocol was validated on three test cases: GpA, KcsA, and MscL. PMID:17496035

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

PubMed Central

Oku, Naoya; Matsumoto, Miyako; Yonejima, Kohsuke; Tansei, Keijiroh

2014-01-01

Summary Macroscopic gelatinous colonies of freshwater cyanobacterium Aphanothece sacrum, a luxury ingredient for Japanese cuisine, were found to contain a new oxylipin-derived macrolide, sacrolide A (1), as an antimicrobial component. The configuration of two chiral centers in 1 was determined by a combination of chiral anisotropy analysis and conformational analysis of different ring-opened derivatives. Compound 1 inhibited the growth of some species of Gram-positive bacteria, yeast Saccharomyces cerevisiae and fungus Penicillium chrysogenum, and was also cytotoxic to 3Y1 rat fibroblasts. Concern about potential food intoxication caused by accidental massive ingestion of A. sacrum was dispelled by the absence of 1 in commercial products. A manual procedure for degrading 1 in raw colonies was also developed, enabling a convenient on-site detoxification at restaurants or for personal consumption. PMID:25161741

Structural characterization of a novel peptide with antimicrobial activity from the venom gland of the scorpion Tityus stigmurus: Stigmurin.

PubMed

de Melo, Edinara Targino; Estrela, Andréia Bergamo; Santos, Elizabeth Cristina Gomes; Machado, Paula Renata Lima; Farias, Kleber Juvenal Silva; Torres, Taffarel Melo; Carvalho, Enéas; Lima, João Paulo Matos Santos; Silva-Júnior, Arnóbio Antonio; Barbosa, Euzébio Guimarães; Fernandes-Pedrosa, Matheus de Freitas

2015-06-01

A new antimicrobial peptide, herein named Stigmurin, was selected based on a transcriptomic analysis of the Brazilian yellow scorpion Tityus stigmurus venom gland, an underexplored source for toxic peptides with possible biotechnological applications. Stigmurin was investigated in silico, by circular dichroism (CD) spectroscopy, and in vitro. The CD spectra suggested that this peptide interacts with membranes, changing its conformation in the presence of an amphipathic environment, with predominance of random coil and beta-sheet structures. Stigmurin exhibited antibacterial and antifungal activity, with minimal inhibitory concentrations ranging from 8.7 to 69.5μM. It was also showed that Stigmurin is toxic against SiHa and Vero E6 cell lines. The results suggest that Stigmurin can be considered a potential anti-infective drug. Copyright © 2015 Elsevier Inc. All rights reserved.

Tool and Technique for Restraining Live-Captured American Martens and Fishers

Treesearch

Linda Ebel Thomasma; Rolf O. Peterson; Rolf O. Peterson

1998-01-01

Restraining live-captured animals poses challenges when working alone, especially in remote field locations. While studying American martens (Marfes americana) and fishers (Martes pennantr) in Michigan, we developed a new tool, trap combs, to restrain a live-captured animal in the trap. The construction and use of trap combs are described.

How restrained eaters perceive the amount they eat.

PubMed

Jansen, A

1996-09-01

The cognitive model of binge eating states that it is the awareness of a broken diet that disinhibits the restrained eater. It is, according to that model, the perception of having overeaten that triggers disinhibited eating. However, although the perception of the amount eaten plays a central role in cognitive restraint theory, it has never directly been tested how restrained subjects perceive the amount of food they eat. In the present studies, participants were given ad libitum access to large amounts of palatable food and both their perception of the amount eaten and their estimated caloric intake were compared with the amount they actually ate. The restrained participants in these studies ate more than the unrestrained participants. In the first and second studies, the restrained participants consumed 571 and 372 'forbidden' calories respectively, without having the feeling that they had eaten very much, let alone too much. Moreover in both studies, the restrained eaters underestimated their caloric intake, whereas unrestrained eaters estimated their caloric intake quite well. The potential implications of the present findings for the cognitive restraint model are discussed.

Trends and correlates of child passenger restraint use in 6 Northwest tribes: the Native Children Always Ride Safe (Native CARS) project.

PubMed

Lapidus, Jodi A; Smith, Nicole Holdaway; Lutz, Tam; Ebel, Beth E

2013-02-01

We compared proportions of children properly restrained in vehicles in 6 Northwest American Indian tribes in 2003 and 2009, and evaluated risks for improper restraint. During spring 2009 we conducted a vehicle observation survey in Oregon, Washington, and Idaho tribal communities. We estimated the proportions of children riding properly restrained and evaluated correlates of improper restraint via log-binomial regression models for clustered data. We observed 1853 children aged 12 years and younger in 1207 vehicles; 49% rode properly restrained. More children aged 8 years and younger rode properly restrained in 2009 than 2003 (51% vs 29%; P < .001). Older booster seat-eligible children were least likely to ride properly restrained in 2009 (25%). American Indian children were more likely to ride improperly restrained than nonnative children in the same communities. Other risk factors included riding with an unrestrained or nonparent driver, riding where child passenger restraint laws were weaker than national guidelines, and taking a short trip. Although proper restraint has increased, it remains low. Tribe-initiated interventions to improve child passenger restraint use are under way.

Design and activity of novel lactoferrampin analogues against O157:H7 enterohemorrhagic Escherichia coli.

PubMed

Cruz, Jenniffer; Ortiz, Claudia; Guzmán, Fanny; Cárdenas, Constanza; Fernandez-Lafuente, Roberto; Torres, Rodrigo

2014-04-01

Lactoferrampin 265-284 (LFampin 265-284) is a peptide consisting of residues 265-284 of N1-domain of bovine Lactoferrin (LF). This peptide has several cationic groups in the C-terminal lobe, exhibiting an antibacterial activity against a wide range of microorganisms. However, LFampin 265-284 exhibits low antimicrobial activity against the O157:H7 enterohaemorrhagic Escherichia coli (EHEC O157:H7) when compared with Lactoferrin chimera and Lactoferricin. Here, we have designed three analogues of LFampin 265-284 based on the distribution of cationic groups, hydrophobicity, size, and sequence. Analogues were synthesized by solid phase chemistry using Fmoc methodology obtaining peptides with 95% purity. All peptides maintain the ability to adopt helical conformations (checked by circular dichroism spectra and molecular simulations). Some of these analogues exhibited a significant increase in antimicrobial activity by counting colony forming units against EHEC O157:H7 compared to native LFampin 265-284, with MIC of 10 and 40 µM for 264G-D265K and 264G-D265K/S272R, respectively. The incorporation of a GKLI sequence in the N-terminal lobe increased dramatically its antibacterial activity, an effect which has been attributed to the addition of cationic groups in the N-terminal side that may stabilize the helical conformation of the new designed peptides. Copyright © 2013 Wiley Periodicals, Inc.

The role of d-allo-isoleucine in the deposition of the anti-Leishmania peptide bombinin H4 as revealed by 31P solid-state NMR, VCD spectroscopy, and MD simulation.

PubMed

Mijiddorj, Batsaikhan; Kaneda, Shiho; Sato, Hisako; Kitahashi, Yuki; Javkhlantugs, Namsrai; Naito, Akira; Ueda, Kazuyoshi; Kawamura, Izuru

2018-07-01

Bombinin H4 is an antimicrobial peptide that was isolated from the toad Bombina variegata. Bombinin H family peptides are active against gram-positive, gram-negative bacteria, and fungi as well as the parasite Leishmania. Among them, bombinin H4 (H4), which contains d-allo-isoleucine (d-allo-Ile) as the second residue in its sequence, is the most active, and its l-isomer is bombinin H2 (H2). H4 has a significantly lower LC50 than H2 against Leishmania. However, the atomic-level mechanism of the membrane interaction and higher activity of H4 has not been clarified. In this work, we investigated the behavior of the conformations and interactions of H2 and H4 with the Leishmania membrane using 31 P solid-state nuclear magnetic resonance (NMR), vibrational circular dichroism (VCD) spectroscopy, and molecular dynamics (MD) simulations. The generation of isotropic 31 P NMR signals depending on the peptide concentration indicated the abilities of H2 and H4 to exert antimicrobial activity via membrane disruption. The VCD experiment and density functional theory calculation confirmed the different stability and conformations of the N-termini of H2 and H4. MD simulations revealed that the N-terminus of H4 is more stable than that of H2 in the membrane, in line with the VCD experiment data. VCD and MD analyses demonstrated that the first l-Ile and second d-allo-Ile of H4 tend to take a cis conformation. These residues function as an anchor and facilitate the easy winding of the helical conformation of H4 in the membrane. It may assist to quickly reach to the threshold concentration of H4 on the Leishmania membrane. This article is part of a Special Issue entitled: d-Amino acids: biology in the mirror, edited by Dr. Loredano Pollegioni, Dr. Jean-Pierre Mothet and Dr. Molla Gianluca. Copyright © 2018 Elsevier B.V. All rights reserved.

Antimycobacterial, antimicrobial activity, experimental (FT-IR, FT-Raman, NMR, UV-Vis, DSC) and DFT (transition state, chemical reactivity, NBO, NLO) studies on pyrrole-isonicotinyl hydrazine

NASA Astrophysics Data System (ADS)

Rawat, Poonam; Singh, R. N.; Ranjan, Alok; Ahmad, Sartaj; Saxena, Rajat

2017-05-01

As part of a study of pyrrole hydrazone, we have investigated quantum chemical calculations, molecular geometry, relative energy, vibrational properties and antimycobacterial/antimicrobial activity of pyrrole-2-carboxaldehyde isonicotinyl hydrazone (PCINH), by applying the density functional theory (DFT) and Hartree Fock (HF). Good reproduction of experimental values is obtained and with small percentage error in majority of the cases in comparison to theoretical result (DFT). The experimental FT-IR and Raman wavenumbers were compared with the respective theoretical values obtained from DFT calculations and found to agree well. In crystal structure studies the hydrated PCINH (syn-syn conformer) shows different conformation than from anhydrous form (syn-anti conformer). The rotational barrier between syn-syn and syn-anti conformers of PCINH is 12.7 kcal/mol in the gas phase. In this work, use of FT-IR, FT-Raman, 1H NMR, 13C NMR and UV-Vis spectroscopies has been made for full characterization of PCINH. A detailed interpretation of the vibrational spectrum was carried out with the aid of normal coordinate analysis using single scaling factor. Our results support the hydrogen bonding pattern proposed by reported crystalline structure. The calculated nature of electronic transitions within molecule found to be π → π*. The electronic descriptors study indicates that PCINH can be used as robust synthon for synthesis of new heterocyclic compounds. The first static hyperpolarizability (β0) of PCINH is calculated as 33.89 × 10- 30 esu, (gas phase); 68.79 × 10- 30 (CHCl3), esu; 76.76 × 10- 30 esu (CH2Cl2), 85.16 × 10- 30 esu (DMSO). The solvent induced effects on the first static hyperpolarizability were studied and found to increase as dielectric constants of the solvents increases. Investigated molecule shows better NLO value than Para nitroaniline (PNA). The compound PCINH shows good antifungal and antibacterial activity against Aspergillus niger and gram-positive bacteria Bacillus subtilis, respectively. The compound also shows good antituberculosis activity against Mycobacterium tuberculosis H37Rv using the microplate alamar blue assay (MABA).

Ocellatin peptides from the skin secretion of the South American frog Leptodactylus labyrinthicus (Leptodactylidae): characterization, antimicrobial activities and membrane interactions.

PubMed

Gusmão, Karla A G; Dos Santos, Daniel M; Santos, Virgílio M; Cortés, María Esperanza; Reis, Pablo V M; Santos, Vera L; Piló-Veloso, Dorila; Verly, Rodrigo M; de Lima, Maria Elena; Resende, Jarbas M

2017-01-01

The availability of antimicrobial peptides from several different natural sources has opened an avenue for the discovery of new biologically active molecules. To the best of our knowledge, only two peptides isolated from the frog Leptodactylus labyrinthicus , namely pentadactylin and ocellatin-F1, have shown antimicrobial activities. Therefore, in order to explore the antimicrobial potential of this species, we have investigated the biological activities and membrane interactions of three peptides isolated from the anuran skin secretion. Three peptide primary structures were determined by automated Edman degradation. These sequences were prepared by solid-phase synthesis and submitted to activity assays against gram-positive and gram-negative bacteria and against two fungal strains. The hemolytic properties of the peptides were also investigated in assays with rabbit blood erythrocytes. The conformational preferences of the peptides and their membrane interactions have been investigated by circular dichroism spectroscopy and liposome dye release assays. The amino acid compositions of three ocellatins were determined and the sequences exhibit 100% homology for the first 22 residues (ocellatin-LB1 sequence). Ocellatin-LB2 carries an extra Asn residue and ocellatin-F1 extra Asn-Lys-Leu residues at C-terminus. Ocellatin-F1 presents a stronger antibiotic potential and a broader spectrum of activities compared to the other peptides. The membrane interactions and pore formation capacities of the peptides correlate directly with their antimicrobial activities, i.e., ocellatin-F1 > ocellatin-LB1 > ocellatin-LB2. All peptides acquire high helical contents in membrane environments. However, ocellatin-F1 shows in average stronger helical propensities. The obtained results indicate that the three extra amino acid residues at the ocellatin-F1 C-terminus play an important role in promoting stronger peptide-membrane interactions and antimicrobial properties. The extra Asn-23 residue present in ocellatin-LB2 sequence seems to decrease its antimicrobial potential and the strength of the peptide-membrane interactions.

Synthesis, spectroscopic characterization, antimicrobial evaluation and molecular docking study of novel triazine-quinazolinone based hybrids

NASA Astrophysics Data System (ADS)

Dinari, Mohammad; Gharahi, Fateme; Asadi, Parvin

2018-03-01

A new series of 1,3,5-triazine incorporating aromatic quinazolinone moieties as a potential antimicrobial agents is reported. The first chlorine group of the cyanuric chloride (1) was replaced by aniline and the second one was replaced by various aromatic amines. The prepared monochlorotriazine was allowed to react with hydrazine and subsequently it was reacted with 2-methyl-4H-benzo[1,3]oxazin-4-one to obtain novel triazine-quinazolinone based hybrids (9a-f). The chemical structure and purity of the hybrid compounds were evaluated by different techniques such as thin layer chromatography, melting point, Fourier-transform infrared (FTIR), 1H and 13C NMR spectra and elemental analysis. Antimicrobial activity of the hybrid compounds were study by three Gram-negative bacteria (Salmonella entritidis, Escherichia coli, Pseudomonas aeruginosa) and three Gram-positive bacteria (Staphylococcus aureus, Listeria monocitogenes, Bacillus subtilis) as well as Candida albicansas a yeast-like fungus using the serial broth dilution method. Among them, compound 9d with benzenesulfonamide group showed higher antimicrobial activity with a minimum inhibitory concentration (MIC) value of 16 μg/mL. Furthermore, compounds 5d, 9a and 9b showed good activity against several tested strains. In addition, docking simulation was perform to position best antibacterial compounds in to the S. aureus dihydrofolate reductase (DHFR) active site to determine the probable binding conformations.

A critical evaluation of random copolymer mimesis of homogeneous antimicrobial peptides

PubMed Central

Hu, Kan; Schmidt, Nathan W.; Zhu, Rui; Jiang, Yunjiang; Lai, Ghee Hwee; Wei, Gang; Palermo, Edmund F.; Kuroda, Kenichi; Wong, Gerard C. L.; Yang, Lihua

2013-01-01

Polymeric synthetic mimics of antimicrobial peptides (SMAMPs) have recently demonstrated similar antimicrobial activity as natural antimicrobial peptides (AMPs) from innate immunity. This is surprising, since polymeric SMAMPs are heterogeneous in terms of chemical structure (random sequence) and conformation (random coil), in contrast to defined amino acid sequence and intrinsic secondary structure. To understand this better, we compare AMPs with a ‘minimal’ mimic, a well characterized family of polydisperse cationic methacrylate-based random copolymer SMAMPs. Specifically, we focus on a comparison between the quantifiable membrane curvature generating capacity, charge density, and hydrophobicity of the polymeric SMAMPs and AMPs. Synchrotron small angle x-ray scattering (SAXS) results indicate that typical AMPs and these methacrylate SMAMPs generate similar amounts of membrane negative Gaussian curvature (NGC), which is topologically necessary for a variety of membrane-destabilizing processes. Moreover, the curvature generating ability of SMAMPs is more tolerant of changes in the lipid composition than that of natural AMPs with similar chemical groups, consistent with the lower specificity of SMAMPs. We find that, although the amount of NGC generated by these SMAMPs and AMPs are similar, the SMAMPs require significantly higher levels of hydrophobicity and cationic charge to achieve the same level of membrane deformation. We propose an explanation for these differences, which has implications for new synthetic strategies aimed at improved mimesis of AMPs. PMID:23750051

Avian Antimicrobial Host Defense Peptides: From Biology to Therapeutic Applications

PubMed Central

Zhang, Guolong; Sunkara, Lakshmi T.

2014-01-01

Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomoduatory properties. Because they act on the microbial membranes or host immune cells, HDPs pose a low risk of triggering microbial resistance and therefore, are being actively investigated as a novel class of antimicrobials and vaccine adjuvants. Cathelicidins and β-defensins are two major families of HDPs in avian species. More than a dozen HDPs exist in birds, with the genes in each HDP family clustered in a single chromosomal segment, apparently as a result of gene duplication and diversification. In contrast to their mammalian counterparts that adopt various spatial conformations, mature avian cathelicidins are mostly α-helical. Avian β-defensins, on the other hand, adopt triple-stranded β-sheet structures similar to their mammalian relatives. Besides classical β-defensins, a group of avian-specific β-defensin-related peptides, namely ovodefensins, exist with a different six-cysteine motif. Like their mammalian counterparts, avian cathelicidins and defensins are derived from either myeloid or epithelial origin expressed in a majority of tissues with broad-spectrum antibacterial and immune regulatory activities. Structure-function relationship studies with several avian HDPs have led to identification of the peptide analogs with potential for use as antimicrobials and vaccine adjuvants. Dietary modulation of endogenous HDP synthesis has also emerged as a promising alternative approach to disease control and prevention in chickens. PMID:24583933

A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.

PubMed

Henke, Brad R; Consler, Thomas G; Go, Ning; Hale, Ron L; Hohman, Dana R; Jones, Stacey A; Lu, Amy T; Moore, Linda B; Moore, John T; Orband-Miller, Lisa A; Robinett, R Graham; Shearin, Jean; Spearing, Paul K; Stewart, Eugene L; Turnbull, Philip S; Weaver, Susan L; Williams, Shawn P; Wisely, G Bruce; Lambert, Millard H

2002-12-05

A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.

Neurocysticercosis: regional status, epidemiology, impact and control measures in the Americas.

PubMed

Flisser, Ana; Sarti, Elsa; Lightowlers, Marshall; Schantz, Peter

2003-06-01

The analysis of epidemiological data concerning human cysticercosis point to important advances in understanding the magnitude and distribution of this parasitic disease in Latin America, as well as the relationship of the elements that conform the life cycle of Taenia solium. The data indicate that the main risk factor for acquiring human neurocysticercosis and swine cysticercosis is the presence of the tapeworm carrier in the household. Therefore, several intervention measures for the control of cysticercosis have been evaluated: mass treatment in order to cure tapeworm carriers, health education towards understanding the risk factors, pig control by restraining them, experimental vaccination of pigs and treatment of swine cysticercosis. In this paper, we review the information obtained in these areas. We hope it will be useful in other endemic countries that wish to elaborate an action plan for the control and ultimate eradication of T. solium.

Effect of aqueous extracts of Mentha arvensis (mint) and Piper betle (betel) on growth and citrinin production from toxigenic Penicillium citrinum.

PubMed

Panda, Pragyanshree; Aiko, Visenuo; Mehta, Alka

2015-06-01

Due to growing concern of consumers about chemical residues in food products, the demand for safe and natural food is increasing greatly. The use of natural additives such as spices and herbal oil as seasoning agents for their antimicrobial activity has been extensively investigated. This paper discusses the efficacy of the aqueous extract of mint (Mentha arvensis) and betel (Piper betle) on the mycelial growth and citrinin production of Penicillium citrinum. The present investigation revealed that mint extract inhibited citrinin production up to 73 % without inhibiting the mycelium growth. The citrinin production decreased with increase in the concentration of mint extract as observed from the data obtained from High pressure liquid chromatography. The samples also showed reduced cytotoxicity on HeLa cells. On the other hand betel extract resulted in stimulatory effect on citrinin production and mycelial growth. The study showed that mint extract has the potential to be used safely for restraining citrinin contamination.

Effect of nano packaging on preservation quality of Nanjing 9108 rice variety at high temperature and humidity.

PubMed

Wang, Fan; Hu, Qiuhui; Mugambi Mariga, Alfred; Cao, Chongjiang; Yang, Wenjian

2018-01-15

A nano packaging material containing nano Ag, nano TiO 2 , nano attapulgite and SiO 2 was prepared, and its impact on quality of Nanjing 9108 rice at 37°C and 85% relative humidity was studied. Effects of the packaging on ambient gases and chromatic aberration of rice were determined. Moreover, oxidation level, molds growth and flavor of rice were also analyzed. Results showed that nano packaging material had antimicrobial effects and maintained low O 2 and high CO 2 content in the packages. The packages thereby inhibited the growth of molds and the production of fatty acids, restrained the increase of lipase activity, and reduced the oxidation of fats and proteins. As a result, the production of yellow and white-belly rice were inhibited. Furthermore, the color and flavor of rice were maintained. Therefore, the nano-packing material could be applied for preservation of rice to improve preservation quality. Copyright © 2017 Elsevier Ltd. All rights reserved.

Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity

PubMed Central

Kanayama, Masashi; Inoue, Makoto; Danzaki, Keiko; Hammer, Gianna; He, You-Wen; Shinohara, Mari L.

2014-01-01

Immune responses must be well restrained in a steady state to avoid excessive inflammation. However, such restraints are quickly removed to exert anti-microbial responses. Here, we report a role of autophagy in an early host anti-fungal response by enhancing NFκB activity through A20 sequestration. Enhancement of NFκB activation is achieved by autophagic depletion of A20, an NFκB inhibitor, in F4/80hi macrophages in the spleen, peritoneum, and kidney. We show that p62, an autophagic adaptor protein, captures A20 to sequester it in the autophagosome. This allows the macrophages to release chemokines to recruit neutrophils. Indeed, mice lacking autophagy in myeloid cells show higher susceptibility to Candida albicans infection due to impairment in neutrophil recruitment. Thus, at least in the specific aforementioned tissues, autophagy appears to break A20-dependent suppression in F4/80hi macrophages, which express abundant A20 and contribute to the initiation of efficient innate immune responses. PMID:25609235

Young Adolescent Batterers: A Profile of Restraining Order Defendants in Massachusetts.

ERIC Educational Resources Information Center

Cochran, Donald; And Others

Research indicates a national trend of increasing violence among the juvenile population. This study examines and profiles adolescent restraining order defendants in one state. The study includes all adolescent defendants between the ages of 11 and 17 who had a restraining order issued against them during a 10-month period. This study examined the…

Body Dissatisfaction Mediates the Relationship between Self-Esteem and Restrained Eating in Female Undergraduates

ERIC Educational Resources Information Center

Gianini, Loren M.; Smith, Jane Ellen

2008-01-01

The purpose of the current study was to examine the eating behavior, self-esteem, and social anxiety of restrained and non-restrained eaters exposed to an interpersonal stressor. Sixty female undergraduate students completed questionnaires and took part in a stressor and taste test. Results indicated that self-esteem was not predictive of eating…

SURVEY AND SUMMARY: The morph server: a standardized system for analyzing and visualizing macromolecular motions in a database framework

PubMed Central

Krebs, Werner G.; Gerstein, Mark

2000-01-01

The number of solved structures of macromolecules that have the same fold and thus exhibit some degree of conformational variability is rapidly increasing. It is consequently advantageous to develop a standardized terminology for describing this variability and automated systems for processing protein structures in different conformations. We have developed such a system as a ‘front-end’ server to our database of macromolecular motions. Our system attempts to describe a protein motion as a rigid-body rotation of a small ‘core’ relative to a larger one, using a set of hinges. The motion is placed in a standardized coordinate system so that all statistics between any two motions are directly comparable. We find that while this model can accommodate most protein motions, it cannot accommodate all; the degree to which a motion can be accommodated provides an aid in classifying it. Furthermore, we perform an adiabatic mapping (a restrained interpolation) between every two conformations. This gives some indication of the extent of the energetic barriers that need to be surmounted in the motion, and as a by-product results in a ‘morph movie’. We make these movies available over the Web to aid in visualization. Many instances of conformational variability occur between proteins with somewhat different sequences. We can accommodate these differences in a rough fashion, generating an ‘evolutionary morph’. Users have already submitted hundreds of examples of protein motions to our server, producing a comprehensive set of statistics. So far the statistics show that the median submitted motion has a rotation of ~10° and a maximum Cα displacement of 17 Å. Almost all involve at least one large torsion angle change of >140°. The server is accessible at http://bioinfo.mbb.yale.edu/MolMovDB PMID:10734184

Serine Phosphorylation of the Insulin-like Growth Factor I (IGF-1) Receptor C-terminal Tail Restrains Kinase Activity and Cell Growth*

PubMed Central

Kelly, Geraldine M.; Buckley, Deirdre A.; Kiely, Patrick A.; Adams, David R.; O'Connor, Rosemary

2012-01-01

Insulin-like growth factor I receptor (IGF-1R) signaling is essential for cell, organ, and animal growth. The C-terminal tail of the IGF-1R exhibits regulatory function, but the mechanism is unknown. Here, we show that mutation of Ser-1248 (S1248A) enhances IGF-1R in vitro kinase activity, autophosphorylation, Akt/mammalian target of rapamycin activity, and cell growth. Ser-1248 phosphorylation is mediated by GSK-3β in a mechanism that involves a priming phosphorylation on Ser-1252. GSK-3β knock-out cells exhibit reduced IGF-1R cell surface expression, enhanced IGF-1R kinase activity, and signaling. Examination of crystallographic structures of the IGF-1R kinase domain revealed that the 1248SFYYS1252 motif adopts a conformation tightly packed against the kinase C-lobe when Ser-1248 is in the unphosphorylated state that favors kinase activity. S1248A mutation is predicted to lock the motif in this position. In contrast, phosphorylation of Ser-1248 will drive profound structural transition of the sequence, critically affecting connection of the C terminus as well as exposing potential protein docking sites. Decreased kinase activity of a phosphomimetic S1248E mutant and enhanced kinase activity in mutants of its predicted target residue Lys-1081 support this auto-inhibitory model. Thus, the SFYYS motif controls the organization of the IGF-1R C terminus relative to the kinase domain. Its phosphorylation by GSK-3β restrains kinase activity and regulates receptor trafficking and signaling. PMID:22685298

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

Tom, Nathan M.; Madhi, Farshad; Yeung, Ronald W.

The aim of this paper is to maximize the power-to-load ratio of the Berkeley Wedge: a one-degree-of-freedom, asymmetrical, energy-capturing, floating breakwater of high performance that is relatively free of viscosity effects. Linear hydrodynamic theory was used to calculate bounds on the expected time-averaged power (TAP) and corresponding surge restraining force, pitch restraining torque, and power take-off (PTO) control force when assuming that the heave motion of the wave energy converter remains sinusoidal. This particular device was documented to be an almost-perfect absorber if one-degree-of-freedom motion is maintained. The success of such or similar future wave energy converter technologies would requiremore » the development of control strategies that can adapt device performance to maximize energy generation in operational conditions while mitigating hydrodynamic loads in extreme waves to reduce the structural mass and overall cost. This paper formulates the optimal control problem to incorporate metrics that provide a measure of the surge restraining force, pitch restraining torque, and PTO control force. The optimizer must now handle an objective function with competing terms in an attempt to maximize power capture while minimizing structural and actuator loads. A penalty weight is placed on the surge restraining force, pitch restraining torque, and PTO actuation force, thereby allowing the control focus to be placed either on power absorption or load mitigation. Thus, in achieving these goals, a per-unit gain in TAP would not lead to a greater per-unit demand in structural strength, hence yielding a favorable benefit-to-cost ratio. Demonstrative results in the form of TAP, reactive TAP, and the amplitudes of the surge restraining force, pitch restraining torque, and PTO control force are shown for the Berkeley Wedge example.« less

Focusing on media body ideal images triggers food intake among restrained eaters: a test of restraint theory and the elaboration likelihood model.

PubMed

Boyce, Jessica A; Kuijer, Roeline G

2014-04-01

Although research consistently shows that images of thin women in the media (media body ideals) affect women negatively (e.g., increased weight dissatisfaction and food intake), this effect is less clear among restrained eaters. The majority of experiments demonstrate that restrained eaters - identified with the Restraint Scale - consume more food than do other participants after viewing media body ideal images; whereas a minority of experiments suggest that such images trigger restrained eaters' dietary restraint. Weight satisfaction and mood results are just as variable. One reason for these inconsistent results might be that different methods of image exposure (e.g., slideshow vs. film) afford varying levels of attention. Therefore, we manipulated attention levels and measured participants' weight satisfaction and food intake. We based our hypotheses on the elaboration likelihood model and on restraint theory. We hypothesised that advertent (i.e., processing the images via central routes of persuasion) and inadvertent (i.e., processing the images via peripheral routes of persuasion) exposure would trigger differing degrees of weight dissatisfaction and dietary disinhibition among restrained eaters (cf. restraint theory). Participants (N = 174) were assigned to one of four conditions: advertent or inadvertent exposure to media or control images. The dependent variables were measured in a supposedly unrelated study. Although restrained eaters' weight satisfaction was not significantly affected by either media exposure condition, advertent (but not inadvertent) media exposure triggered restrained eaters' eating. These results suggest that teaching restrained eaters how to pay less attention to media body ideal images might be an effective strategy in media-literary interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Balancing Power Absorption and Structural Loading for an Asymmetric Heave Wave-Energy Converter in Regular Waves

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

Tom, Nathan M.; Madhi, Farshad; Yeung, Ronald W.

2016-06-24

The aim of this paper is to maximize the power-to-load ratio of the Berkeley Wedge: a one-degree-of-freedom, asymmetrical, energy-capturing, floating breakwater of high performance that is relatively free of viscosity effects. Linear hydrodynamic theory was used to calculate bounds on the expected time-averaged power (TAP) and corresponding surge restraining force, pitch restraining torque, and power take-off (PTO) control force when assuming that the heave motion of the wave energy converter remains sinusoidal. This particular device was documented to be an almost-perfect absorber if one-degree-of-freedom motion is maintained. The success of such or similar future wave energy converter technologies would requiremore » the development of control strategies that can adapt device performance to maximize energy generation in operational conditions while mitigating hydrodynamic loads in extreme waves to reduce the structural mass and overall cost. This paper formulates the optimal control problem to incorporate metrics that provide a measure of the surge restraining force, pitch restraining torque, and PTO control force. The optimizer must now handle an objective function with competing terms in an attempt to maximize power capture while minimizing structural and actuator loads. A penalty weight is placed on the surge restraining force, pitch restraining torque, and PTO actuation force, thereby allowing the control focus to be placed either on power absorption or load mitigation. Thus, in achieving these goals, a per-unit gain in TAP would not lead to a greater per-unit demand in structural strength, hence yielding a favorable benefit-to-cost ratio. Demonstrative results in the form of TAP, reactive TAP, and the amplitudes of the surge restraining force, pitch restraining torque, and PTO control force are shown for the Berkeley Wedge example.« less

A twin study of differences in the response of plasma ghrelin to a milkshake preload in restrained eaters

PubMed Central

Myhre, Rachel; Kratz, Mario; Goldberg, Jack; Polivy, Janet; Melhorn, Susan; Buchwald, Dedra; Cummings, David E.; Schur, Ellen A.

2014-01-01

Background Genetic, physiological, and psychological factors can affect food intake, but twin studies can distinguish inherited from environmental contributors. We examined the influence of attempted cognitive control of eating (“restrained eating”) on levels of appetite-regulating hormones. Methods Sixteen female, monozygotic twin pairs, discordant for Restraint Scale score (i.e., one twin a restrained eater with score > 15 whereas the co-twin was unrestrained), were selected from the University of Washington Twin Registry. Serial plasma ghrelin concentrations were monitored during meals and a preload study paradigm involving intake of a milkshake followed by an ad libitum ice cream “taste test.” Results Body weight, body mass index, resting energy expenditure, and fasting leptin levels were very similar between restrained and unrestrained twins. In a preload study, twins ate similar amounts of ice cream shortly after drinking identical milkshakes (mean ±SD; restrained 239 ±158 vs. unrestrained 228 ±132 kilocalories; P = 0.83). However, ghrelin concentrations during the preload study were significantly higher (P = 0.03) in restrained twins than in their unrestrained co-twins. Regardless of restraint status, ghrelin levels prior to the preload study were prospectively and positively associated with ice cream intake (P = 0.001). Conclusions Compared to their unrestrained co-twins, restrained twins had higher endogenous ghrelin levels during a preload study, but ate similar amounts. This finding is consistent with exertion of cognitive control relative to the state of physiologic appetite stimulation. Moreover, these findings in twins suggest that higher ghrelin levels result from restrained eating behavior and not from genetic predisposition. PMID:24534168

Preparation of Shrinkage Compensating Concrete with HCSA Expansive Agent

NASA Astrophysics Data System (ADS)

Li, Changcheng; Jia, Fujia

2017-10-01

Shrinkage compensating concrete (SCC) has become one of the best effective methods of preventing and reducing concrete cracking. SCC is prepared by HCSA high performance expansive agent for concrete which restrained expansion rate is optimized by 0.057%. Slump, compressive strength, restrained expansion rate and cracking resistance test were carried out on SCC. The results show that the initial slump of fresh SCC was about 220mm-230mm, while slump after 2 hours was 180mm-200mm. The restrained expansion rate of SCC increased with the mixing amount of expansive agent. After cured in water for 14 days, the restrained expansion rate of C35 and C40 SCC were 0.020%-0.032%. With the dosage of expansive agent increasing, restrained expansion rate of SCC increased, maximum compressive stress and cracking stress improved, cracking temperature fell, thus cracking resistance got effectively improvement.

Non-invasive SFG spectroscopy: a tool to reveal the conformational change of grafted chains due to bacterial adhesion

NASA Astrophysics Data System (ADS)

Bulard, Emilie; Dubost, Henri; Fontaine-Aupart, Marie-Pierre; Zheng, Wanquan; Herry, Jean-Marie; Bellon-Fontaine, Marie-No"lle; Briandet, Romain; Bourguignon, Bernard

2011-07-01

In many fields such as biomedical or food industry, surface colonization by micro-organisms leads to biofilms formation that are tridimentional biostructures highly resistant to the action of antimicrobials, by mechanisms still unclear. In order to deepen our understanding of the initial interaction of bacteria cells with a solid surface, we analyze by in situ vibrational Sum Frequency Generation (SFG) spectroscopy the effect of the adhesion of hydrophilic Lactoccocus lactis bacteria and its hydrophobic mutants in distilled water on a self-assembled monolayer (SAM) of octadecanethiol (ODT) on a gold film. When a homogeneous bacterial monolayer is deposited on this ordered surface, SFG spectrum of the ODT SAM shows significant intensity changes from that in air or in water. Its modelling as a function of conformation allows to distinguish optical effects due to the water solution surrounding bacteria from conformational changes of the ODT SAM due to the presence of the bacteria cells. Futhermore, bacterial adhesion induces different measurable effects on the ODT SAM conformation, depending on the hydrophobic / hydrophilic character of the bacterial surface. Such a result deserves to be taken into account for the design of new materials with improved properties or to control biofilm formation.

Self-limiting atomic layer deposition of conformal nanostructured silver films

NASA Astrophysics Data System (ADS)

Golrokhi, Zahra; Chalker, Sophia; Sutcliffe, Christopher J.; Potter, Richard J.

2016-02-01

The controlled deposition of ultra-thin conformal silver nanoparticle films is of interest for applications including anti-microbial surfaces, plasmonics, catalysts and sensors. While numerous techniques can produce silver nanoparticles, few are able to produce highly conformal coatings on high aspect ratio surfaces, together with sub-nanometre control and scalability. Here we develop a self-limiting atomic layer deposition (ALD) process for the deposition of conformal metallic silver nanoparticle films. The films have been deposited using direct liquid injection ALD with ((hexafluoroacetylacetonato)silver(I)(1,5-cyclooctadiene)) and propan-1-ol. An ALD temperature window between 123 and 128 °C is identified and within this range self-limiting growth is confirmed with a mass deposition rate of ∼17.5 ng/cm2/cycle. The effects of temperature, precursor dose, co-reactant dose and cycle number on the deposition rate and on the properties of the films have been systematically investigated. Under self-limiting conditions, films are metallic silver with a nano-textured surface topography and nanoparticle size is dependent on the number of ALD cycles. The ALD reaction mechanisms have been elucidated using in-situ quartz crystal microbalance (QCM) measurements, showing chemisorption of the silver precursor, followed by heterogeneous catalytic dehydrogenation of the alcohol to form metallic silver and an aldehyde.

Trends and Correlates of Child Passenger Restraint Use in 6 Northwest Tribes: The Native Children Always Ride Safe (Native CARS) Project

PubMed Central

Smith, Nicole Holdaway; Lutz, Tam; Ebel, Beth E.

2013-01-01

Objectives. We compared proportions of children properly restrained in vehicles in 6 Northwest American Indian tribes in 2003 and 2009, and evaluated risks for improper restraint. Methods. During spring 2009 we conducted a vehicle observation survey in Oregon, Washington, and Idaho tribal communities. We estimated the proportions of children riding properly restrained and evaluated correlates of improper restraint via log-binomial regression models for clustered data. Results. We observed 1853 children aged 12 years and younger in 1207 vehicles; 49% rode properly restrained. More children aged 8 years and younger rode properly restrained in 2009 than 2003 (51% vs 29%; P < .001). Older booster seat–eligible children were least likely to ride properly restrained in 2009 (25%). American Indian children were more likely to ride improperly restrained than nonnative children in the same communities. Other risk factors included riding with an unrestrained or nonparent driver, riding where child passenger restraint laws were weaker than national guidelines, and taking a short trip. Conclusions. Although proper restraint has increased, it remains low. Tribe-initiated interventions to improve child passenger restraint use are under way. PMID:23237177

Color-dependent learning in restrained Africanized honey bees.

PubMed

Jernigan, C M; Roubik, D W; Wcislo, W T; Riveros, A J

2014-02-01

Associative color learning has been demonstrated to be very poor using restrained European honey bees unless the antennae are amputated. Consequently, our understanding of proximate mechanisms in visual information processing is handicapped. Here we test learning performance of Africanized honey bees under restrained conditions with visual and olfactory stimulation using the proboscis extension response (PER) protocol. Restrained individuals were trained to learn an association between a color stimulus and a sugar-water reward. We evaluated performance for 'absolute' learning (learned association between a stimulus and a reward) and 'discriminant' learning (discrimination between two stimuli). Restrained Africanized honey bees (AHBs) readily learned the association of color stimulus for both blue and green LED stimuli in absolute and discriminatory learning tasks within seven presentations, but not with violet as the rewarded color. Additionally, 24-h memory improved considerably during the discrimination task, compared with absolute association (15-55%). We found that antennal amputation was unnecessary and reduced performance in AHBs. Thus color learning can now be studied using the PER protocol with intact AHBs. This finding opens the way towards investigating visual and multimodal learning with application of neural techniques commonly used in restrained honey bees.

Interaction of multiple biomimetic antimicrobial polymers with model bacterial membranes

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

Baul, Upayan, E-mail: upayanb@imsc.res.in; Vemparala, Satyavani, E-mail: vani@imsc.res.in; Kuroda, Kenichi, E-mail: kkuroda@umich.edu

Using atomistic molecular dynamics simulations, interaction of multiple synthetic random copolymers based on methacrylates on prototypical bacterial membranes is investigated. The simulations show that the cationic polymers form a micellar aggregate in water phase and the aggregate, when interacting with the bacterial membrane, induces clustering of oppositely charged anionic lipid molecules to form clusters and enhances ordering of lipid chains. The model bacterial membrane, consequently, develops lateral inhomogeneity in membrane thickness profile compared to polymer-free system. The individual polymers in the aggregate are released into the bacterial membrane in a phased manner and the simulations suggest that the most probablemore » location of the partitioned polymers is near the 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) clusters. The partitioned polymers preferentially adopt facially amphiphilic conformations at lipid-water interface, despite lacking intrinsic secondary structures such as α-helix or β-sheet found in naturally occurring antimicrobial peptides.« less

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

Mehboob, Shahila; Hevener, Kirk E.; Truong, Kent

Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motifmore » of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.« less

Effectiveness of Disinfectants on Antimicrobial and Physical Properties of Dental Impression Materials.

PubMed

Demajo, Jean Karl; Cassar, Valter; Farrugia, Cher; Millan-Sango, David; Sammut, Charles; Valdramidis, Vasilis; Camilleri, Josette

2016-01-01

The aim of this study was to assess the antimicrobial activity of chemical disinfectants on alginate and silicone impression materials. The effect of chemical disinfectants on the dimensional stability of the impression materials was also assessed. For the microbiologic assessment, impressions of the maxillary arch were taken from 14 participants, 7 using alginate and 7 using an addition silicone. The impressions were divided into three sections. Each section was subjected to spraying with MD 520 or Minuten or no disinfection (control), respectively. Antimicrobial action of the chemical disinfectants was assessed by measuring microbial counts in trypticase soy agar (TSA) media and expressing the results in colony-forming units/cm2. The surface area of the dental impressions was calculated by scanning a stone cast using computer-aided design/computer-assisted manufacture and analyzing the data using a custom computer program. The dimensional stability of the impression materials after immersion in disinfectants was assessed by measuring the linear displacement of horizontally restrained materials using a traveling microscope. The percent change in length over 3 hours was thus determined. Alginate exhibited a higher microbial count than silicone. MD 520 eliminated all microbes as opposed to Minuten. The bacterial growth after Minuten disinfection was almost twice as much for alginate than for addition silicone impressions. The chemical disinfectants affected the alginate dimensional stability. Minuten reduced the shrinkage sustained by alginate during the first hour of storage. Alginate harbors three times more microorganisms than silicone impression material. Chemical disinfection by glutaraldehyde-based disinfectant was effective in eliminating all microbial forms for both alginate and silicone without modifying the dimensional stability. Alcohol-based disinfectants, however, reduced the alginate shrinkage during the first 90 minutes of setting. The current studies also propose another method to report the surface area based on accurate estimation by 3D image analysis.

As-CATH1-6, novel cathelicidins with potent antimicrobial and immunomodulatory properties from Alligator sinensis, play pivotal roles in host antimicrobial immune responses.

PubMed

Chen, Yan; Cai, Shasha; Qiao, Xue; Wu, Mali; Guo, Zhilai; Wang, Renping; Kuang, Yi-Qun; Yu, Haining; Wang, Yipeng

2017-08-10

Crocodilians are regarded as possessing a powerful immune system. However, the composition and action of the crocodilian immune system have remained unclear until now. Cathelicidins, the principal family of host defense peptides, play pivotal roles in vertebrate immune defense against microbial invasions. However, cathelicidins from crocodilians have not been extensively studied to date. In the present study, six novel cathelicidins (As-CATH1-6) were identified and characterized from the endangered Chinese alligator ( Alligator sinensis ). As-CATH1-6 exhibit no sequence similarity with any of the known cathelicidins. Structure analysis indicated that As-CATH1-3 adopt a random coil secondary conformation, whereas As-CATH4-6 were predicted to mainly adopt an amphipathic α-helix conformation. Among them, As-CATH4-6 exhibited potent, broad-spectrum and rapid antimicrobial activity by inducing the disruption of cell membrane integrity. They also exhibited strong ability to prevent the formation of bacterial biofilms and eradicate preformed biofilms. Furthermore, As-CATH4-6 exhibited potent anti-inflammatory activity by inhibiting the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and pro-inflammatory cytokines in mouse peritoneal macrophages. They directly neutralized LPS toxicity and therefore inhibited the binding of LPS to the TLR4 receptor and the subsequent activation of inflammatory response pathways. In a peritonitis mice model, As-CATH2-6 provided effective protection against bacterial infection through enhanced immune cell recruitment. In the host Chinese alligator, As-CATH1-6 are mainly expressed in immune organs and epithelial tissues. Bacterial infection significantly enhances their expression, which implies an important role in host anti-infective response. Taken together, the diversity and multiple functions of As-CATH1-6 partially reveal the powerful immune system of the Chinese alligator. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Investigation of the binding of a carbohydrate-mimetic peptide to its complementary anticarbohydrate antibody by STD-NMR spectroscopy and molecular-dynamics simulations.

PubMed

Szczepina, Monica G; Bleile, Dustin W; Pinto, B Mario

2011-10-04

Saturation transfer difference (STD)-NMR spectroscopy was used to probe experimentally the bioactive solution conformation of the carbohydrate mimic MDWNMHAA 1 of the O-polysaccharide of Shigella flexneri Y when bound to its complementary antibody, mAb SYA/J6. Molecular dynamics simulations using the ZymeCAD™ Molecular Dynamics platform were also undertaken to give a more accurate picture of the conformational flexibility and the possibilities for bound ligand conformations. The ligand topology, or the dynamic epitope, was mapped with the CORCEMA-ST (COmplete Relaxation and Conformational Exchange Matrix Analysis of Saturation Transfer) program that calculates a total matrix analysis of relaxation and exchange effects to generate predicted STD-NMR intensities from simulation. The comparison of these predicted STD enhancements with experimental data was used to select a representative binding mode. A protocol that employed theoretical STD effects calculated at snapshots during the entire course of a molecular dynamics (MD) trajectory of the peptide bound to the Fv portion of the antibody, and not the averaged atomic positions of receptor-ligand complexes, was also examined. In addition, the R factor was calculated on the basis of STD (fit) to avoid T1 bias, and an effective R factor, R(eff), was defined such that if the calculated STD (fit) for proton k was within error of the experimental STD (fit) for proton k, then that calculated STD (fit) for proton k was not included in the calculation of the R factor. This protocol was effective in deriving the antibody-bound solution conformation of the peptide which also differed from the bound conformation determined by X-ray crystallography; however, several discrepancies between experimental and calculated STD (fit) values were observed. The bound conformation was therefore further refined with a simulated annealing refinement protocol known as STD-NMR intensity-restrained CORCEMA optimization (SICO) to give a more accurate representation of the bound peptide epitope. Further optimization was required in this case, but a satisfactory correlation between experimental and calculated STD values was obtained. Attempts were also made to obtain STD enhancements with a synthetic pentasaccharide hapten, corresponding to the O-polysaccharide, while bound to the antibody. However, unfavorable kinetics of binding in this system prevented sufficient STD build-up, which, in turn, hindered a rigorous analysis via full STD build-up curves. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Conformer-Specific IR Spectroscopy of Laser-Desorbed Sulfonamide Drugs: Tautomeric and Conformational Preferences of Sulfanilamide and its Derivatives

NASA Astrophysics Data System (ADS)

Uhlemann, Thomas; Seidel, Sebastian; Müller, Christian W.

2017-06-01

Molecules containing the sulfonamide group R^{1}-SO_2-NHR^{2} have a longstanding history as antimicrobial agents. Even though nowadays they are not commonly used in treating humans anymore, they continue to be studied as effective inhibitors of metalloenzyme carbonic anhydrases. These enzymes are important targets for a variety of diseases, such as, for instance, breast cancer, glaucoma, and obesity. Here we present the results of our laser desorption single-conformation UV and IR study of sulfanilamide (NH_2Ph-SO_2-NHR, R=H), a variety of singly substituted derivatives, and their monohydrated complexes. Depending on the substituent, the sulfonamide group can either adopt an amino or an imino tautomeric form. The form prevalent in the crystal is not necessarily also the tautomeric form we identified in the molecular beam after laser desorbing the sample. Furthermore, we explored the effect of complexation with a single water molecule on the tautomeric and conformational preferences of the sulfonamides. Our conformer-specific IR spectra in the NH and OH stretch region (3200-3750 \\wn) suggest that the intra- and intermolecular interactions governing the structures of the monomers and water complexes are surprisingly diverse. We have undertaken both Quantum Theory of Atoms in Molecules (QTAIM) and Interacting Quantum Atoms (IQA) analyses of calculated electron densities to quantitatively characterize the nature and strengths of the intra- and intermolecular interactions prevalent in the monomer and water complex structures.

Studies on the antimicrobial activity and brine shrimp toxicity of Zeyheria tuberculosa (Vell.) Bur. (Bignoniaceae) extracts and their main constituents

PubMed Central

Bastos, Maria Lysete A; Lima, Maria Raquel F; Conserva, Lucia M; Andrade, Vânia S; Rocha, Eliana MM; Lemos, Rosangela PL

2009-01-01

Background Due to the indiscriminate use of antimicrobial drugs, the emergence of human pathogenic microorganisms resistant to major classes of antibiotics has been increased and has caused many clinical problems in the treatment of infectious diseases. Thus, the aim of this study was to evaluate for the first time the in vitro antimicrobial activity and brine shrimp lethality of extracts and isolated compounds from Zeyheria tuberculosa (Vell.) Bur., a species used in Brazilian folk medicine for treatment of cancer and skin diseases. Methods Using the disc diffusion method, bioautography assay and brine shrimp toxicity test (Artemia salina Leach), we studied the antimicrobial activity and lethality of extracts and isolated compounds against three microorganisms strains, including Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria and yeasts (Candida albicans). Results In this study, the extracts inhibited S. aureus (8.0 ± 0.0 to 14.0 ± 0.0 mm) and C. albicans (15.3 ± 0.68 to 25.6 ± 0.4 mm) growth. In the brine shrimp test, only two of them showed toxic effects (LC50 29.55 to 398.05 μg/mL) and some extracts were non-toxic or showed weak lethality (LC50 705.02 to > 1000 μg/mL). From these extracts, four flavones [5,6,7,8-tetramethoxyflavone (1), 5,6,7-trimethoxyflavone (2), 4'-hydroxy-5,6,7,8-tetramethoxyflavone (3), and 4'-hydroxy-5,6,7-trimethoxyflavone (4)] were isolated through bioassay-guided fractionation and identified based on the 1D and 2D NMR spectral data. By bioautography assays, compounds 1 [S. aureus (16.0 ± 0.0 mm) and C. albicans (20.0 ± 0.0 mm)] and 3 [S. aureus (10.3 ± 0.6 mm) and C. albicans (19.7 ± 0.6 mm)] inhibited both microorganisms while 2 inhibited only S. aureus (11.7 ± 0.6 mm). Compound 4 did not restrain the growth of any tested microorganism. Conclusion Our results showed that extracts and isolated flavones from Z. tuberculosa may be particularly useful against two pathogenic microorganisms, S. aureus and C. albicans. These results may justify the popular use this species since some fractions tested had antimicrobial activity and others showed significant toxic effects on brine shrimps. However, in order to evaluate possible clinical application in therapy of infectious diseases, further studies about the safety and toxicity of isolated compounds are needed. PMID:19450272

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

PubMed Central

Malik, Erum; Dennison, Sarah R.; Harris, Frederick; Phoenix, David A.

2016-01-01

Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era. PMID:27809281

An activation switch in the rhodopsin family of G protein-coupled receptors: the thyrotropin receptor.

PubMed

Urizar, Eneko; Claeysen, Sylvie; Deupí, Xavier; Govaerts, Cedric; Costagliola, Sabine; Vassart, Gilbert; Pardo, Leonardo

2005-04-29

We aimed at understanding molecular events involved in the activation of a member of the G protein-coupled receptor family, the thyrotropin receptor. We have focused on the transmembrane region and in particular on a network of polar interactions between highly conserved residues. Using molecular dynamics simulations and site-directed mutagenesis techniques we have identified residue Asn-7.49, of the NPxxY motif of TM 7, as a molecular switch in the mechanism of thyrotropin receptor (TSHr) activation. Asn-7.49 appears to adopt two different conformations in the inactive and active states. These two states are characterized by specific interactions between this Asn and polar residues in the transmembrane domain. The inactive gauche+ conformation is maintained by interactions with residues Thr-6.43 and Asp-6.44. Mutation of these residues into Ala increases the constitutive activity of the receptor by factors of approximately 14 and approximately 10 relative to wild type TSHr, respectively. Upon receptor activation Asn-7.49 adopts the trans conformation to interact with Asp-2.50 and a putatively charged residue that remains to be identified. In addition, the conserved Leu-2.46 of the (N/S)LxxxD motif also plays a significant role in restraining the receptor in the inactive state because the L2.46A mutation increases constitutive activity by a factor of approximately 13 relative to wild type TSHr. As residues Leu-2.46, Asp-2.50, and Asn-7.49 are strongly conserved, this molecular mechanism of TSHr activation can be extended to other members of the rhodopsin-like family of G protein-coupled receptors.

Effect of altered 'weight' upon animal tolerance to restraint.

NASA Technical Reports Server (NTRS)

Burton, R. R.; Smith, A. H.; Beljan, J. R.

1971-01-01

The effect of altered weight upon animal tolerance to restraint was determined by simulating various accelerative forces with directed lead weights using restrained and nonrestrained domestic fowl (chickens). Weighting (increased weight) and conterweighting (reduced weight) produced a stressed condition - reduced relative lymphocyte counts, loss of body mass, and/or the development of a disorientation syndrome - in both restrained and nonrestrained (caged only) birds. The animal's tolerance to altered weight appeared to be a function of its body weight. Unrestrained birds were stressed by counterweighting (mean plus or minus standard error) 58.3 plus or minus 41% of their body weight, whereas restrained birds tolerated only 32.2 plus or minus 2.6% reduction in body weight. A training regimen for restrained birds was not effective in improving their tolerance to a reduced weight environment. It was concluded that domestic fowl living in a weightless (space) environment should be restrained minimally and supported by ventrally directed tension equivalent to approximately 50% of their body mass (their weight in a 1 G environment).

Alterations of Ca(v)1.2 and 5-hydroxytryptamine in rat hearts after positional asphyxia.

PubMed

Li, X-F; Huang, Q-Y

2015-01-01

We investigated alterations of cardiac Ca(v)1.2 and 5-hydroxytryptamine (5-HT) associated with positional asphyxia. Male rats were divided into five groups: a control group with no restraint, group 1 restrained for 1 h, group 2 restrained for 2 h, group 3 restrained for 4 h, and group 4 restrained for 8 h. The rats that were restrained for 8 h ultimately suffered fatal asphyxia. After the restraint periods, the rats were sacrificed and immunohistochemistry was performed to evaluate the expressions of Ca(v)1.2 and 5-HT in the heart. Sections were analyzed by digital image analysis. Cardiac expression of Ca(v)1.2 and 5-HT proteins were significantly decreased by positional asphyxia in the rat, shown by integrated optical density (IOD) compared to controls. Our findings indicate that Ca(v)1.2 and 5-HT alterations could cause abnormal cardiac function, and the proteins investigated here may be useful for investigating the mechanisms underlying positional asphyxia.

Positive fantasies or negative contrasts: the effect of media body ideals on restrained eaters' mood, weight satisfaction, and food intake.

PubMed

Boyce, Jessica A; Kuijer, Roeline G; Gleaves, David H

2013-09-01

Although viewing media body ideals promotes body dissatisfaction and problematic eating among women (e.g., extreme restraint/overeating), some argue that women only report such negative effects because they think that they are meant to (i.e., demand characteristics). Because restrained eaters are trying to lose weight, they might be vulnerable to such media exposure. However, because of demand characteristics, evidence is mixed. Therefore, we minimized demand characteristics and explored whether media body ideals would trigger restrained eaters to report negative (negative mood, weight dissatisfaction) or positive (positive mood, weight satisfaction) effects. We also hypothesized that this change (negative or positive) would encourage food intake. Restrained and unrestrained eaters (n=107) memorized media or control images. Restrained eaters exposed to media images reported decreased weight satisfaction and increased negative mood, but their food intake was not significantly affected. Perhaps paying advertent attention to the images caused goal-related negative affect, which triggered restraint. Copyright © 2013 Elsevier Ltd. All rights reserved.

Responsiveness to healthy advertisements in adults: An experiment assessing beyond brand snack selection and the impact of restrained eating.

PubMed

Dovey, Terence M; Torab, Tina; Yen, Dorothy; Boyland, E J; Halford, Jason C G

2017-05-01

The objective of this study was to explore the impact of different advertising messages on adults' snack choice. Eighty participants (18-24 years old) were offered the choice between two snack packs following exposure to one of three advertising conditions. The snack packs contained either healthy or high fat, sugar or salt (HFSS) foods. Participants were exposed to commercials containing either non-food products, healthy food products or HFSS food products and their subsequent choice of snack pack was recorded. The Dutch Eating Behaviour Questionnaire (DEBQ) was used to assess the impact of external, restrained and emotional eating behaviour on snack pack selection following exposure to advertisements. The majority of unrestrained participants preferentially choose the HFSS snack pack irrespective of advertisement condition. In contrast, high restrained individuals exposed to the healthy eating advertisement condition preferentially selected the healthy snack pack while those in other advertisement conditions refused to take either snack pack. The healthy eating message, when distributed through mass media, resonated with restrained eaters only. Exposure to healthy food adverts provoked restrained eaters into choosing a snack pack; while exposure to other messages results in restrained eaters refusing to take any foods. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Social exclusion intensifies anxiety-like behavior in adolescent rats.

PubMed

Lee, Hyunchan; Noh, Jihyun

2015-05-01

Social connection reduces the physiological reactivity to stressors, while social exclusion causes emotional distress. Stressful experiences in rats result in the facilitation of aversive memory and induction of anxiety. To determine the effect of social interaction, such as social connection, social exclusion and equality or inequality, on emotional change in adolescent distressed rats, the emotional alteration induced by restraint stress in individual rats following exposure to various social interaction circumstances was examined. Rats were assigned to one of the following groups: all freely moving rats, all rats restrained, rats restrained in the presence of freely moving rats and freely moving rats with a restrained rat. No significant difference in fear-memory and sucrose consumption between all groups was found. Change in body weight significantly increased in freely moving rats with a restrained rat, suggesting that those rats seems to share the stressful experience of the restrained rat. Interestingly, examination of the anxiety-like behavior revealed only rats restrained in the presence of freely moving rats to have a significant increase, suggesting that emotional distress intensifies in positions of social exclusion. These results demonstrate that unequally excluded social interaction circumstances could cause the amplification of distressed status and anxiety-related emotional alteration. Copyright © 2015 Elsevier B.V. All rights reserved.

The effect of unilateral arm swing motion on lower extremity running mechanics associated with injury risk.

PubMed

Agresta, Cristine; Ward, Christian R; Wright, W Geoffrey; Tucker, Carole A

2018-06-01

Many field sports involve equipment that restricts one or both arms from moving while running. Arm swing during running has been examined from a biomechanical and physiologic perspective but not from an injury perspective. Moreover, only bilateral arm swing suppression has been studied with respect to running. The purpose of this study was to determine the influence of running with one arm restrained on lower extremity mechanics associated with running or sport-related injury. Fifteen healthy participants ran at a self-selected speed with typical arm swing, with one arm restrained and with both arms restrained. Lower extremity kinematics and spatiotemporal measures were analysed for all arm swing conditions. Running with one arm restrained resulted in increased frontal plane knee and hip angles, decreased foot strike angle, and decreased centre of mass vertical displacement compared to typical arm swing or bilateral arm swing restriction. Stride length was decreased and step frequency increased when running with one or both arms restrained. Unilateral arm swing restriction induces changes in lower extremity kinematics that are not similar to running with bilateral arm swing restriction or typical arm swing motion. Running with one arm restrained increases frontal plane mechanics associated with risk of knee injury.

Make up your mind about food: A healthy mindset attenuates attention for high-calorie food in restrained eaters.

PubMed

Werthmann, Jessica; Jansen, Anita; Roefs, Anne

2016-10-01

Attention bias for food could be a cognitive pathway to overeating in obesity and restrained eating. Yet, empirical evidence for individual differences (e.g., in restrained eating and body mass index) in attention bias for food is mixed. We tested experimentally if temporarily induced health versus palatability mindsets influenced attention bias for food, and whether restrained eating moderated this relation. After manipulating mindset (health vs. palatability) experimentally, food-related attention bias was measured by eye-movements (EM) and response latencies (RL) during a visual probe task depicting high-calorie food and non-food. Restrained eating was assessed afterwards. A significant interaction of mindset and restrained eating on RL bias emerged, β = 0.36, t(58) = 2.05, p = 0.045: A health mindset - as compared to a palatability mindset - attenuated attention bias for high-caloric food only in participants with higher eating restraint. No effects were observed on EM biases. The current results demonstrate that state differences in health versus palatability mindsets can cause attenuated attention bias for high-calorie food cues in participants with higher eating restraint. Our findings add to emerging evidence that state differences in mindsets can bias attention for food, above the influence of trait differences. Copyright © 2016. Published by Elsevier Ltd.

SEX DIFFERENCES IN THE ASSOCIATION BETWEEN DIETARY RESTRAINT, INSULIN RESISTANCE AND OBESITY

PubMed Central

Jastreboff, Ania M.; Gaiser, Edward C.; Gu, Peihua; Sinha, Rajita

2014-01-01

Background & Aims Restrained food consumption may alter metabolic function and contribute to eventual weight gain; however, sex differences in these relationships have not been assessed. The objective of this study was to examine the relationship between restrained eating and insulin resistance and the influence of body mass index and sex on this relationship in a large community sample of both men and women. We hypothesized that restrained eating would be related to insulin resistance and this relationship would be influenced by sex and body mass index. Methods In this cross-sectional, observational study, we studied 487 individuals from the community (men N=222, women N=265), who ranged from lean (body mass index 18.5–24.9kg/m2, N=173), overweight (body mass index 25–29.9kg/m2, N=159) and obese (body mass index >30kg/m2, N=155) weight categories. We assessed restrained eating using the Dutch Eating Behavior Questionnaire and obtained fasting morning plasma insulin and glucose on all subjects. Results In men, but not in women, restrained eating was related to homeostatic model assessment of insulin resistance (HOMA-IR) (p<0.0001). Furthermore, homeostatic model assessment of insulin resistance levels were significantly higher in men who were high-versus low-restrained eaters (p=0.0006). Conclusions This study is the first to report sex differences with regard to the relationship between restrained eating and insulin resistance. Our results suggest that high restraint eating is associated with insulin resistance in men but not in women. PMID:24854820

Membrane-Active Epithelial Keratin 6A Fragments (KAMPs) Are Unique Human Antimicrobial Peptides with a Non-αβ Structure

PubMed Central

Lee, Judy T. Y.; Wang, Guangshun; Tam, Yu Tong; Tam, Connie

2016-01-01

Antibiotic resistance is a pressing global health problem that threatens millions of lives each year. Natural antimicrobial peptides and their synthetic derivatives, including peptoids and peptidomimetics, are promising candidates as novel antibiotics. Recently, the C-terminal glycine-rich fragments of human epithelial keratin 6A were found to have bactericidal and cytoprotective activities. Here, we used an improved 2-dimensional NMR method coupled with a new protocol for structural refinement by low temperature simulated annealing to characterize the solution structure of these kerain-derived antimicrobial peptides (KAMPs). Two specific KAMPs in complex with membrane mimicking sodium dodecyl sulfate (SDS) micelles displayed amphipathic conformations with only local bends and turns, and a central 10-residue glycine-rich hydrophobic strip that is central to bactericidal activity. To our knowledge, this is the first report of non-αβ structure for human antimicrobial peptides. Direct observation of Staphylococcus aureus and Pseudomonas aeruginosa by scanning and transmission electron microscopy showed that KAMPs deformed bacterial cell envelopes and induced pore formation. Notably, in competitive binding experiments, KAMPs demonstrated binding affinities to LPS and LTA that did not correlate with their bactericidal activities, suggesting peptide-LPS and peptide-LTA interactions are less important in their mechanisms of action. Moreover, immunoprecipitation of KAMPs-bacterial factor complexes indicated that membrane surface lipoprotein SlyB and intracellular machineries NQR sodium pump and ribosomes are potential molecular targets for the peptides. Results of this study improve our understanding of the bactericidal function of epithelial cytokeratin fragments, and highlight an unexplored class of human antimicrobial peptides, which may serve as non-αβ peptide scaffolds for the design of novel peptide-based antibiotics. PMID:27891122

Investigating the effect of a single glycine to alanine substitution on interactions of antimicrobial peptide latarcin 2a with a lipid membrane.

PubMed

Idiong, Grace; Won, Amy; Ruscito, Annamaria; Leung, Bonnie O; Hitchcock, Adam P; Ianoul, Anatoli

2011-09-01

Latarcins are linear, α-helical antimicrobial peptides purified from the venom of the Central Asian spider Lachesana tarabaevi, with lytic activity against Gram-positive and Gram-negative bacteria, erythrocytes, and yeast at micromolar concentrations. In this work, we investigated the role of the hinge in latarcin 2a (ltc2a, GLFGKLIKKFGRKAISYAVKKARGKH-COOH), which adopts a helix-hinge-helix conformation in membrane-mimicking environments, on peptide-membrane interactions and its potential effect on the selective toxicity of the peptide. A modified latarcin 2a, ltc2aG11A, obtained by replacing the glycine at position 11 with alanine (ltc2aG11A, GLFGKLIKKFARKAISYAVKKARGKH-COOH), adopts a more rigid structure due to the reduced conformational flexibility. Langmuir monolayer measurements combined with atomic force microscopy and X-ray photoemission electron microscopy (X-PEEM) indicate that both peptides bind and insert preferentially into anionic compared with zwitterionic phospholipid monolayers. Modified ltc2aG11A was found to be more disruptive of supported phospholipid bilayer modeling mammalian cell membrane. However, no considerable difference in lytic activity of the two peptides toward bacterial membrane was found. Overall the data indicate that decrease in the flexibility of ltc2a induced by the modification in the hinge region is likely to increase the peptide's nonspecific interactions with zwitterionic cell membranes and potentially increase its toxicity against eukaryotic cells.

Designed β-Boomerang Antiendotoxic and Antimicrobial Peptides

PubMed Central

Bhunia, Anirban; Mohanram, Harini; Domadia, Prerna N.; Torres, Jaume; Bhattacharjya, Surajit

2009-01-01

Lipopolysaccharide (LPS), an integral part of the outer membrane of Gram-negative bacteria, is involved in a variety of biological processes including inflammation, septic shock, and resistance to host-defense molecules. LPS also provides an environment for folding of outer membrane proteins. In this work, we describe the structure-activity correlation of a series of 12-residue peptides in LPS. NMR structures of the peptides derived in complex with LPS reveal boomerang-like β-strand conformations that are stabilized by intimate packing between the two aromatic residues located at the 4 and 9 positions. This structural feature renders these peptides with a high ability to neutralize endotoxicity, >80% at 10 nm concentration, of LPS. Replacements of these aromatic residues either with Ala or with Leu destabilizes the boomerang structure with the concomitant loss of antiendotoxic and antimicrobial activities. Furthermore, the aromatic packing stabilizing the β-boomerang structure in LPS is found to be maintained even in a truncated octapeptide, defining a structured LPS binding motif. The mode of action of the active designed peptides correlates well with their ability to perturb LPS micelle structures. Fourier transform infrared spectroscopy studies of the peptides delineate β-type conformations and immobilization of phosphate head groups of LPS. Trp fluorescence studies demonstrated selective interactions with LPS and the depth of insertion into the LPS bilayer. Our results demonstrate the requirement of LPS-specific structures of peptides for endotoxin neutralizations. In addition, we propose that structures of these peptides may be employed to design proteins for the outer membrane. PMID:19520860

Development of a new family of conformationally restricted peptides as potent nucleators of beta-turns. Design, synthesis, structure, and biological evaluation of a beta-lactam peptide analogue of melanostatin.

PubMed

Palomo, Claudio; Aizpurua, Jesus M; Benito, Ana; Miranda, José Ignacio; Fratila, Raluca M; Matute, Carlos; Domercq, Maria; Gago, Federico; Martin-Santamaria, Sonsoles; Linden, Anthony

2003-12-31

Novel enantiopure (i)-(beta-lactam)-(Gly)-(i+3) peptide models, defined by the presence of a central alpha-alkyl-alpha-amino-beta-lactam ring placed as the (i+1) residue, have been synthesized in a totally stereocontrolled way by alpha-alkylation of suitable N-[bis(trimethylsilyl)methyl]-beta-lactams. The structural properties of these beta-lactam pseudopeptides have been studied by X-ray crystallography, Molecular Dynamics simulation, and NOESY-restrained NMR simulated annealing techniques, showing a strong tendency to form stable type II or type II' beta-turns either in the solid state or in highly coordinating DMSO solutions. Tetrapeptide models containing syn- or anti-alpha,beta-dialkyl-alpha-amino-beta-lactam rings have also been synthesized and their conformations analyzed, revealing that alpha-alkyl substitution is essential for beta-turn stabilization. A beta-lactam analogue of melanostatin (PLG amide) has also been prepared, characterized as a type-II beta-turn in DMSO-d6 solution, and tested by competitive binding assay as a dopaminergic D2 modulator in rat neuron cultured cells, displaying moderate agonist activity in the micromolar concentration range. On the basis of these results, a novel peptidomimetic design concept, based on the separation of constraint and recognition elements, is proposed.

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.

PubMed

Das, Pronay; Babbar, Palak; Malhotra, Nipun; Sharma, Manmohan; Jachak, Gorakhnath R; Gonnade, Rajesh G; Shanmugam, Dhanasekaran; Harlos, Karl; Yogavel, Manickam; Sharma, Amit; Reddy, D Srinivasa

2018-05-21

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332. Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.

Synthesis, stereochemistry, crystal structure, docking study and biological evaluation of some new N-benzylpiperidin-4-ones

NASA Astrophysics Data System (ADS)

Ponnuswamy, S.; Kayalvizhi, R.; Sethuvasan, S.; Sugumar, P.; Ponnuswamy, M. N.

2018-03-01

Two new N-benzylpiperidin-4-ones 3 and 4 have been synthesized and characterized using IR, 1D and 2D NMR spectral studies. The NMR data of N-benzylpiperidin-4-ones 3 and 4 reveal that the compounds prefer to exist in chair conformation with equatorial orientation of the bulky substituents and the single crystal X-ray structure of compound 4 also reveals a similar conformation in solid state. Furthermore, the antimicrobial studies carried out for the compounds 1-4 indicate moderate activities with the selected strains. The antioxidant potency of 3 is superior whereas 4 exhibits moderate activity when compared to that of standard drug. The results of molecular docking studies with the AmpC β-lactamase enzyme indicate that compound 3 shows better docking score and binding energy than the co-crystal ligand.

Three-dimensional solution structure of lactoferricin B, an antimicrobial peptide derived from bovine lactoferrin.

PubMed

Hwang, P M; Zhou, N; Shan, X; Arrowsmith, C H; Vogel, H J

1998-03-24

The solution structure of bovine lactoferricin (LfcinB) has been determined using 2D 1H NMR spectroscopy. LfcinB is a 25-residue antimicrobial peptide released by pepsin cleavage of lactoferrin, an 80 kDa iron-binding glycoprotein with many immunologically important functions. The NMR structure of LfcinB reveals a somewhat distorted antiparallel beta-sheet. This contrasts with the X-ray structure of bovine lactoferrin, in which residues 1-13 (of LfcinB) form an alpha-helix. Hence, this region of lactoferricin B appears able to adopt a helical or sheetlike conformation, similar to what has been proposed for the amyloidogenic prion proteins and Alzheimer's beta-peptides. LfcinB has an extended hydrophobic surface comprised of residues Phe1, Cys3, Trp6, Trp8, Pro16, Ile18, and Cys20. The side chains of these residues are well-defined in the NMR structure. Many hydrophilic and positively charged residues surround the hydrophobic surface, giving LfcinB an amphipathic character. LfcinB bears numerous similarities to a vast number of cationic peptides which exert their antimicrobial activities through membrane disruption. The structures of many of these peptides have been well characterized, and models of their membrane-permeabilizing mechanisms have been proposed. The NMR solution structure of LfcinB may be more relevant to membrane interaction than that suggested by the X-ray structure of intact lactoferrin. Based on the solution structure, it is now possible to propose potential mechanisms for the antimicrobial action of LfcinB.

Latching device

NASA Technical Reports Server (NTRS)

Ulrich, G. W. (Inventor)

1975-01-01

A latching device is suited for use in establishing a substantially motionless connection between a stationary receiver and a movable latching mechanism. The latching mechanism includes a pivotally supported restraining hook continuously urged into a capturing relationship with the receiver, characterized by a spring-biased pawl having a plurality of aligned teeth. The teeth are seated in the surface of the throat of the hook and positionable into restraining engagement with a rigid restraining shoulder projected from the receiver.

Structure-activity analysis and biological studies of chensinin-1b analogues.

PubMed

Dong, Weibing; Dong, Zhe; Mao, Xiaoman; Sun, Yue; Li, Fei; Shang, Dejing

2016-06-01

Chensinin-1b shows a potent and broad-spectrum bactericidal activity and no hemolytic activity and thus is a potential therapeutic agent against bacterial infection. The NMR structure of chensinin-1b consists of a partially α-helical region (residues 8-14) in a membrane-mimic environment that is distinct from other common antimicrobial peptides. However, further analysis of the structural features of chensinin-1b is required to better understand its bactericidal activity. In this study, a series of N- and C-terminally truncated or amino acid-substituted chensinin-1b analogues were synthesized. Next, the bactericidal activity and bacterial membrane effects of the analogues were investigated. The results indicated that the N-terminal residues play a more significant role than the C-terminal residues in the antimicrobial activity of chensinin-1b. The removal of five amino acids from the C-terminus of chensinin-1b did not affect its biological properties, but helix disruption significantly decreased bactericidal activity. The substitution of positively charged residues increased the helicity and antimicrobial activity of the peptide. We also identified a novel analogue [R(4),R(10)]C1b(3-13) that exhibited similar bactericidal properties with its parent peptide chensinin-1b. Electrostatic interactions between the selected analogues and lipopolysaccharides or cells were detected using isothermal titration calorimetry or zeta potential. The thermodynamic parameters ΔH and ΔS for [R(4),R(10)]C1b(3-13) were -20.48kcalmol(-1) and -0.0408kcalmol(-1)deg(-1), respectively. Chensinin-1b yielded similar results of -26.36kcalmol(-1) and -0.0559kcalmol(-1)deg(-1) for ΔH and ΔS, respectively. These results are consistence with their antimicrobial activities. Lastly, membrane depolarization studies showed that selected analogues exerted bactericidal activity by damaging the cytoplasmic membrane. Antimicrobial peptide chensinin-1b is a candidate for the development of new drugs and a template for the design of synthetic analogues. It mainly exhibits a random coil conformation in membrane environment, and in this manuscript, we characterized the structure of chensinin-1b using NMR spectroscopy, its structure is different than the structures of magainin 2, which has an α-helical conformation and indolicidin, which has a random coil structure. The structural features of chensinin-1b that are required for its potent bactericidal activity were also elucidated. Based on these data, we can fully understand the structure-activity relationship of such peptide and identified a novel analogue with properties that make it an attractive topic for future therapeutic research. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Direct Investigation of Slow Correlated Dynamics in Proteins via Dipolar Interactions

PubMed Central

Fenwick, R. Bryn; Schwieters, Charles D.; Vögeli, Beat

2016-01-01

The synchronization of native state motions as they transition between microstates influences catalysis kinetics, mediates allosteric interactions and reduces the conformational entropy of proteins. However, it has proven difficult to describe native microstates because they are usually minimally frustrated and may interconvert on the μs-ms time scale. Direct observation of concerted equilibrium fluctuations would therefore be an important tool for describing protein native states. Here we propose a strategy that relates NMR cross-correlated relaxation (CCR) rates between dipolar interactions to residual dipolar couplings (RDCs) of individual consecutive HN–N and Hα–Cα bonds, which act as a proxy for the peptide planes and the side chains respectively. Using Xplor-NIH ensemble structure calculations restrained with the RDC and CCR data we observe collective motions on time scales slower than nanoseconds in the backbone for GB3. To directly access the correlations from CCR we develop a structure-free data analysis. The resulting dynamic correlation map is consistent with the ensemble-restrained simulations and reveals a complex network. In general we find that the bond motions are on average slightly correlated, and that the local environment dominates many observations. Despite this, some patterns are typical over entire secondary structure elements. In the β-sheet, nearly all bonds are weakly correlated and there is an approximately binary alternation in correlation intensity corresponding to the solvent exposure/shielding alternation of the side chains. For α-helices there is also a weak correlation in the HN-N bonds and the degree of correlation involving Hα-Cα bonds is directly affected by side-chain fluctuations, while loops show complex and non-uniform behavior. PMID:27331619

Ensemble MD simulations restrained via crystallographic data: Accurate structure leads to accurate dynamics

PubMed Central

Xue, Yi; Skrynnikov, Nikolai R

2014-01-01

Currently, the best existing molecular dynamics (MD) force fields cannot accurately reproduce the global free-energy minimum which realizes the experimental protein structure. As a result, long MD trajectories tend to drift away from the starting coordinates (e.g., crystallographic structures). To address this problem, we have devised a new simulation strategy aimed at protein crystals. An MD simulation of protein crystal is essentially an ensemble simulation involving multiple protein molecules in a crystal unit cell (or a block of unit cells). To ensure that average protein coordinates remain correct during the simulation, we introduced crystallography-based restraints into the MD protocol. Because these restraints are aimed at the ensemble-average structure, they have only minimal impact on conformational dynamics of the individual protein molecules. So long as the average structure remains reasonable, the proteins move in a native-like fashion as dictated by the original force field. To validate this approach, we have used the data from solid-state NMR spectroscopy, which is the orthogonal experimental technique uniquely sensitive to protein local dynamics. The new method has been tested on the well-established model protein, ubiquitin. The ensemble-restrained MD simulations produced lower crystallographic R factors than conventional simulations; they also led to more accurate predictions for crystallographic temperature factors, solid-state chemical shifts, and backbone order parameters. The predictions for 15N R1 relaxation rates are at least as accurate as those obtained from conventional simulations. Taken together, these results suggest that the presented trajectories may be among the most realistic protein MD simulations ever reported. In this context, the ensemble restraints based on high-resolution crystallographic data can be viewed as protein-specific empirical corrections to the standard force fields. PMID:24452989

Method for hot press forming articles

DOEpatents

Baker, Robert R.; Hartsock, Dale L.

1982-01-01

This disclosure relates to an improved method for achieving the best bond strength and for minimizing distortion and cracking of hot pressed articles. In particular, in a method for hot press forming both an outer facing circumferential surface of and an inner portion of a hub, and of bonding that so-formed outer facing circumferential surface to an inner facing circumferential surface of a pre-formed ring thereby to form an article, the following improvement is made. Normally, in this method, the outside ring is restrained by a restraining sleeve of ring-shaped cross-section having an inside diameter. A die member, used to hot press form the hub, is so-formed as to have an outside diameter sized to engage the inside diameter of the restraining sleeve in a manner permitting relative movement therebetween. The improved method is one in which several pairs of matched restraining sleeve and die member are formed with each matched pair having a predetermined diameter. The predetermined diameter of each matched pair is different from another matched pair by stepped increments. The largest inside diameter of a restraining sleeve is equal to the diameter of the outer facing circumferential surface of the hub. Each pair of the matched restraining sleeve and die member is used to form an article in which an inside hub is bonded to an outside ring. The several samples so-formed are evaluated to determine which sample has the best bond formed between the hub and the ring with the least or no cracking or distortion in the ring portion of the article. Thereafter, the matched restraining sleeve and die member which form the article having the best bonding characteristics and least distortion cracking is then used for repeated formations of articles.

Automatic Approach Tendencies toward High and Low Caloric Food in Restrained Eaters: Influence of Task-Relevance and Mood

PubMed Central

Neimeijer, Renate A. M.; Roefs, Anne; Ostafin, Brian D.; de Jong, Peter J.

2017-01-01

Objective: Although restrained eaters are motivated to control their weight by dieting, they are often unsuccessful in these attempts. Dual process models emphasize the importance of differentiating between controlled and automatic tendencies to approach food. This study investigated the hypothesis that heightened automatic approach tendencies in restrained eaters would be especially prominent in contexts where food is irrelevant for their current tasks. Additionally, we examined the influence of mood on the automatic tendency to approach food as a function of dietary restraint. Methods: An Affective Simon Task-manikin was administered to measure automatic approach tendencies where food is task-irrelevant, and a Stimulus Response Compatibility task (SRC) to measure automatic approach in contexts where food is task-relevant, in 92 female participants varying in dietary restraint. Prior to the task, sad, stressed, neutral, or positive mood was induced. Food intake was measured during a bogus taste task after the computer tasks. Results: Consistent with their diet goals, participants with a strong tendency to restrain their food intake showed a relatively weak approach bias toward food when food was task-relevant (SRC) and this effect was independent of mood. Restrained eaters showed a relatively strong approach bias toward food when food was task-irrelevant in the positive condition and a relatively weak approach in the sad mood. Conclusion: The weak approach bias in contexts where food is task-relevant may help high-restrained eaters to comply with their diet goal. However, the strong approach bias in contexts where food is task-irrelevant and when being in a positive mood may interfere with restrained eaters’ goal of restricting food-intake. PMID:28443045

Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

PubMed

Kokel, Anne; Torok, Marianna

2018-01-17

Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Although further research is needed taking into account both environmental and human health consequences of novel AMPs several of these compounds are promising drug candidates for use in sustainable medicine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Power-to-load balancing for asymmetric heave wave energy converters with nonideal power take-off

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

Tom, Nathan M.; Madhi, Farshad; Yeung, Ronald W.

The aim of this study is to maximize the power-to-load ratio for asymmetric heave wave energy converters. Linear hydrodynamic theory was used to calculate bounds of the expected time-averaged power (TAP) and corresponding surge-restraining force, pitch-restraining torque, and power take-off (PTO) control force with the assumption of sinusoidal displacement. This paper formulates an optimal control problem to handle an objective function with competing terms in an attempt to maximize power capture while minimizing structural and actuator loads in regular and irregular waves. Penalty weights are placed on the surge-restraining force, pitch-restraining torque, and PTO actuation force, thereby allowing the controlmore » focus to concentrate on either power absorption or load mitigation. The penalty weights are used to control peak structural and actuator loads that were found to curb the additional losses in power absorption associated with a nonideal PTO. Thus, in achieving these goals, a per-unit gain in TAP would not lead to a greater per-unit demand in structural strength, hence yielding a favorable benefit-to-cost ratio. Demonstrative results for 'The Berkeley Wedge' in the form of output TAP, reactive TAP needed to drive WEC motion, and the amplitudes of the surge-restraining force, pitch-restraining torque, and PTO control force are shown.« less

Restraint use in acute and extended mental health services for older persons.

PubMed

Gerace, Adam; Mosel, Krista; Oster, Candice; Muir-Cochrane, Eimear

2013-12-01

Restraint of older persons in inpatient and residential care is used to control aggression, and prevent falls and other adverse outcomes. Initiatives to reduce these practices are being implemented worldwide. However, there has been little examination of restraint practice in psychiatric services for older persons. This paper reports a retrospective comparative analysis of restraint use in three acute and two extended care psychiatric inpatient wards in Australia. The analysis involved examination of restraint incidents and comparison of restrained and non-restrained patients. There was significant variation in restraint use between wards. On one acute ward, 12.74% of patients were restrained, although restraint use declined during the data collection period. Patients with dementia were restrained at higher rates than patients with other diagnoses, and restrained patients stayed in hospital for a longer duration. Restraint occurred early in admission, and few differences emerged between those restrained once or multiple times. Mechanical restraint was more prevalent than physical restraint, with restraint predominantly used to manage aggression and falls. Findings provide new data on restraint in older persons' psychiatric services. Greater conceptual understandings of behaviours associated with dementia and the unique needs of patients with these disorders may assist in reducing restraint use in these settings. © 2012 The Authors; International Journal of Mental Health Nursing © 2012 Australian College of Mental Health Nurses Inc.

Power-to-load balancing for asymmetric heave wave energy converters with nonideal power take-off

DOE PAGES

Tom, Nathan M.; Madhi, Farshad; Yeung, Ronald W.

2017-12-11

The aim of this study is to maximize the power-to-load ratio for asymmetric heave wave energy converters. Linear hydrodynamic theory was used to calculate bounds of the expected time-averaged power (TAP) and corresponding surge-restraining force, pitch-restraining torque, and power take-off (PTO) control force with the assumption of sinusoidal displacement. This paper formulates an optimal control problem to handle an objective function with competing terms in an attempt to maximize power capture while minimizing structural and actuator loads in regular and irregular waves. Penalty weights are placed on the surge-restraining force, pitch-restraining torque, and PTO actuation force, thereby allowing the controlmore » focus to concentrate on either power absorption or load mitigation. The penalty weights are used to control peak structural and actuator loads that were found to curb the additional losses in power absorption associated with a nonideal PTO. Thus, in achieving these goals, a per-unit gain in TAP would not lead to a greater per-unit demand in structural strength, hence yielding a favorable benefit-to-cost ratio. Demonstrative results for 'The Berkeley Wedge' in the form of output TAP, reactive TAP needed to drive WEC motion, and the amplitudes of the surge-restraining force, pitch-restraining torque, and PTO control force are shown.« less

Social factors modulate restraint stress induced hyperthermia in mice.

PubMed

Watanabe, Shigeru

2015-10-22

Stress-induced hyperthermia (SIH) was examined in three different social conditions in mice by thermographic measurement of the body surface temperature. Placing animals in cylindrical holders induced restraint stress. I examined the effect of the social factors in SIH using the thermograph (body surface temperature). Mice restrained in the holders alone showed SIH. Mice restrained in the holders at the same time as other similarly restrained cage mates (social equality condition) showed less hyperthermia. Interestingly, restrained mice with free moving cage mates (social inequality condition) showed the highest hyperthermia. These results are consistent with a previous experiment measuring the memory-enhancing effects of stress and the stress-induced elevation of corticosterone, and suggest that social inequality enhances stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Biological evaluation of some new N-(2,6-dimethoxypyrimidinyl) thioureido benzenesulfonamide derivatives as potential antimicrobial and anticancer agents.

PubMed

Ghorab, Mostafa M; Alsaid, Mansour S; El-Gaby, Mohamed S A; Safwat, Nesreen A; Elaasser, Mahmoud M; Soliman, Aiten M

2016-11-29

A series of novel heterocyclic thioureas 3a-u containing sulfonamide moiety have been synthesized by the condensation of isothiocyanatobenzenesulfonamide 2 with a variety of heterocyclic amines. The newly synthesized heterocyclic thioureas were investigated for their antimicrobial and anticancer activity. The in vitro antibacterial and antifungal activity were done using well diffusion method. Interestingly, compounds 3j and 3m, showed similar or better activity compared with the reference drug against the tested microorganisms. Although, 3j was less active among its analogues to inhibit the breast carcinoma cells, it exhibit strong broad spectrum antimicrobial activities. However, The results of the cytotoxic activity revealed that compound 3p was the most active against the breast carcinoma cell line (MCF-7) giving promising IC 50 value of 1.72 μg/mL, compared with reference drug (5-flourouracil) with IC 50 value of 4.8 μg/mL. The most potent compounds in cytotoxic activity 3b and 3p were further docked inside the active site of CAIX and were found to exhibit a proper binding with the active site amino acids according to their bond lengths, angles and conformational energy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Physical restraint produces rapid acquisition of the pigeon's key peck

PubMed Central

Locurto, C. M.; Travers, Tania; Terrace, H. S.; Gibbon, John

1980-01-01

The acquisition and maintenance of autoshaped key pecking in pigeons was studied as a function of intertrial interval. At each of six intervals, which ranged from 12 seconds to 384 seconds, four pigeons were physically restrained during training while four other pigeons were not restrained. Restrained subjects acquired key pecking faster and with less intragroup variability at each interval. The effects of restraint were specific to acquisition and were not evident in maintained responding after five postacquisition sessions. PMID:16812175

Molecular dynamics and mutational analysis of the catalytic and translocation cycle of RNA polymerase

PubMed Central

2012-01-01

Background During elongation, multi-subunit RNA polymerases (RNAPs) cycle between phosphodiester bond formation and nucleic acid translocation. In the conformation associated with catalysis, the mobile “trigger loop” of the catalytic subunit closes on the nucleoside triphosphate (NTP) substrate. Closing of the trigger loop is expected to exclude water from the active site, and dehydration may contribute to catalysis and fidelity. In the absence of a NTP substrate in the active site, the trigger loop opens, which may enable translocation. Another notable structural element of the RNAP catalytic center is the “bridge helix” that separates the active site from downstream DNA. The bridge helix may participate in translocation by bending against the RNA/DNA hybrid to induce RNAP forward movement and to vacate the active site for the next NTP loading. The transition between catalytic and translocation conformations of RNAP is not evident from static crystallographic snapshots in which macromolecular motions may be restrained by crystal packing. Results All atom molecular dynamics simulations of Thermus thermophilus (Tt) RNAP reveal flexible hinges, located within the two helices at the base of the trigger loop, and two glycine hinges clustered near the N-terminal end of the bridge helix. As simulation progresses, these hinges adopt distinct conformations in the closed and open trigger loop structures. A number of residues (described as “switch” residues) trade atomic contacts (ion pairs or hydrogen bonds) in response to changes in hinge orientation. In vivo phenotypes and in vitro activities rendered by mutations in the hinge and switch residues in Saccharomyces cerevisiae (Sc) RNAP II support the importance of conformational changes predicted from simulations in catalysis and translocation. During simulation, the elongation complex with an open trigger loop spontaneously translocates forward relative to the elongation complex with a closed trigger loop. Conclusions Switching between catalytic and translocating RNAP forms involves closing and opening of the trigger loop and long-range conformational changes in the atomic contacts of amino acid side chains, some located at a considerable distance from the trigger loop and active site. Trigger loop closing appears to support chemistry and the fidelity of RNA synthesis. Trigger loop opening and limited bridge helix bending appears to promote forward nucleic acid translocation. PMID:22676913

Ligand Entry and Exit Pathways in the β2-adrenergic Receptor

PubMed Central

Wang, Ting; Duan, Yong

2009-01-01

The recently determined crystal structure of the human β2-adrenergic (β2AR) G-protein coupled receptor provides an excellent structural basis for exploring β2AR -ligand binding and dissociation process. Based on this crystal structure, we simulated ligand exit from the β2AR receptor by applying the random acceleration molecular dynamics (RAMD) simulation method. The simulation results showed that the extracellular opening on the receptor surface was the most frequently observed egress point (referred to as pathway A) and a few other pathways through inter-helical clefts were also observed with significantly lower frequencies. In the egress trajectories along pathway A, the D192-K305 salt bridge between the extracellular loop 2 (ECL2) and the apex of the transmembrane helix 7 (TM7) was exclusively broken. The spatial occupancy maps of the ligand computed from the 100 RAMD simulation trajectories indicated that the receptor-ligand interactions that restrained the ligand in the binding pocket were the major resistance encountered by the ligand during exit and no second barrier was notable. We next performed RAMD simulations by using a putative ligand-free conformation of the receptor as input structure. This conformation was obtained in a standard MD simulation in the absence of the ligand and it differed from the ligand-bound conformation in a hydrophobic patch bridging ECL2 and TM7 due to the rotation of F193 of ECL2. Results from the RAMD simulations with this putative ligand-free conformation suggest that the cleft formed by the hydrophobic bridge, TM2, TM3 and TM7 on the extracellular surface likely serves as a more specific ligand-entry site and the ECL2-TM7 hydrophobic junction can be partially interrupted upon the entry of ligand that pushes F193 to rotate, resulting in a conformation as observed in the ligand-bound crystal structure. These results may help design β2AR-targeting drugs with improved efficacy as well as understand the receptor subtype-selectivity of ligand binding in the β family of the adrenergic receptors that share almost identical ligand-binding pockets but show notable amino acid sequence divergence in the putative ligand-entry site, including ECL2 and the extracellular end of TM7. PMID:19665031

Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes

PubMed Central

2017-01-01

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that display a wide variety of biological activities, from antimicrobial to antiallodynic. Lanthipeptides that display antimicrobial activity are called lantibiotics. The post-translational modification reactions of lanthipeptides include dehydration of Ser and Thr residues to dehydroalanine and dehydrobutyrine, a transformation that is carried out in three unique ways in different classes of lanthipeptides. In a cyclization process, Cys residues then attack the dehydrated residues to generate the lanthionine and methyllanthionine thioether cross-linked amino acids from which lanthipeptides derive their name. The resulting polycyclic peptides have constrained conformations that confer their biological activities. After installation of the characteristic thioether cross-links, tailoring enzymes introduce additional post-translational modifications that are unique to each lanthipeptide and that fine-tune their activities and/or stability. This review focuses on studies published over the past decade that have provided much insight into the mechanisms of the enzymes that carry out the post-translational modifications. PMID:28135077

Fidaxomicin jams Mycobacterium tuberculosis RNA polymerase motions needed for initiation via RbpA contacts

PubMed Central

Lilic, Mirjana; Palka, Margaret; Mooney, Rachel Anne; Landick, Robert

2018-01-01

Fidaxomicin (Fdx) is an antimicrobial RNA polymerase (RNAP) inhibitor highly effective against Mycobacterium tuberculosis RNAP in vitro, but clinical use of Fdx is limited to treating Clostridium difficile intestinal infections due to poor absorption. To identify the structural determinants of Fdx binding to RNAP, we determined the 3.4 Å cryo-electron microscopy structure of a complete M. tuberculosis RNAP holoenzyme in complex with Fdx. We find that the actinobacteria general transcription factor RbpA contacts fidaxomycin, explaining its strong effect on M. tuberculosis. Additional structures define conformational states of M. tuberculosis RNAP between the free apo-holoenzyme and the promoter-engaged open complex ready for transcription. The results establish that Fdx acts like a doorstop to jam the enzyme in an open state, preventing the motions necessary to secure promoter DNA in the active site. Our results provide a structural platform to guide development of anti-tuberculosis antimicrobials based on the Fdx binding pocket. PMID:29480804

Interaction of antimicrobial peptides with bacterial polysaccharides from lung pathogens.

PubMed

Herasimenka, Yury; Benincasa, Monica; Mattiuzzo, Maura; Cescutti, Paola; Gennaro, Renato; Rizzo, Roberto

2005-07-01

The interaction of two cathelicidin antimicrobial peptides, LL-37 and SMAP-29, with three bacterial polysaccharides, respectively, produced by Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae, was investigated to identify possible mechanisms adopted by lung pathogens to escape the action of innate immunity effectors. In vitro assays indicated that the antibacterial activity of both peptides was inhibited to a variable extent by the three polysaccharides. Circular dichroism experiments showed that these induced an alpha-helical conformation in the two peptides, with the polysaccharides from K. pneumoniae and B. cepacia showing, respectively, the highest and the lowest effect. Fluorescence measurements also indicated the presence of peptide-polysaccharide interactions. A model is proposed in which the binding of peptides to the polysaccharide molecules induces, at low polysaccharide to peptide ratios, a higher order of aggregation, due to peptide-peptide interactions. Overall, these results suggest that binding of the peptides by the polysaccharides produced by lung pathogens can contribute to the impairment of peptide-based innate defenses of airway surface.

Special issue : child safety

DOT National Transportation Integrated Search

1999-10-02

Despite extensive publicity aimed at getting children restrained and riding in rear seats, observational surveys in three states show many children still ride unrestrained, improperly restrained, or in the front seats of cars equipped with passenger ...

Prediction of cyclohexane-water distribution coefficient for SAMPL5 drug-like compounds with the QMPFF3 and ARROW polarizable force fields.

PubMed

Kamath, Ganesh; Kurnikov, Igor; Fain, Boris; Leontyev, Igor; Illarionov, Alexey; Butin, Oleg; Olevanov, Michael; Pereyaslavets, Leonid

2016-11-01

We present the performance of blind predictions of water-cyclohexane distribution coefficients for 53 drug-like compounds in the SAMPL5 challenge by three methods currently in use within our group. Two of them utilize QMPFF3 and ARROW, polarizable force-fields of varying complexity, and the third uses the General Amber Force-Field (GAFF). The polarizable FF's are implemented in an in-house MD package, Arbalest. We find that when we had time to parametrize the functional groups with care (batch 0), the polarizable force-fields outperformed the non-polarizable one. Conversely, on the full set of 53 compounds, GAFF performed better than both QMPFF3 and ARROW. We also describe the torsion-restrain method we used to improve sampling of molecular conformational space and thus the overall accuracy of prediction. The SAMPL5 challenge highlighted several drawbacks of our force-fields, such as our significant systematic over-estimation of hydrophobic interactions, specifically for alkanes and aromatic rings.

Designed beta-boomerang antiendotoxic and antimicrobial peptides: structures and activities in lipopolysaccharide.

PubMed

Bhunia, Anirban; Mohanram, Harini; Domadia, Prerna N; Torres, Jaume; Bhattacharjya, Surajit

2009-08-14

Lipopolysaccharide (LPS), an integral part of the outer membrane of Gram-negative bacteria, is involved in a variety of biological processes including inflammation, septic shock, and resistance to host-defense molecules. LPS also provides an environment for folding of outer membrane proteins. In this work, we describe the structure-activity correlation of a series of 12-residue peptides in LPS. NMR structures of the peptides derived in complex with LPS reveal boomerang-like beta-strand conformations that are stabilized by intimate packing between the two aromatic residues located at the 4 and 9 positions. This structural feature renders these peptides with a high ability to neutralize endotoxicity, >80% at 10 nM concentration, of LPS. Replacements of these aromatic residues either with Ala or with Leu destabilizes the boomerang structure with the concomitant loss of antiendotoxic and antimicrobial activities. Furthermore, the aromatic packing stabilizing the beta-boomerang structure in LPS is found to be maintained even in a truncated octapeptide, defining a structured LPS binding motif. The mode of action of the active designed peptides correlates well with their ability to perturb LPS micelle structures. Fourier transform infrared spectroscopy studies of the peptides delineate beta-type conformations and immobilization of phosphate head groups of LPS. Trp fluorescence studies demonstrated selective interactions with LPS and the depth of insertion into the LPS bilayer. Our results demonstrate the requirement of LPS-specific structures of peptides for endotoxin neutralizations. In addition, we propose that structures of these peptides may be employed to design proteins for the outer membrane.

Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin.

PubMed

Ovchinnikov, Victor; Karplus, Martin

2012-07-26

The popular targeted molecular dynamics (TMD) method for generating transition paths in complex biomolecular systems is revisited. In a typical TMD transition path, the large-scale changes occur early and the small-scale changes tend to occur later. As a result, the order of events in the computed paths depends on the direction in which the simulations are performed. To identify the origin of this bias, and to propose a method in which the bias is absent, variants of TMD in the restraint formulation are introduced and applied to the complex open ↔ closed transition in the protein calmodulin. Due to the global best-fit rotation that is typically part of the TMD method, the simulated system is guided implicitly along the lowest-frequency normal modes, until the large spatial scales associated with these modes are near the target conformation. The remaining portion of the transition is described progressively by higher-frequency modes, which correspond to smaller-scale rearrangements. A straightforward modification of TMD that avoids the global best-fit rotation is the locally restrained TMD (LRTMD) method, in which the biasing potential is constructed from a number of TMD potentials, each acting on a small connected portion of the protein sequence. With a uniform distribution of these elements, transition paths that lack the length-scale bias are obtained. Trajectories generated by steered MD in dihedral angle space (DSMD), a method that avoids best-fit rotations altogether, also lack the length-scale bias. To examine the importance of the paths generated by TMD, LRTMD, and DSMD in the actual transition, we use the finite-temperature string method to compute the free energy profile associated with a transition tube around a path generated by each algorithm. The free energy barriers associated with the paths are comparable, suggesting that transitions can occur along each route with similar probabilities. This result indicates that a broad ensemble of paths needs to be calculated to obtain a full description of conformational changes in biomolecules. The breadth of the contributing ensemble suggests that energetic barriers for conformational transitions in proteins are offset by entropic contributions that arise from a large number of possible paths.

Attention bias for food is independent of restraint in healthy weight individuals-an eye tracking study.

PubMed

Werthmann, Jessica; Roefs, Anne; Nederkoorn, Chantal; Mogg, Karin; Bradley, Brendan P; Jansen, Anita

2013-08-01

Restrained eating style and weight status are highly correlated. Though both have been associated with an attentional bias for food cues, in prior research restraint and BMI were often confounded. The aim of the present study was to determine the existence and nature of an attention bias for food cues in healthy-weight female restrained and unrestrained eaters, when matching the two groups on BMI. Attention biases for food cues were measured by recordings of eye movements during a visual probe task with pictorial food versus non-food stimuli. Healthy weight high restrained (n = 24) and low restrained eaters (n = 21) were matched on BMI in an attempt to unconfound the effects of restraint and weight on attention allocation patterns. All participants showed elevated attention biases for food stimuli in comparison to neutral stimuli, independent of restraint status. These findings suggest that attention biases for food-related cues are common for healthy weight women and show that restrained eating (per se) is not related to biased processing of food stimuli, at least not in healthy weight participants. Copyright © 2013 Elsevier Ltd. All rights reserved.

The influence of individualized music on patients in physical restraints: a pilot study.

PubMed

Janelli, Linda M; Kanski, Genevieve W; Wu, Yow-Wu Bill

This pilot study explored the relationship between listening to preferred music and the behavioral responses of patients who are physically restrained. Thirty patients, ranging in age from 65 to 93, participated in one of three groups. The first group included patients who were out of restraining devices while listening to preferred music. Patients in the second group were out of restraining devices and not exposed to music. The third group comprised patients who were in restraining devices while listening to preferred music. Listening to preferred music had no significant effect on decreasing patients' negative behaviors or on increasing positive behaviors observed during the intervention phase of the study. The higher mean scores for positive behaviors and lower mean scores for negative behaviors for the first group may indicate some benefits to patients who are out of restraints and listening to preferred music.

PARTIAL RESTRAINING FORCE INTRODUCTION METHOD FOR DESIGNING CONSTRUCTION COUNTERMESURE ON ΔB METHOD

NASA Astrophysics Data System (ADS)

Nishiyama, Taku; Imanishi, Hajime; Chiba, Noriyuki; Ito, Takao

Landslide or slope failure is a three-dimensional movement phenomenon, thus a three-dimensional treatment makes it easier to understand stability. The ΔB method (simplified three-dimensional slope stability analysis method) is based on the limit equilibrium method and equals to an approximate three-dimensional slope stability analysis that extends two-dimensional cross-section stability analysis results to assess stability. This analysis can be conducted using conventional spreadsheets or two-dimensional slope stability computational software. This paper describes the concept of the partial restraining force in-troduction method for designing construction countermeasures using the distribution of the restraining force found along survey lines, which is based on the distribution of survey line safety factors derived from the above-stated analysis. This paper also presents the transverse distributive method of restraining force used for planning ground stabilizing on the basis of the example analysis.

On the statistical equivalence of restrained-ensemble simulations with the maximum entropy method

PubMed Central

Roux, Benoît; Weare, Jonathan

2013-01-01

An issue of general interest in computer simulations is to incorporate information from experiments into a structural model. An important caveat in pursuing this goal is to avoid corrupting the resulting model with spurious and arbitrary biases. While the problem of biasing thermodynamic ensembles can be formulated rigorously using the maximum entropy method introduced by Jaynes, the approach can be cumbersome in practical applications with the need to determine multiple unknown coefficients iteratively. A popular alternative strategy to incorporate the information from experiments is to rely on restrained-ensemble molecular dynamics simulations. However, the fundamental validity of this computational strategy remains in question. Here, it is demonstrated that the statistical distribution produced by restrained-ensemble simulations is formally consistent with the maximum entropy method of Jaynes. This clarifies the underlying conditions under which restrained-ensemble simulations will yield results that are consistent with the maximum entropy method. PMID:23464140

Mere exposure to palatable food cues reduces restrained eaters' physical effort to obtain healthy food.

PubMed

van Koningsbruggen, Guido M; Stroebe, Wolfgang; Aarts, Henk

2012-04-01

We examined whether exposure to cues of attractive food reduces effortful behavior toward healthy foods for restrained eaters. After manipulating food pre-exposure, we recorded handgrip force while presenting participants with pictures of healthy food objects. Because participants were led to expect that they could obtain each object (not specified beforehand) by squeezing the handgrip as forcefully as possible while the object was displayed on the screen, the recorded handgrip force constitutes a measure of spontaneous effortful behavior. Results show that restrained eaters, but not unrestrained eaters, displayed less forceful action toward healthy food objects (i.e., lower exertion of force) when pre-exposed to tempting food cues. No effects were found on palatability perceptions of the healthy foods. The results provide further insight into why restrained eaters have difficulties in maintaining a low-calorie diet in food-rich environments. Copyright © 2011 Elsevier Ltd. All rights reserved.

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

PubMed Central

Hritz, Jozef; Läppchen, Tilman

2010-01-01

The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants 3J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution. PMID:20559630

A nudge in a healthier direction: How environmental cues help restrained eaters pursue their weight-control goal.

PubMed

Stämpfli, Aline E; Stöckli, Sabrina; Brunner, Thomas A

2017-03-01

Losing weight is a goal for many people, but it is hard to pursue. However, dieting cues in the environment hold promise for improving individuals' eating behavior. For example, exposure to thin, human-like sculptures by the artist Alberto Giacometti has been found to promote healthy snack choices at a vending machine. Whether health- or weight-related processes drive such effects has not yet been determined. However, a detailed understanding of the content-related drivers of environmental cues' effects provides the first indications regarding a cue's possible use. Therefore, two laboratory studies were conducted. They examined the Giacometti sculptures' effects on unhealthy and healthy food intake (Study 1) and on the completion of weight- and health-related fragmented words (Study 2). Study 1 indicated that the sculptures are weight-related by showing that they reduced food intake independent of food healthiness. Furthermore, the "Giacometti effect" was moderated by restrained eating. Restrained eaters, who are known for their weight-control goal, ate less after having been exposed to the thin sculptures. The results of Study 2 pointed in the same direction. Restrained eaters completed more weight-related words after being exposed to the sculptures. Overall, these studies suggest that the thin sculptures are primarily weight-related cues and particularly helpful for restrained eaters. Environmental weight-control cues such as the Giacometti sculptures could act as a counterforce to our obesogenic environment and help restrained eaters pursue their weight-control goal. In this way, they could nudge food decisions in a healthier direction. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neural correlates of restrained eaters' high susceptibility to food cues: An fMRI study.

PubMed

Wang, Yu; Dong, Debo; Todd, Jackson; Du, Jie; Yang, Zhou; Lu, Hui; Chen, Hong

2016-09-19

Many studies have reported that specific susceptibility to food cues plays an important role in disordered eating behavior. However, whether restraint status modulates the neural bases of attentional bias to different types of food cues remains unknown. Thus, functional magnetic resonance imaging (fMRI) was conducted in individuals (12 restraint eaters, 12 unrestraint eaters) exposed to high/low-energy food and neutral images while performing a two-choice oddball task. The results indicated that restrained eaters responded more quickly to high-energy food images than to neutral and low-energy food images. More notably, compared with unrestrained eaters, restrained eaters showed faster reaction times, hyper-activation in a much wider array of reward (e.g., insula/orbitofrontal cortex), attention (superior frontal gyrus) and visual processing (e.g., superior temporal gyrus) regions, and hypo-activation in cognitive control areas (e.g., anterior cingulate) in response to high-energy food cues. Furthermore, among restrained eaters, the longest reaction times were found for low-energy food images, and activation of the attention and visual-related cortex (e.g., superior parietal gyrus) in the low-neutral contrast condition was significantly stronger than in unrestrained eaters. These findings contribute to our understanding of susceptibility to food cues: in addition to the special sensitivity (attentional bias) to high-energy food images, restrained eaters may also be more sensitive (allocate more attentional resources) to low-energy food images. These potential neural bases of restrained eaters may help clarify why dieting to lose or maintain weight is so often unsuccessful. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Orthorexic and restrained eating behaviour in vegans, vegetarians, and individuals on a diet.

PubMed

Barthels, Friederike; Meyer, Frank; Pietrowsky, Reinhard

2018-04-01

Orthorexic eating behaviour, restrained eating, and veganism/vegetarianism are food selection strategies sharing several characteristics. Since there are no studies investigating their interrelationships, aim of the present study was to analyse orthorexic and restrained eating behaviour in (1) a sample of vegans and vegetarians and (2) a sample of individuals on a diet to lose weight. Division of samples according to pre-defined criteria in (1) vegans (n = 114), vegetarians (n = 63), individuals with rare meat consumption (n = 83) and individuals with frequent meat consumption (n = 91) and in (2) participants on a diet with dietary change (n = 104), without dietary change (n = 37) and a control group of individuals not on a diet (n = 258). Orthorexic eating behaviour was assessed with the Düsseldorfer Orthorexie Skala and restrained eating was assessed with the Restraint Eating Scale. Vegans and vegetarians do not differ in orthorexic eating behaviour, but both groups score higher in orthorexic eating behaviour than individuals consuming red meat. There are no differences regarding restrained eating. Individuals on a diet with dietary change score higher in both orthorexic and restrained eating, than individuals without dietary change and individuals not on a diet. Individuals who restrict their eating behaviour, either predominantly due to ethical reasons or with the intention to lose weight, display more orthorexic eating behaviour than individuals not limiting their food consumption. Further research is needed to investigate whether veganism, vegetarianism, or frequent dieting behaviour serve as risk factors for orthorexia. Level V, cross-sectional descriptive study.

29 CFR 101.37 - Application for temporary relief or restraining orders.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PROCEDURES Procedure Under Section 10 (j) and (l) of the Act § 101.37 Application for temporary relief or restraining orders. Whenever it is deemed advisable to seek temporary injunctive relief under section 10(j) or...

Restraint of the Automobile in American Residential Neighborhoods

DOT National Transportation Integrated Search

1978-04-01

Two techniques for restraining the use of the automobile have recently become popular in the United States: residential parking permit programs and traffic restraint devices. While both the these approaches are aimed at restraining the use of the aut...

Design of novel antimicrobial peptide dimer analogues with enhanced antimicrobial activity in vitro and in vivo by intermolecular triazole bridge strategy.

PubMed

Liu, Beijun; Huang, Haifeng; Yang, Zhibin; Liu, Beiyin; Gou, Sanhu; Zhong, Chao; Han, Xiufeng; Zhang, Yun; Ni, Jingman; Wang, Rui

2017-02-01

Currently, antimicrobial peptides have attracted considerable attention because of their broad-sprectum activity and low prognostic to induce antibiotic resistance. In our study, for the first time, a series of side-chain hybrid dimer peptides J-AA (Anoplin-Anoplin), J-RR (RW-RW), and J-AR (Anoplin-RW) based on the wasp peptide Anoplin and the arginine- and tryptophan-rich hexapeptide RW were designed and synthesized by click chemistry, with the intent to improve the antimicrobial efficacy of peptides against bacterial pathogens. The results showed that all dimer analogues exhibited up to a 4-16 fold increase in antimicrobial activity compared to the parental peptides against bacterial strains. Furthermore, the antimicrobial activity was confirmed by time-killing kinetics assay with two strains which showed that these dimer analogues at 1, 2×MIC were rapidly bactericidal and reduced the initial inoculum significantly during the first 2-6h. Notably, dimer peptides showed synergy and additivity effects when used in combination with conventional antibiotics rifampin or penicillin respectively against the multidrug-resistant strains. In the Escherichia coli-infected mouse model, all of hybrid dimer analogues had significantly lower degree of bacterial load than the untreated control group when injected once i.p. at 5mg/kg. In addition, the infected mice by methicillin-resistant (MRSA) strain could be effectively treated with J-RR. All of dimer analogues had membrane-active action mode. And the membrane-dependent mode of action signifies that peptides functions freely and without regard to conventional resistant mechanisms. Circular dichroism analyses of all dimer analogues showed a general predominance of α-helix conformation in 50% trifluoroethanol (TFE). Additionally, the acute toxicities study indicated that J-RR or J-AR did not show the signs of toxicity when adult mice exposed to concentration up to 120mg/kg. The 50% lethal dose (LD 50 ) of J-AA was 53.6mg/kg. In conclusion, to design and synthesize side chain-hybrid dimer analogues via click chemistry may offer a new strategy for antibacterial therapeutic option. Copyright © 2016 Elsevier Inc. All rights reserved.

A Conserved Surface Loop in Type I Dehydroquinate Dehydratases Positions an Active Site Arginine and Functions in Substrate Binding

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

Light, Samuel H.; Minasov, George; Shuvalova, Ludmilla

2012-04-18

Dehydroquinate dehydratase (DHQD) catalyzes the third step in the biosynthetic shikimate pathway. We present three crystal structures of the Salmonella enterica type I DHQD that address the functionality of a surface loop that is observed to close over the active site following substrate binding. Two wild-type structures with differing loop conformations and kinetic and structural studies of a mutant provide evidence of both direct and indirect mechanisms of involvement of the loop in substrate binding. In addition to allowing amino acid side chains to establish a direct interaction with the substrate, closure of the loop necessitates a conformational change ofmore » a key active site arginine, which in turn positions the substrate productively. The absence of DHQD in humans and its essentiality in many pathogenic bacteria make the enzyme a target for the development of nontoxic antimicrobials. The structures and ligand binding insights presented here may inform the design of novel type I DHQD inhibiting molecules.« less

Non-opioid analgesic drug flupirtine: Spectral analysis, DFT computations, in vitro bioactivity and molecular docking study

NASA Astrophysics Data System (ADS)

Leenaraj, D. R.; Hubert Joe, I.

2017-06-01

Spectral features of non-opioid analgesic drug flupirtine have been explored by the Fourier transform infrared, Raman and Nuclear magnetic resonance spectroscopic techniques combined with density functional theory computations. The bioactive conformer of flupirtine is stabilized by an intramolecular Csbnd H⋯N hydrogen bonding resulting by the steric strain of hydrogen atoms. Natural bond orbital and natural population analysis support this result. The charge redistribution also has been analyzed. Antimicrobial activities of flupirtine have been screened by agar well disc diffusion and molecular docking methods, which exposes the importance of triaminopyridine in flupirtine.

Determination of conformation and orientation of immobilized peptides and proteins at buried interfaces

NASA Astrophysics Data System (ADS)

Shen, Lei; Ulrich, Nathan W.; Mello, Charlene M.; Chen, Zhan

2015-01-01

Surface immobilized peptides/proteins have important applications such as antimicrobial coating and biosensing. We report a study of such peptides/proteins using sum frequency generation vibrational spectroscopy and ATR-FTIR. Immobilization on surfaces via physical adsorption and chemical coupling revealed that structures of chemically immobilized peptides are determined by immobilization sites, chemical environments, and substrate surfaces. In addition, controlling enzyme orientation by engineering the surface immobilization site demonstrated that structures can be well-correlated to measured chemical activity. This research facilitates the development of immobilized peptides/proteins with improved activities by optimizing their surface orientation and structure.

Characterization of Antibacterial and Hemolytic Activity of Synthetic Pandinin 2 Variants and Their Inhibition against Mycobacterium tuberculosis

PubMed Central

Rodríguez, Alexis; Villegas, Elba; Montoya-Rosales, Alejandra; Rivas-Santiago, Bruno; Corzo, Gerardo

2014-01-01

The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects. PMID:25019413

Peptoid-Substituted Hybrid Antimicrobial Peptide Derived from Papiliocin and Magainin 2 with Enhanced Bacterial Selectivity and Anti-inflammatory Activity.

PubMed

Shin, Areum; Lee, Eunjung; Jeon, Dasom; Park, Young-Guen; Bang, Jeong Kyu; Park, Yong-Sun; Shin, Song Yub; Kim, Yangmee

2015-06-30

Antimicrobial peptides (AMPs) are important components of the host innate immune system. Papiliocin is a 37-residue AMP purified from larvae of the swallowtail butterfly Papilio xuthus. Magainin 2 is a 23-residue AMP purified from the skin of the African clawed frog Xenopus laevis. We designed an 18-residue hybrid peptide (PapMA) incorporating N-terminal residues 1-8 of papiliocin and N-terminal residues 4-12 of magainin 2, joined by a proline (Pro) hinge. PapMA showed high antimicrobial activity but was cytotoxic to mammalian cells. To decrease PapMA cytotoxicity, we designed a lysine (Lys) peptoid analogue, PapMA-k, which retained high antimicrobial activity but displayed cytotoxicity lower than that of PapMA. Fluorescent dye leakage experiments and confocal microscopy showed that PapMA targeted bacterial cell membranes whereas PapMA-k penetrated bacterial cell membranes. Nuclear magnetic resonance experiments revealed that PapMA contained an N-terminal α-helix from Lys(3) to Lys(7) and a C-terminal α-helix from Lys(10) to Lys(17), with a Pro(9) hinge between them. PapMA-k also had two α-helical structures in the same region connected with a flexible hinge residue at Nlys(9), which existed in a dynamic equilibrium of cis and trans conformers. Using lipopolysaccharide-stimulated RAW264.7 macrophages, the anti-inflammatory activity of PapMA and PapMA-k was confirmed by inhibition of nitric oxide and inflammatory cytokine production. In addition, treatment with PapMA and PapMA-k decreased the level of ultraviolet irradiation-induced expression of genes encoding matrix metalloproteinase-1 (MMP-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in human keratinocyte HaCaT cells. Thus, PapMA and PapMA-k are potent peptide antibiotics with antimicrobial and anti-inflammatory activity, with PapMA-k displaying enhanced bacterial selectivity.

RESTRAINING SYSTEM FOR PLETHYSMOGRAPHY IN SMALL ANIMALS

EPA Science Inventory

A restraining technique for immobilizing awake guinea pigs and rats during physiological measurements is described. The basic device consists of an adjustable acrylic holder that supports the animal in a standing position while restricting movement of the four legs. The holder al...

Intraoperative brachial plexus injury during emergence following movement with arms restrained: a preventable complication?

PubMed Central

Chandler, Mark H; DiMatteo, Laura; Hasenboehler, Erik A; Temple, Michael

2007-01-01

Background Despite considerable analysis and preventive strategies, brachial plexus injuries remain fairly common in the perioperative setting. These injuries range from brief periods of numbness or discomfort in the immediate postoperative period to, in rare cases, profound, prolonged losses of sensation and function. We present a case of an orthopedic surgery patient who suffered a brachial plexus injury while under anesthesia after trying to sit upright with his arms restrained. Case presentation After the uneventful placement of an intramedullary tibial nail, an 18 year old patient tried to sit upright with his arms restrained while still under the influence of anesthesia. In the immediate postoperative period, the patient complained of a profound loss of sensation in his left arm and an inability to flex his left elbow, suppinate his arm, or abduct and rotate his shoulder. Neurological examination and subsequent studies revealed a C5-6 brachial plexus injury. The patient underwent range of motion physical therapy and, over the next three months, regained the full function and sensation of his left arm. Conclusion Restraining arms during general anesthesia to prevent injury remains a wise practice. However, to avoid injuring the brachial plexus while the arms are restrained, extra caution must be used to prevent unexpected patient movement and to ensure gentle emergence. PMID:18271944

Investigation into scatter radiation dose levels received by a restrainer in small animal radiography.

PubMed

Barber, J; McNulty, J P

2012-10-01

To measure the intensity and distribution of scatter radiation received by a restrainer in veterinary radiography including the intensity of scatter radiation passing through lead protective devices at pre-defined positions. Anthropomorphic phantoms and a Labrador dog cadaver were used to simulate a restrainer and patient. Scatter dose measurements were recorded at the position of the restraining hands, thyroid, breast and gonads with and without appropriate lead protection. This was repeated for the eight most common projections as identified in an initial retrospective survey. Manual restraint of an animal for a radiographic procedure will result in a scatter radiation dose to the restrainer. The level of radiation dose varies between body regions and between projections. The use of appropriate lead protection resulted in statistically significant dose reductions to all body regions with maximum scatter dose reductions between 93 and 100%. While the doses recorded were small (μGy) in terms of associated risk, they are nonetheless cumulative which can result in a more significant dose. Therefore manual restraint should be avoided and forms of immobilisation should be used such as mechanical means, sedation or general anaesthesia. However, if completely necessary both principles of distance and adequate lead protection should be employed. © 2012 British Small Animal Veterinary Association.

Enterocin C, a class IIb bacteriocin produced by E. faecalis C901, a strain isolated from human colostrum.

PubMed

Maldonado-Barragán, Antonio; Caballero-Guerrero, Belén; Jiménez, Esther; Jiménez-Díaz, Rufino; Ruiz-Barba, José L; Rodríguez, Juan M

2009-07-31

Enterocin C (EntC), a class IIb bacteriocin was purified from culture supernatants of Enterococcus faecalis C901, a strain isolated from human colostrum. Enterocin C consists of two distinct peptides, named EntC1 and EntC2, whose complementary action is required for full antimicrobial activity. The structural genes entC1 and entC2 encoding enterocins EntC1 and EntC2, respectively, and that encoding the putative immunity protein (EntCI) are located in the 9-kb plasmid pEntC, harboured by E. faecalis C901. The N-terminal sequence of both antimicrobial peptides revealed that EntC1 (4284 Da) is identical to Ent1071A, one of the two peptides that form enterocin 1071 (Ent1071), a bacteriocin produced by E. faecalis BFE 1071. In contrast, EntC2 (3867 Da) presents the non-polar alanine residue at position 17 (Ala(17)) instead of the polar threonine residue (Thr(17)) in Ent1071B, the second peptide constituting Ent1071. In spite of peptide similarities, EntC differs from Ent1071 in major aspects, including the complementary activity among its constitutive peptides and its wider inhibitory spectrum of activity. Different amphiphilic alpha-helical conformations between EntC2 and Ent1071B could explain both, acquired complementary activity and increased antimicrobial spectrum.

Crystal structures, in-silico study and anti-microbial potential of synthetic monocarbonyl curcuminoids

NASA Astrophysics Data System (ADS)

Ud Din, Zia; Serrano, N. F. G.; Ademi, Kastriot; Sousa, C. P.; Deflon, Victor Marcelo; Maia, Pedro Ivo da Silva; Rodrigues-Filho, Edson

2017-09-01

In this work the screening of 20 unsymmetrical chalcone and curcuminoids analogues in regard of their antimicrobial properties was conducted. Electron donating groups in the aromatic rings in the chalcone and curcuminoid derivatives produced higher antimicrobial effect. Compounds 1, 9 and 15 exhibited good activity against Escherichia coli and Staphylococcus aureus. These compounds were further evaluated against nine micro-organisms of pathological interest. Pharmmaper was used for target fishing of compounds against important bacterial targets. Molecular Docking helped to verify the results of these compounds against the selected bacterial target D-alanyl-D-alanine carboxypeptidase (PDB ID: 1PW1). The crystal structure of ligand and docked conformers in the active site of 1PW1 were analyzed. As a result structure-activity relationships are proposed. Structures of compounds 14 and 16 were obtained through single crystals X-ray diffraction studies. Compound 14 crystallizes in monoclinic space group P21/c with unit cell dimensions a = 13.1293(3) Å, b = 17.5364(4) Å, c = 15.1433(3) Å, β = 95.6440(10), V = 3469.70(13) Å3 and Z = 8. Compound 16 crystallizes in triclinic space group Pī with unit cell dimensions a = 6.8226(4) Å, b = 7.2256(4) Å, c = 18.1235(12) Å, β = 87.322(4), V = 850.57(9) Å3 and Z = 2.

U.S. Transit Track Restraining Rail. Volume II : Guidelines.

DOT National Transportation Integrated Search

1981-12-01

This report covers a study of restraining rails in transit track, which is part of the current research program of UMTA and was initiated: (1) to assist in the analysis, design, and maintenance and operation of transit track; (2) to compile guideline...

National occupant protection use survey 2000 : controlled intersection study

DOT National Transportation Integrated Search

2001-08-01

In the Fall of 2000, 21 percent more Young Adults (persons 16 24 years of age) were restrained by shoulder belts than were restrained in the Fall of 1998. These estimates were obtained through the National Occupant Protection Use Survey (NOPUS) which...

Frequency Response of a Protein to Local Conformational Perturbations

PubMed Central

Eren, Dilek; Alakent, Burak

2013-01-01

Signals created by local perturbations are known to propagate long distances through proteins via backbone connectivity and nonbonded interactions. In the current study, signal propagation from the flexible ligand binding loop to the rest of Protein Tyrosine Phosphatase 1B (PTP1B) was investigated using frequency response techniques. Using restrained Targeted Molecular Dynamics (TMD) potential on WPD and R loops, PTP1B was driven between its crystal structure conformations at different frequencies. Propagation of the local perturbation signal was manifested via peaks at the fundamental frequency and upper harmonics of 1/f distributed spectral density of atomic variables, such as Cα atoms, dihedral angles, or polar interaction distances. Frequency of perturbation was adjusted high enough (simulation length >∼10×period of a perturbation cycle) not to be clouded by random diffusional fluctuations, and low enough (<∼0.8 ns−1) not to attenuate the propagating signal and enhance the contribution of the side-chains to the dissipation of the signals. Employing Discrete Fourier Transform (DFT) to TMD simulation trajectories of 16 cycles of conformational transitions at periods of 1.2 to 5 ns yielded Cα displacements consistent with those obtained from crystal structures. Identification of the perturbed atomic variables by statistical t-tests on log-log scale spectral densities revealed the extent of signal propagation in PTP1B, while phase angles of the filtered trajectories at the fundamental frequency were used to cluster collectively fluctuating elements. Hydrophobic interactions were found to have a higher contribution to signal transduction between side-chains compared to the role of polar interactions. Most of in-phase fluctuating residues on the signaling pathway were found to have high identity among PTP domains, and located over a wide region of PTP1B including the allosteric site. Due to its simplicity and efficiency, the suggested technique may find wide applications in identification of signaling pathways of different proteins. PMID:24086121

Housing in Pyramid Counteracts Neuroendocrine and Oxidative Stress Caused by Chronic Restraint in Rats

PubMed Central

Rao, Guruprasad; Murthy, K. Dilip; Bhat, P. Gopalakrishna

2007-01-01

The space within the great pyramid and its smaller replicas is believed to have an antistress effect. Research has shown that the energy field within the pyramid can protect the hippocampal neurons of mice from stress-induced atrophy and also reduce neuroendocrine stress, oxidative stress and increase antioxidant defence in rats. In this study, we have, for the first time, attempted to study the antistress effects of pyramid exposure on the status of cortisol level, oxidative damage and antioxidant status in rats during chronic restraint stress. Adult female Wistar rats were divided into four groups as follows: normal controls (NC) housed in home cage and left in the laboratory; restrained rats (with three subgroups) subject to chronic restraint stress by placing in a wire mesh restrainer for 6 h per day for 14 days, the restrained controls (RC) having their restrainers kept in the laboratory; restrained pyramid rats (RP) being kept in the pyramid; and restrained square box rats (RS) in the square box during the period of restraint stress everyday. Erythrocyte malondialdehyde (MDA) and plasma cortisol levels were significantly increased and erythrocyte-reduced glutathione (GSH) levels, erythrocyte glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were significantly decreased in RC and RS rats as compared to NC. However, these parameters were maintained to near normal levels in RP rats which showed significantly decreased erythrocyte MDA and plasma cortisol and significantly increased erythrocyte GSH levels, erythrocyte GSH-Px and SOD activities when compared with RS rats. The results showed that housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats. PMID:17342239

Impact of an Infection Control and Antimicrobial Stewardship Program on Solid Organ Transplantation and Hepatobiliary Surgical Site Infections.

PubMed

Frenette, Charles; Sperlea, David; Leharova, Yveta; Thirion, Daniel J G

2016-12-01

OBJECTIVE The goal of this long-term quasi-experimental retrospective study was to assess the impact of a 5-year serial infection control and antimicrobial stewardship intervention on surgical site infections (SSIs). METHODS This study was conducted in a tertiary-care public teaching institution over a 5-year period from January 2010 to December 2014. All patients undergoing hepatobiliary surgery and liver, kidney, pancreas, and simultaneous pancreas-kidney transplantation were included. Outcomes were compared between a preintervention group (2010-2011) and a postintervention group (2012-2014). RESULTS A total of 1,424 procedures averaged an overall SSI rate of 11.2%. After implementation of the interventions, a decrease of 52.8% in SSI rates from 17.4% to 8.2% was observed (P50% (relative rate; P<.001) was observed in superficial incisional and organ-space infections between pre- and postintervention groups. In addition, a 54.9% decrease from 19.7% to 8.9% (P<.001; OR, 2.2; 95% CI, 1.4-3.5) and a 51.6% decrease from 15.5% to 7.5% (P=.001; OR, 2.2; 95% CI, 1.4-3.5) were observed for SSI rates in hepatobiliary surgery and solid organ transplantation, respectively. The antimicrobial stewardship intervention increased overall conformity to the internal surgical prophylaxis protocol by 15.2% (absolute rate) from 45.1% to 60.3% (P<.003; 95% CI, 5.4-24.9). CONCLUSIONS A long-term serial infection control and antimicrobial stewardship intervention decreased SSIs among patients undergoing hepatobiliary surgery and liver, kidney, pancreas, and simultaneous pancreas-kidney transplantation. Infect Control Hosp Epidemiol 2016;1468-1474.

Rational design of antimicrobial C3a analogues with enhanced effects against Staphylococci using an integrated structure and function-based approach.

PubMed

Pasupuleti, Mukesh; Walse, Björn; Svensson, Bo; Malmsten, Martin; Schmidtchen, Artur

2008-09-02

The anaphylatoxin C3a and its inactivated derivative C3adesArg, generated during complement activation, exert direct antimicrobial effects, mediated via its C-terminal region [Nordahl et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 16879-16884]. During evolution, this region of C3a displays subtle changes in net charge, while preserving a moderate but variable amphipathicity [Pasupuleti et al. (2007) J. Biol. Chem. 282, 2520-2528]. In this study, we mimic these evolutionary changes, employing a design approach utilizing selected amino acid substitutions at strategic and structurally relevant positions in the original human C3a peptide CNYITELRRQHARASHLGLA, followed by structure-activity studies incorporating sequence-dependent QSAR models as tools for generation of C3a peptide variants with enhanced effects. While the native peptide and related amphipathic analogues of moderate positive net charge were active against the Gram-negative Escherichia coli, activity against the Gram-positive Staphylococcus aureus was primarily observed for peptides characterized by a combination of a relatively high net charge (+6-7) and a propensity to adopt an alpha-helical conformation with amphipathic character. Such increased helicity and charge also conferred activity against the fungus Candida albicans. A central histidine residue (H11), evolutionarily conserved among vertebrates, conferred high selectivity toward microbes, while substitutions with leucine rendered the peptides hemolytic. Selected C3a analogues retained their specificity against staphylococci in the presence of human plasma, while showing low cytotoxicity. The work illustrates structure-activity relationships underlying the function and specificity of antimicrobial C3a and related analogues and provides insights into the forces that drive evolution of antimicrobial peptides.

Seismic rehabilitation of skewed and curved bridges using a new generation of buckling restrained braces.

DOT National Transportation Integrated Search

2016-12-01

The objective of this project is to find effective configurations for using buckling restrained braces (BRBs) in both skewed and curved bridges for reducing the effects of strong earthquakes. Verification is performed by numerical simulation using an...

Experimental Tests of a Real Building Seismically Retrofitted by Special Buckling-Restrained Braces

NASA Astrophysics Data System (ADS)

D'Aniello, Mario; Corte, Gaetano Della; Mazzolani, Federico M.

2008-07-01

Buckling Restrained Braces (BRBs), differently from conventional braces, do not exhibit appreciable difference between the tensile and compression capacity and no strength degradation of brace capacity under compressive and cyclic loading. Since lateral and local buckling behaviour modes are restrained, large inelastic capacities are attainable. Hence, BRBs may represent an efficient and reliable solution for reducing the seismic vulnerability of buildings. Results of experimental tests on the response of a real two-story reinforced concrete (RC) building equipped with BRBs are presented and discussed. The considered BRBs are a special `only-steel' version of the more common `unbonded braces'. In particular, two different BRBs have been tested. Both of them are detachable "only-steel" devices, consisting in a rectangular steel plate and a restraining steel sleeve. The latter is composed by two omega shapes which are bolted together. The main characteristic of the braces consists in the possibility to hide them within the space between the facing and the backing of masonry infill walls commonly used for RC buildings.

Regional rat brain noradrenaline turnover in response to restraint stress.

PubMed

Glavin, G B; Tanaka, M; Tsuda, A; Kohno, Y; Hoaki, Y; Nagasaki, N

1983-08-01

Male Wistar rats were starved for 12 hr and then subjected to either 2 hr of wire mesh "envelope" restraint at room temperature; 2 hr of supine restraint in a specially constructed harness at room temperature or were not restrained. Eight brain regions were examined for NA level and the level of its major metabolite, MHPG-SO4. Plasma corticosterone and gastric ulcer incidence were also measured. All restrained rats displayed marked elevations in MHPG-SO4 levels in most brain regions. In addition, several brain regions in restrained animals showed a reduction in NA level. All restrained rats showed elevated plasma corticosterone levels and evidence of gastric lesions. In general, supine restraint produced greater alterations in regional brain NA turnover, greater evidence of ulcer disease, and higher plasma corticosterone levels than did wire mesh restraint. These data suggest that acute but intense stress in the form of restraint causes markedly altered brain NA activity--a possible neurochemical mechanism underlying the phenomenon of stress-induced disease.

Fold-Unfold Transitions in the Selectivity and Mechanism of Action of the N-Terminal Fragment of the Bactericidal/Permeability-Increasing Protein (rBPI21)

PubMed Central

Domingues, Marco M.; Lopes, Sílvia C.D.N.; Santos, Nuno C.; Quintas, Alexandre; Castanho, Miguel A.R.B.

2009-01-01

Septic or endotoxic shock is a common cause of death in hospital intensive care units. In the last decade numerous antimicrobial peptides and proteins have been tested in the search for an efficient drug to treat this lethal disease. Now in phase III clinical trials, rBPI21, a recombinant N-terminal fragment of the bactericidal/permeability-increasing protein (BPI), is a promising drug to reduce lesions caused by meningococcal sepsis. We correlated structural and stability data with functional information of rBPI21 bound to both model systems of eukaryotic and bacterial membranes. On interaction with membranes, rBPI21 loses its conformational stability, as studied by circular dichroism. This interaction of rBPI21 at membrane level was higher in the presence of negatively charged phospholipid relatively to neutral ones, with higher partition coefficients (Kp), suggesting a preference for bacterial membranes over mammalian membranes. rBPI21 binding to membranes is reinforced when its disulfide bond is broken due to conformational changes of the protein. This interaction is followed by liposome aggregation due to unfolding, which ensures protein aggregation, and interfacial localization of rBPI21 in membranes, as studied by extensive quenching by acrylamide and 5-deoxylstearic acid and not by 16-deoxylstearic acid. An uncommon model of the selectivity and mechanism of action is proposed, where membrane induces unfolding of the antimicrobial protein, rBPI21. The unfolding ensures protein aggregation, established by protein-protein interaction at membrane surface or between adjacent membranes covered by the unfolded protein. This protein aggregation step may lead to membrane perturbation. PMID:19186136

Removing guns from batterers: findings from a pilot survey of domestic violence restraining order recipients in California.

PubMed

Vittes, Katherine A; Webster, Daniel W; Frattaroli, Shannon; Claire, Barbara E; Wintemute, Garen J

2013-05-01

Persons under certain domestic violence restraining orders in California are required to surrender any firearms in their possession within 24 hours of service. The California Department of Justice funded a pilot program in which Sheriff's Offices in two counties developed a system for better enforcing the firearm surrender requirement. As part of a larger process evaluation, 17 restraining order recipients were interviewed about their experiences with and feelings about the removal of firearms from their abusers. Most women surveyed wanted firearms removed and felt safer as a result of their removal. Implications of the findings are discussed.

U.S. Transit Track Restraining Rail. Volume I : Study of Requirements and Practices

DOT National Transportation Integrated Search

1981-12-01

This report covers a study of restraining rails in transit track, which is part of the current research program of UMTA and was initiated: (1) to assist in the analysis, design, and maintenance and operation of transit track; (2) to compile guideline...

Gravitropism in Higher Plant Shoots 1

PubMed Central

Mueller, Wesley J.; Salisbury, Frank B.; Blotter, P. Thomas

1984-01-01

Dimensional changes during gravitropic bending of cocklebur (Xanthium strumarium L.) dicot stems were measured using techniques of stereo photogrammetry. The differential growth is from an increased growth rate on the bottom of the stem and a stopping or contraction of the top. Contraction of the top was especially evident upon release and immediate bending of horizontal stems that had been restrained between stiff wires for 36 hours. The energy for this could have been stored in both the top and bottom, since the bottom elongated, and the top contracted. Forces developed during bending were measured by fastening a stem tip to the end of a bar with attached strain gauges and recording electrical output from the strain gauges. Restrained mature cocklebur stems continued to accumulate potential energy for bending for about 120 hours, after which the recorded force reached a maximum. Pressures within castor bean (Ricinus communis L.) stems were also measured with 3.5-millimeter diameter pressure transducers. As expected, the pressure on the bottom of the restrained plants increased with time; pressures decreased in vertical controls, tops of restrained stems, and bottoms of free-bending stems. Pressures increased in tops of free-bending stems. When restrained plants were released, pressure on the bottom decreased and pressure on the top increased. Results suggest a possible role for cell contraction in the top of stems bending upward in response to gravity. Images Fig. 5 Fig. 11 PMID:16663987

Racemic crystallography of synthetic protein enantiomers used to determine the X-ray structure of plectasin by direct methods

PubMed Central

Mandal, Kalyaneswar; Pentelute, Brad L; Tereshko, Valentina; Thammavongsa, Vilasak; Schneewind, Olaf; Kossiakoff, Anthony A; Kent, Stephen B H

2009-01-01

We describe the use of racemic crystallography to determine the X-ray structure of the natural product plectasin, a potent antimicrobial protein recently isolated from fungus. The protein enantiomers l-plectasin and d-plectasin were prepared by total chemical synthesis; interestingly, l-plectasin showed the expected antimicrobial activity, while d-plectasin was devoid of such activity. The mirror image proteins were then used for racemic crystallization. Synchrotron X-ray diffraction data were collected to atomic resolution from a racemic plectasin crystal; the racemate crystallized in the achiral centrosymmetric space group with one l-plectasin molecule and one d-plectasin molecule forming the unit cell. Dimer-like intermolecular interactions between the protein enantiomers were observed, which may account for the observed extremely low solvent content (13%–15%) and more highly ordered nature of the racemic crystals. The structure of the plectasin molecule was well defined for all 40 amino acids and was generally similar to the previously determined NMR structure, suggesting minimal impact of the crystal packing on the plectasin conformation. PMID:19472324

Molecular cloning of a cDNA encoding the precursor of adenoregulin from frog skin. Relationships with the vertebrate defensive peptides, dermaseptins.

PubMed

Amiche, M; Ducancel, F; Lajeunesse, E; Boulain, J C; Ménez, A; Nicolas, P

1993-03-31

Adenoregulin has recently been isolated from Phyllomedusa skin as a 33 amino acid residues peptide which enhanced binding of agonists to the A1 adenosine receptor. In order to study the structure of the precursor of adenoregulin we constructed a cDNA library from mRNAs extracted from the skin of Phyllomedusa bicolor. We detected the complete nucleotide sequence of a cDNA encoding the adenoregulin biosynthetic precursor. The deduced sequence of the precursor is 81 amino acids long, exhibits a putative signal sequence at the NH2 terminus and contains a single copy of the biologically active peptide at the COOH terminus. Structural and conformational homologies that are observed between adenoregulin and the dermaseptins, antimicrobial peptides exhibiting strong membranolytic activities against various pathogenic agents, suggest that adenoregulin is an additional member of the growing family of cytotropic antimicrobial peptides that allow vertebrate animals to defend themselves against microorganisms. As such, the adenosine receptor regulating activity of adenoregulin could be due to its ability to interact with and disrupt membranes lipid bilayers.

Investigating the role of GXXXG motifs in helical folding and self-association of plasticins, Gly/Leu-rich antimicrobial peptides.

PubMed

Carlier, Ludovic; Joanne, Pierre; Khemtémourian, Lucie; Lacombe, Claire; Nicolas, Pierre; El Amri, Chahrazade; Lequin, Olivier

2015-01-01

Plasticins (PTC) are dermaseptin-related antimicrobial peptides characterized by a large number of leucine and glycine residues arranged in GXXXG motifs that are often described to promote helix association within biological membranes. We report the structure and interaction properties of two plasticins, PTC-B1 from Phyllomedusa bicolor and a cationic analog of PTC-DA1 from Pachymedusa dacnicolor, which exhibit membrane-lytic activities on a broad range of microorganisms. Despite a high number of glycine, CD and NMR spectroscopy show that the two plasticins adopt mainly alpha-helical conformations in a wide variety of environments such as trifluoroethanol, detergent micelles and lipid vesicles. In DPC and SDS, plasticins adopt well-defined helices that lie parallel to the micelle surface, all glycine residues being located on the solvent-exposed face. Spectroscopic data and cross-linking experiments indicate that the GXXXG repeats in these amphipathic helices do not provide a strong oligomerization interface, suggesting a different role from GXXXG motifs found in transmembrane helices. Copyright © 2014 Elsevier B.V. All rights reserved.

Structure, synthesis, and molecular cloning of dermaseptins B, a family of skin peptide antibiotics.

PubMed

Charpentier, S; Amiche, M; Mester, J; Vouille, V; Le Caer, J P; Nicolas, P; Delfour, A

1998-06-12

Analysis of antimicrobial activities that are present in the skin secretions of the South American frog Phyllomedusa bicolor revealed six polycationic (lysine-rich) and amphipathic alpha-helical peptides, 24-33 residues long, termed dermaseptins B1 to B6, respectively. Prepro-dermaseptins B all contain an almost identical signal peptide, which is followed by a conserved acidic propiece, a processing signal Lys-Arg, and a dermaseptin progenitor sequence. The 22-residue signal peptide plus the first 3 residues of the acidic propiece are encoded by conserved nucleotides encompassed by the first coding exon of the dermaseptin genes. The 25-residue amino-terminal region of prepro-dermaseptins B shares 50% identity with the corresponding region of precursors for D-amino acid containing opioid peptides or for antimicrobial peptides originating from the skin of distantly related frog species. The remarkable similarity found between prepro-proteins that encode end products with strikingly different sequences, conformations, biological activities and modes of action suggests that the corresponding genes have evolved through dissemination of a conserved "secretory cassette" exon.

Inhibition of cathelicidin activity by bacterial exopolysaccharides.

PubMed

Foschiatti, Michela; Cescutti, Paola; Tossi, Alessandro; Rizzo, Roberto

2009-06-01

The interaction of bacterial exopolysaccharides, produced by opportunistic lung pathogens, with antimicrobial peptides of the innate primate immune system was investigated. The exopolysaccharides were produced by Pseudomonas aeruginosa, Inquilinus limosus and clinical isolates of the Burkholderia cepacia complex, bacteria that are all involved in lung infections of cystic fibrosis patients. The effects of the biological activities of three orthologous cathelicidins from Homo sapiens sapiens, Pongo pygmaeus (orangutan) and Presbitys obscurus (dusky leaf monkey) were examined. Inhibition of the antimicrobial activity of peptides was assessed using minimum inhibitory concentration assays on a reference Escherichia coli strain in the presence and absence of exopolysaccharides, whereas complex formation between peptides and exopolysaccharides was investigated by means of circular dichroism, fluorescence spectroscopy and atomic force microscopy. Biological assays revealed that the higher the negative charge of exopolysaccharides the stronger was their inhibiting effect. Spectroscopic studies indicated the formation of molecular complexes of varying stability between peptides and exopolysaccharides, explaining the inhibition. Atomic force microscopy provided a direct visualization of the molecular complexes. A model is proposed where peptides with an alpha-helical conformation interact with exopolysaccharides through electrostatic and other non-covalent interactions.

System and Apparatus for Deploying a Satellite

NASA Technical Reports Server (NTRS)

Santos, Luis H. (Inventor); Hudeck, John D. (Inventor)

2016-01-01

A frictionless satellite constraint system is provided. The constraint system includes at least one clamp bar configured to restrain a satellite within the constraint system in an axial direction. The constraint system also includes a plurality of pins configured to restrain the satellite within the constraint system in a lateral direction.

Proanthocyanidins-Will they effectively restrain conspicuous bacterial strains devolving on urinary tract infection?

PubMed

Jagannathan, Venkataseshan; Viswanathan, Pragasam

2018-05-18

Struvite or infection stones are one of the major clinical burdens among urinary tract infection, which occur due to the interaction between microbes and urine mineral components. Numerous urinary tract infection (UTI) causing microbes regulate through biofilm formation for survival from host defense, it is often found difficult in its eradication with simple anti-microbial agents and also the chance of recurrence and resistance development is significantly high. Cranberry consumption and maintenance of urinary tract health have been supported by clinical, epidemiological, and mechanistic studies. It predominantly contains proanthocyanidins that belong to the class of polyphenols with repeating catechin and epicatechin monomeric units. Numerous studies have correlated proanthocyanidin consumption and prevention of bacterial adhesion to uroepithelial cells. Quorum sensing (QS) is the prime mechanism that drives bacteria to coordinate biofilm development and virulence expression. Reports have shown that proanthocyanidins are effective in disrupting cell-cell communication by quenching signal molecules. Overall, this review assesses the merits of proanthocyanidins and its effective oppression on adherence, motility, QS, and biofilm formation of major UTI strains such as Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis by comparing and evaluating results from many significant findings. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of the Aqueous Extract from Tabebuia roseoalba and Phenolic Acids on Hyperuricemia and Inflammation

PubMed Central

Ferraz-Filha, Zilma Schimith; Ferrari, Fernanda Cristina; Araújo, Marcela Carolina de Paula Michel; Bernardes, Ana Catharina Fernandes P. F.

2017-01-01

Tabebuia species (Bignoniaceae) have long been used in folk medicine as anti-inflammatory, antirheumatic, antimicrobial, and antitumor. The aim of this study was to investigate if aqueous extract from the leaves (AEL) of Tabebuia roseoalba (Ridl.) Sandwith, Bignoniaceae, and its constituents could be useful to decrease serum uric acid levels and restrain the gout inflammatory process. HPLC analysis identified caffeic acid and chlorogenic acid in AEL. Antihyperuricemic effects and inhibition of liver XOD (xanthine oxidoreductase) by AEL and identified compounds were evaluated in hyperuricemic mice. Anti-inflammatory activity was evaluated on MSU (monosodium urate) crystal-induced paw edema. In addition, AEL antioxidant activity in vitro was evaluated. AEL, caffeic, and chlorogenic acids were able to reduce serum uric acid levels in hyperuricemic mice probably through inhibition of liver xanthine oxidase activity and significantly decreased the paw edema induced by MSU crystals. AEL showed significant antioxidant activity in all evaluated assays. The results show that the AEL of Tabebuia roseoalba can be a promising agent for treatment for gout and inflammatory diseases. We suggest that caffeic and chlorogenic acids may be responsible for the activities demonstrated by the species. PMID:29375639

Atomic layer deposition of titanium oxide films on As-synthesized magnetic Ni particles: Magnetic and safety properties

NASA Astrophysics Data System (ADS)

Uudeküll, Peep; Kozlova, Jekaterina; Mändar, Hugo; Link, Joosep; Sihtmäe, Mariliis; Käosaar, Sandra; Blinova, Irina; Kasemets, Kaja; Kahru, Anne; Stern, Raivo; Tätte, Tanel; Kukli, Kaupo; Tamm, Aile

2017-05-01

Spherical nickel particles with size in the range of 100-400 nm were synthesized by non-aqueous liquid phase benzyl alcohol method. Being developed for magnetically guided biomedical applications, the particles were coated by conformal and antimicrobial thin titanium oxide films by atomic layer deposition. The particles retained their size and crystal structure after the deposition of oxide films. The sensitivity of the coated particles to external magnetic fields was increased compared to that of the uncoated powder. Preliminary toxicological investigations on microbial cells and small aquatic crustaceans revealed non-toxic nature of the synthesized particles.

Role of Tryptophan Side Chain Dynamics on the Trp-Cage Mini-Protein Folding Studied by Molecular Dynamics Simulations

PubMed Central

Kannan, Srinivasaraghavan; Zacharias, Martin

2014-01-01

The 20 residue Trp-cage mini-protein is one of smallest proteins that adopt a stable folded structure containing also well-defined secondary structure elements. The hydrophobic core is arranged around a single central Trp residue. Despite several experimental and simulation studies the detailed folding mechanism of the Trp-cage protein is still not completely understood. Starting from fully extended as well as from partially folded Trp-cage structures a series of molecular dynamics simulations in explicit solvent and using four different force fields was performed. All simulations resulted in rapid collapse of the protein to on average relatively compact states. The simulations indicate a significant dependence of the speed of folding to near-native states on the side chain rotamer state of the central Trp residue. Whereas the majority of intermediate start structures with the central Trp side chain in a near-native rotameric state folded successfully within less than 100 ns only a fraction of start structures reached near-native folded states with an initially non-native Trp side chain rotamer state. Weak restraining of the Trp side chain dihedral angles to the state in the folded protein resulted in significant acceleration of the folding both starting from fully extended or intermediate conformations. The results indicate that the side chain conformation of the central Trp residue can create a significant barrier for controlling transitions to a near native folded structure. Similar mechanisms might be of importance for the folding of other protein structures. PMID:24563686

Cyclic AMP Inhibits the Activity and Promotes the Acetylation of Acetyl-CoA Synthetase through Competitive Binding to the ATP/AMP Pocket.

PubMed

Han, Xiaobiao; Shen, Liqiang; Wang, Qijun; Cen, Xufeng; Wang, Jin; Wu, Meng; Li, Peng; Zhao, Wei; Zhang, Yu; Zhao, Guoping

2017-01-27

The high-affinity biosynthetic pathway for converting acetate to acetyl-coenzyme A (acetyl-CoA) is catalyzed by the central metabolic enzyme acetyl-coenzyme A synthetase (Acs), which is finely regulated both at the transcriptional level via cyclic AMP (cAMP)-driven trans-activation and at the post-translational level via acetylation inhibition. In this study, we discovered that cAMP directly binds to Salmonella enterica Acs (SeAcs) and inhibits its activity in a substrate-competitive manner. In addition, cAMP binding increases SeAcs acetylation by simultaneously promoting Pat-dependent acetylation and inhibiting CobB-dependent deacetylation, resulting in enhanced SeAcs inhibition. A crystal structure study and site-directed mutagenesis analyses confirmed that cAMP binds to the ATP/AMP pocket of SeAcs, and restrains SeAcs in an open conformation. The cAMP contact residues are well conserved from prokaryotes to eukaryotes, suggesting a general regulatory mechanism of cAMP on Acs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Rotation of Guanine Amino Groups in G-Quadruplexes: A Probe for Local Structure and Ligand Binding.

PubMed

Adrian, Michael; Winnerdy, Fernaldo Richtia; Heddi, Brahim; Phan, Anh Tuân

2017-08-22

Nucleic acids are dynamic molecules whose functions may depend on their conformational fluctuations and local motions. In particular, amino groups are dynamic components of nucleic acids that participate in the formation of various secondary structures such as G-quadruplexes. Here, we present a cost-efficient NMR method to quantify the rotational dynamics of guanine amino groups in G-quadruplex nucleic acids. An isolated spectrum of amino protons from a specific tetrad-bound guanine can be extracted from the nuclear Overhauser effect spectroscopy spectrum based on the close proximity between the intra-residue imino and amino protons. We apply the method in different structural contexts of G-quadruplexes and their complexes. Our results highlight the role of stacking and hydrogen-bond interactions in restraining amino-group rotation. The measurement of the rotation rate of individual amino groups could give insight into the dynamic processes occurring at specific locations within G-quadruplex nucleic acids, providing valuable probes for local structure, dynamics, and ligand binding. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

A Test of the Abstinence Violation Effect.

ERIC Educational Resources Information Center

Ruderman, Audrey J.

According to the abstinence violation effect, highly controlled drinkers tend to overindulge following an initial slip. To investigate this relapse model, 47 male college students, ranging in age from 21 to 46, were assigned either to an unrestrained or a restrained drinker group according to their scores on the Restrained Drinking Scale. Subjects…

Taking Guns from Batterers: Public Support and Policy Implications

ERIC Educational Resources Information Center

Sorenson, Susan B.

2006-01-01

Federal law prohibits the purchase or possession of a firearm by persons convicted of misdemeanor domestic violence and those under certain domestic violence restraining orders. The purpose of this investigation is to examine public sentiment about the removal of firearms in the absence of a restraining order or misdemeanor conviction following…

Geneva mechanism. [including star wheel and driver

NASA Technical Reports Server (NTRS)

Summers, R. H.; Kenney, R. L. (Inventor)

1974-01-01

An improved Geneva mechanism is characterized by a driven star-wheel having a segmented cam-follower surface. Star-wheel driver includes a restraining cam having a segmented cam surface for engaging the cam-follower surface of the star-wheel and antifriction rollers pinned to the restraining cam for engaging the cam-follower surface.

Eating behaviors and weight over time in a prospective study: the Healthy Twin Study.

PubMed

Song, Yun-Mi; Lee, Kayoung; Sung, Joohon

2014-01-01

We examined the relationships of combined initial restrained and external/emotional eating with initial BMI and change in weight and these subscales over time. BMI and the Dutch Eating Behavior Questionnaire were twicemeasured in 1361 Korean twins and families (482 men, 879 women) over a period of 2.7±0.9 years. Subjects were classified by combination of initial sex-specific restrained and external (or emotional) eating tertiles. Linear mixed models were performed after adjusting for confounders at baseline (household, sibling relations, sex, age, education level, smoking, alcohol use, energy intake, physical activity, and medical history). In adjusted models, initial BMI increased with increasing tertiles of initial restrained eating across initial external/emotional eating tertiles. Weight was less likely to increase over time with increasing tertiles of initial restrained eating in the lowest external eating tertile and middle tertile of emotional eating at baseline. Subscale scores decreased over time with increasing tertiles of corresponding subscales at baseline. These findings suggest that high dietary restraint and external/emotional eating may indicate concurrent high BMI and attenuated weight gain and decreases in corresponding subscales over time.

Inspiration or deflation? Feeling similar or dissimilar to slim and plus-size models affects self-evaluation of restrained eaters.

PubMed

Papies, Esther K; Nicolaije, Kim A H

2012-01-01

The present studies examined the effect of perceiving images of slim and plus-size models on restrained eaters' self-evaluation. While previous research has found that such images can lead to either inspiration or deflation, we argue that these inconsistencies can be explained by differences in perceived similarity with the presented model. The results of two studies (ns=52 and 99) confirmed this and revealed that restrained eaters with high (low) perceived similarity to the model showed more positive (negative) self-evaluations when they viewed a slim model, compared to a plus-size model. In addition, Study 2 showed that inducing in participants a similarities mindset led to more positive self-evaluations after viewing a slim compared to a plus-size model, but only among restrained eaters with a relatively high BMI. These results are discussed in the context of research on social comparison processes and with regard to interventions for protection against the possible detrimental effects of media images. Copyright © 2011 Elsevier Ltd. All rights reserved.

Visual Associative Learning in Restrained Honey Bees with Intact Antennae

PubMed Central

Dobrin, Scott E.; Fahrbach, Susan E.

2012-01-01

A restrained honey bee can be trained to extend its proboscis in response to the pairing of an odor with a sucrose reward, a form of olfactory associative learning referred to as the proboscis extension response (PER). Although the ability of flying honey bees to respond to visual cues is well-established, associative visual learning in restrained honey bees has been challenging to demonstrate. Those few groups that have documented vision-based PER have reported that removing the antennae prior to training is a prerequisite for learning. Here we report, for a simple visual learning task, the first successful performance by restrained honey bees with intact antennae. Honey bee foragers were trained on a differential visual association task by pairing the presentation of a blue light with a sucrose reward and leaving the presentation of a green light unrewarded. A negative correlation was found between age of foragers and their performance in the visual PER task. Using the adaptations to the traditional PER task outlined here, future studies can exploit pharmacological and physiological techniques to explore the neural circuit basis of visual learning in the honey bee. PMID:22701575

Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment.

PubMed

Henriques, João; Cragnell, Carolina; Skepö, Marie

2015-07-14

An increasing number of studies using molecular dynamics (MD) simulations of unfolded and intrinsically disordered proteins (IDPs) suggest that current force fields sample conformations that are overly collapsed. Here, we study the applicability of several state-of-the-art MD force fields, of the AMBER and GROMOS variety, for the simulation of Histatin 5, a short (24 residues) cationic salivary IDP with antimicrobial and antifungal properties. The quality of the simulations is assessed in three complementary analyses: (i) protein shape and size comparison with recent experimental small-angle X-ray scattering data; (ii) secondary structure prediction; (iii) energy landscape exploration and conformational class analysis. Our results show that, indeed, standard force fields sample conformations that are too compact, being systematically unable to reproduce experimental evidence such as the scattering function, the shape of the protein as compared with the Kratky plot, and intrapeptide distances obtained through the pair distance distribution function, p(r). The consistency of this deviation suggests that the problem is not mainly due to protein-protein or water-water interactions, whose parametrization varies the most between force fields and water models. In fact, as originally proposed in [ Best et al. J. Chem. Theory Comput. 2014, 10, 5113 - 5124.], balanced protein-water interactions may be the key to solving this problem. Our simulations using this approach produce results in very good agreement with experiment.

How brain response and eating habits modulate food energy estimation.

PubMed

Mengotti, P; Aiello, M; Terenzi, D; Miniussi, C; Rumiati, R I

2018-05-01

The estimates we do of the energy content of different foods tend to be inaccurate, depending on several factors. The elements influencing such evaluation are related to the differences in the portion size of the foods shown, their energy density (kcal/g), but also to individual differences of the estimators, such as their body-mass index (BMI) or eating habits. Within this context the contribution of brain regions involved in food-related decisions to the energy estimation process is still poorly understood. Here, normal-weight and overweight/obese women with restrained or non-restrained eating habits, received anodal transcranial direct current stimulation (AtDCS) to modulate the activity of the left dorsolateral prefrontal cortex (dlPFC) while they performed a food energy estimation task. Participants were asked to judge the energy content of food images, unaware that all foods, for the quantity presented, shared the same energy content. Results showed that food energy density was a reliable predictor of their energy content estimates, suggesting that participants relied on their knowledge about the food energy density as a proxy for estimating food energy content. The neuromodulation of the dlPFC interacted with individual differences in restrained eating, increasing the precision of the energy content estimates in participants with higher scores in the restrained eating scale. Our study highlights the importance of eating habits, such as restrained eating, in modulating the activity of the left dlPFC during food appraisal. Copyright © 2018 Elsevier Inc. All rights reserved.

Evolution of restraint in a structured rock–paper–scissors community

PubMed Central

Nahum, Joshua R.; Harding, Brittany N.; Kerr, Benjamin

2011-01-01

It is not immediately clear how costly behavior that benefits others evolves by natural selection. By saving on inherent costs, individuals that do not contribute socially have a selective advantage over altruists if both types receive equal benefits. Restrained consumption of a common resource is a form of altruism. The cost of this kind of prudent behavior is that restrained individuals give up resources to less-restrained individuals. The benefit of restraint is that better resource management may prolong the persistence of the group. One way to dodge the problem of defection is for altruists to interact disproportionately with other altruists. With limited dispersal, restrained individuals persist because of interaction with like types, whereas it is the unrestrained individuals that must face the negative long-term consequences of their rapacity. Here, we study the evolution of restraint in a community of three competitors exhibiting a nontransitive (rock–paper–scissors) relationship. The nontransitivity ensures a form of negative feedback, whereby improvement in growth of one competitor has the counterintuitive consequence of lowering the density of that improved player. This negative feedback generates detrimental long-term consequences for unrestrained growth. Using both computer simulations and evolution experiments with a nontransitive community of Escherichia coli, we find that restrained growth can evolve under conditions of limited dispersal in which negative feedback is present. This research, thus, highlights a set of ecological conditions sufficient for the evolution of one form of altruism. PMID:21690371

Evolution of restraint in a structured rock-paper-scissors community.

PubMed

Nahum, Joshua R; Harding, Brittany N; Kerr, Benjamin

2011-06-28

It is not immediately clear how costly behavior that benefits others evolves by natural selection. By saving on inherent costs, individuals that do not contribute socially have a selective advantage over altruists if both types receive equal benefits. Restrained consumption of a common resource is a form of altruism. The cost of this kind of prudent behavior is that restrained individuals give up resources to less-restrained individuals. The benefit of restraint is that better resource management may prolong the persistence of the group. One way to dodge the problem of defection is for altruists to interact disproportionately with other altruists. With limited dispersal, restrained individuals persist because of interaction with like types, whereas it is the unrestrained individuals that must face the negative long-term consequences of their rapacity. Here, we study the evolution of restraint in a community of three competitors exhibiting a nontransitive (rock-paper-scissors) relationship. The nontransitivity ensures a form of negative feedback, whereby improvement in growth of one competitor has the counterintuitive consequence of lowering the density of that improved player. This negative feedback generates detrimental long-term consequences for unrestrained growth. Using both computer simulations and evolution experiments with a nontransitive community of Escherichia coli, we find that restrained growth can evolve under conditions of limited dispersal in which negative feedback is present. This research, thus, highlights a set of ecological conditions sufficient for the evolution of one form of altruism.

Design and Engineering Strategies for Synthetic Antimicrobial Peptides

NASA Astrophysics Data System (ADS)

Tossi, Alessandro

Thousands of antimicrobial peptides (AMPs) of prokaryotic, fungal, plant, or animal origin have been identified, and their potential as lead compounds for the design of novel therapeutic agents in the treatment of infection, for stimulating the immune system, or in countering septic shock has been widely recognized. Added to this is their possible use in prophylaxis of infectious diseases for animal or plant protection, for disinfection of surgical instruments or industrial surfaces, and for food preservation among other commercially important applications. Since the early eighties, AMPs have been subject to a vast number of studies aimed at understanding what determines their potency and spectrum of activities against bacterial or fungal pathogens, and at maximizing these while limiting cytotoxic activities toward host cells. Much research has also been directed toward understanding specific mechanisms of action underlying the antimicrobial activity and selectivity, to be able to redesign the peptides for optimal performance. A central theme in the mode of action of many AMPs is their dynamic interaction with biological membranes, which involves various properties of these peptides such as, among others, surface hydrophobicity and polarity, charge, structure, and induced conformational variations. These features are often intimately interconnected so that engineering peptides to independently adjust any one property in particular is not an easy task. However, solid-phase peptide synthesis allows the use of a large repertoire of nonproteinogenic amino acids that can be used in the rational design of peptides to finely tune structural and physicochemical properties and precisely probe structure-function relationships.

Differential Interaction of Antimicrobial Peptides with Lipid Structures Studied by Coarse-Grained Molecular Dynamics Simulations.

PubMed

Balatti, Galo E; Ambroggio, Ernesto E; Fidelio, Gerardo D; Martini, M Florencia; Pickholz, Mónica

2017-10-20

In this work; we investigated the differential interaction of amphiphilic antimicrobial peptides with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid structures by means of extensive molecular dynamics simulations. By using a coarse-grained (CG) model within the MARTINI force field; we simulated the peptide-lipid system from three different initial configurations: (a) peptides in water in the presence of a pre-equilibrated lipid bilayer; (b) peptides inside the hydrophobic core of the membrane; and (c) random configurations that allow self-assembled molecular structures. This last approach allowed us to sample the structural space of the systems and consider cooperative effects. The peptides used in our simulations are aurein 1.2 and maculatin 1.1; two well-known antimicrobial peptides from the Australian tree frogs; and molecules that present different membrane-perturbing behaviors. Our results showed differential behaviors for each type of peptide seen in a different organization that could guide a molecular interpretation of the experimental data. While both peptides are capable of forming membrane aggregates; the aurein 1.2 ones have a pore-like structure and exhibit a higher level of organization than those conformed by maculatin 1.1. Furthermore; maculatin 1.1 has a strong tendency to form clusters and induce curvature at low peptide-lipid ratios. The exploration of the possible lipid-peptide structures; as the one carried out here; could be a good tool for recognizing specific configurations that should be further studied with more sophisticated methodologies.

Anhydrous polymer-based coating with sustainable controlled release functionality for facile, efficacious impregnation, and delivery of antimicrobial peptides.

PubMed

Lim, Kaiyang; Saravanan, Rathi; Chong, Kelvin K L; Goh, Sharon H M; Chua, Ray R Y; Tambyah, Paul A; Chang, Matthew W; Kline, Kimberly A; Leong, Susanna S J

2018-04-17

Anhydrous polymers are actively explored as alternative materials to overcome limitations of conventional hydrogel-based antibacterial coating. However, the requirement for strong organic solvent in polymerization reactions often necessitates extra protection steps for encapsulation of target biomolecules, lowering encapsulation efficiency, and increasing process complexity. This study reports a novel coating strategy that allows direct solvation and encapsulation of antimicrobial peptides (HHC36) into anhydrous polycaprolactone (PCL) polymer-based dual layer coating. A thin 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) film is layered onto the peptide-impregnated PCL as a diffusion barrier, to modulate and enhance release kinetics. The impregnated peptides are eventually released in a controlled fashion. The use of 2,2,2-trifluoroethanol (TFE), as polymerization and solvation medium, induces the impregnated peptides to adopt highly stable turned conformation, conserving peptide integrity, and functionality during both encapsulation and subsequent release processes. The dual layer coating showed sustained antibacterial functionality, lasting for 14 days. In vivo assessment using an experimental mouse wounding model demonstrated good biocompatibility and significant antimicrobial efficacy of the coating under physiological conditions. The coating was translated onto silicone urinary catheters and showed promising antibacterial efficacy, even outperforming commercial silver-based Dover cather. This anhydrous polymer-based platform holds immense potential as an effective antibacterial coating to prevent clinical device-associated infections. The simplicity of the coating process enhances its industrial viability. © 2018 Wiley Periodicals, Inc.

Trends in antibiotic use and microbial diagnostics in periodontal treatment: comparing surveys of German dentists in a ten-year period.

PubMed

Falkenstein, Svenja; Stein, Jamal M; Henne, Karsten; Conrads, Georg

2016-11-01

The use of antibiotics and microbial tests in periodontal treatment among German dental practitioners was investigated in 2012-2013 and compared with 2002-2003 data. One thousand four hundred representative German practitioners received a postal questionnaire requesting their prescribing habits concerning type, dose, frequency, and sequence of antibiotics adjunctive to mechanical debridement. Additionally, the use of local antimicrobials and microbial tests were recorded. The response rate was 29.1 % (407 reports). Drug combinations, especially amoxicillin plus metronidazole, were prescribed most frequently (32.8 %) with an increase of 7.4 % during the past decade, followed by clindamycin (29.3 %). Amoxicillin monotherapy was used unexpectedly frequently (17.0 %) and doxycycline (2.8 %) very infrequently. Then, 24.7 % prescribed antibiotics prior to mechanical therapy, while most dentists followed the recommended sequence. The use of local antimicrobials increased by 6.2 % and of microbial diagnostics by 20.8 %. Positive trends regarding position-paper-conform prescribing habits including the scheduling of systemic antibiotics and increasing use of local antimicrobials and microbial tests were observed. However, deficits and malpractice still exist in German practices. Unexpected is the widespread and increasing use of clindamycin. Continuing educational campaigns and strictly expressed real guidelines are needed. Indication and choice of antibiotic agents in causal periodontal therapy among German dentists have changed between 2003 and 2013 toward a more position-paper-based concept, but inappropriate prescriptions of second choice antibiotics still remain conspicuous.

The Effect of Booster Seat Use on Pediatric Injuries in Motor Vehicle Frontal Crashes.

PubMed

Caskey, Sean; Hammond, Joshua; Peck, Jeffery; Sardelli, Matthew; Atkinson, Theresa

2018-04-20

Motor vehicle crashes are a significant source of pediatric mortality and morbidity. Studies indicate that booster seats significantly improve seat belt fit for children who have not attained a height of 145 cm (4' 9"). This study examined injuries occurring in booster age children up to age 12, as the majority of children do not attain 145 cm until this age. The purpose of the study was to identify differences in injuries due to the type of restraint used, with attention to musculoskeletal injuries. Vehicle and occupant data were obtained from a publically available statistical sample of tow-away crashes. Frontal crashes over an 8-year period were examined. A data set of cases was created involving children ages 5 to 12 years who were unrestrained, restrained using the vehicle's lap and shoulder belt, and restrained using a booster seat with the vehicle's lap and shoulder seat belt. Injury severity, frequency, and patterns of distribution were compared. Unrestrained children experienced moderate to severe injuries 3.8 to 19 times more frequently than children using restraints. There were more injuries to the head and face in unrestrained versus restrained children, but the head and face was the most frequently injured region for all groups. There were no serious cervical spine injuries reported for any group. Lower extremity fractures were not observed in booster seat users but occurred at similar rates in both unrestrained and seat belt restrained children. These fractures occurred in older children who were involved in more severe crashes. Unrestrained children were more likely to experience moderate and severe injuries than restrained children. The data sample suggests that booster use may reduce the risk of extremity fracture, as there were no extremity fractures in children restrained with booster seats. This work provides evidence for the efficacy of booster use for preventing orthopaedic injury in children. This evidence can be used to inform parents and establish recommendations for best practices in transporting children.

Novel designed VmCT1 analogs with increased antimicrobial activity.

PubMed

Pedron, Cibele Nicolaski; Torres, Marcelo Der Torossian; Lima, Julia Aparecida da Silva; Silva, Pedro Ismael; Silva, Fernanda Dias; Oliveira, Vani Xavier

2017-01-27

Antimicrobial peptides are biologically active molecules produced by a wide range of organisms as an essential component of the innate immune response. They have recently attracted great interest, since they have antimicrobial activity against a broad spectrum of microorganisms. VmCT1 is a cationic peptide from the venom of Vaejovis mexicanus smithi scorpions, which presents antibacterial activity and tends to helical structures. Its analogs were synthesized, characterized and the conformational studies were performed by circular dichroism. The peptides were designed to verify if the single and double substitutions proposed at the hydrophilic and hydrophobic portions of the amphipathic structure would alter antimicrobial activity against Gram-negative and Gram-positive bacteria, yeast and filamentous fungus, besides the hemolytic activity in human erythrocytes. Total charge of the peptides were modified from +2 to +3 by the introduction of a Lysine residue in the hydrophilic face of the amphiphilic helical structure leading to enhanced antimicrobial activity. [K] 11 -VmCT1-NH 2 presented the lower MIC value against the microorganisms (from 0.39 to 6.25 μmol L -1 ), however it showed higher hemolytic activity. The other Lysine-substituted analogs presented also lower MIC values ranging from 0.39 to 25 μmol L -1 for the microorganisms assessed. The circular dichroism spectra analyses suggest that the Lysine-substituted analogs tend to adopt helical structures in trifluoroethanol solution and vesicles (f H : 0.43-1), however they were coiled in water. Alanine substitution by a Glutamic acid residue in the hydrophilic face promotes the increase of polar angle in [E] 4 -VmCT1-NH 2 analog, which was important to led lower hemolytic activity (MHC value = 25 μmol L -1 ). [W] 9 -VmCT1-NH 2 and [E] 4 [W] 9 -VmCT1-NH 2 were designed to favors hydrophobic interactions by the introduction of Tryptophan residue. [W] 9 -VmCT1-NH 2 presented MIC values lower or similar than the model molecule in the most of microorganisms tested. These results provided information about the structure-activity relationship and showed the influence of physicochemical parameters on antimicrobial and hemolytic activity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Influence of chain rigidity on the conformation of model lipid membranes in the presence of cylindrical nanoparticle inclusions

NASA Astrophysics Data System (ADS)

Diloreto, Chris; Wickham, Robert

2012-02-01

We employ real-space self-consistent field theory to study the conformation of model lipid membranes in the presence of solvent and cylindrical nanoparticle inclusions (''peptides''). Whereas it is common to employ a polymeric Gaussian chain model for the lipids, here we model the lipids as persistent, worm-like chains. Our motivation is to develop a more realistic field theory to describe the action of pore-forming anti-microbial peptides that disrupt the bacterial cell membrane. We employ operator-splitting and a pseudo-spectral algorithm, using SpharmonicKit for the chain tangent degrees of freedom, to solve for the worm-like chain propagator. The peptides, modelled using a mask function, have a surface patterned with hydrophobic and hydrophillic patches, but no charge. We examine the role chain rigidity plays in the hydrophobic mismatch, the membrane-mediated interaction between two peptides, the size and structure of pores formed by peptide aggregates, and the free-energy barrier for peptide insertion into the membrane. Our results suggest that chain rigidity influences both the pore structure and the mechanism of pore formation.

75 FR 68664 - Federal Motor Vehicle Safety Standards; Child Restraint Systems; Booster Seat Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-08

... early graduation from booster seats to lap and shoulder belts. Estimates are computed by double-pair... 3-4-year-olds there is evidence of increased risk of injury when restrained in booster seats rather.... Among 4-8-year-olds there is strong evidence of increased risk of injury when restrained by lap and...

School-Based Mentoring Programs. Untangling the Tensions between Theory and Practice. Research Report 90-7.

ERIC Educational Resources Information Center

Reiman, Alan J.; Edelfelt, Roy A.

This paper describes the contextual dimensions of eight school sites that ameliorate or restrain relationships between mentor and novice teachers. Interview data from 23 mentors, 16 novice teachers, and 8 principals suggest 5 contextual themes that ameliorate or restrain an effective induction for novice teachers: (1) early experiences; (2)…

Small amplitude, transverse vibrations of circular plates with an eccentric rectangular perforation elastically restrained against rotation and translation on both edges

NASA Astrophysics Data System (ADS)

Laura, P. A. A.; Avalos, D. R.

2008-05-01

The Rayleigh-Ritz variational method is applied to the determination of the first four frequency coefficients for small amplitude, transverse vibrations of circular plates with an eccentric, rectangular perforation that is elastically restrained against rotation and translation on both edges. Coordinate functions are used which identically satisfy the boundary conditions at the outer circular edge, while the restraining boundary conditions at the inner edge of the cutout are dealt with directly through the energetic terms in the functional expressions. The procedure seems to show very good numerical stability and convergence properties. As an added bonus, the method allows for increased flexibility in dealing with boundary conditions at the edge of the cutout.

Relationship of Dieting and Restrained Eating to Self-Reported Caloric Intake in Female College Freshmen

PubMed Central

Goldstein, Stephanie P.; Katterman, Shawn N.; Lowe, Michael R.

2012-01-01

Evidence indicates that restrained eaters do not eat less than unrestrained eaters in the natural environment. However, no study has examined caloric intake in those who are currently dieting to lose, or avoid gaining, weight. The current study examined caloric intake using 24-hour food recalls among individuals dieting to lose weight, dieting to avoid weight gain, restrained nondieters, and unrestrained nondieters. Participants were 246 female college students participating in a weight gain prevention trial. The predicted significant difference in caloric intake across the four groups was found for beverage but not for food intake. Results reinforce past literature indicating that dieting/restraint status does not reflect hypo-caloric intake in naturalistic settings. PMID:23557829

Using THz Spectroscopy, Evolutionary Network Analysis Methods, and MD Simulation to Map the Evolution of Allosteric Communication Pathways in c-Type Lysozymes.

PubMed

Woods, Kristina N; Pfeffer, Juergen

2016-01-01

It is now widely accepted that protein function is intimately tied with the navigation of energy landscapes. In this framework, a protein sequence is not described by a distinct structure but rather by an ensemble of conformations. And it is through this ensemble that evolution is able to modify a protein's function by altering its landscape. Hence, the evolution of protein functions involves selective pressures that adjust the sampling of the conformational states. In this work, we focus on elucidating the evolutionary pathway that shaped the function of individual proteins that make-up the mammalian c-type lysozyme subfamily. Using both experimental and computational methods, we map out specific intermolecular interactions that direct the sampling of conformational states and accordingly, also underlie shifts in the landscape that are directly connected with the formation of novel protein functions. By contrasting three representative proteins in the family we identify molecular mechanisms that are associated with the selectivity of enhanced antimicrobial properties and consequently, divergent protein function. Namely, we link the extent of localized fluctuations involving the loop separating helices A and B with shifts in the equilibrium of the ensemble of conformational states that mediate interdomain coupling and concurrently moderate substrate binding affinity. This work reveals unique insights into the molecular level mechanisms that promote the progression of interactions that connect the immune response to infection with the nutritional properties of lactation, while also providing a deeper understanding about how evolving energy landscapes may define present-day protein function. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Disarming Batterers through Restraining Orders: The Promise and the Reality in California

ERIC Educational Resources Information Center

Seave, Paul L.

2006-01-01

Laws that prohibit persons under a domestic violence restraining order from purchasing or possessing a firearm are a primary way to keep guns out of the hands of batterers. In July 2005, the California Attorney General's Task Force on the Local Criminal Justice Response to Domestic Violence issued a report called Keeping the Promise: Victim Safety…

The Minimum Data Set Prevalence of Restraint Quality Indicator: Does It Reflect Differences in Care?

ERIC Educational Resources Information Center

Schnelle, John F.; Bates-Jensen, Barbara M.; Levy-Storms, Lene; Grbic, Valena; Yoshii, June; Cadogan, Mary; Simmons, Sandra F.

2004-01-01

Purpose: This study investigated whether the use of restraining devices and related measures of care quality are different in nursing homes that score in the upper and lower quartiles on the Minimum Data Set (MDS) "prevalence of restraint" quality indicator, which assesses daily use of restraining devices when residents are out of bed. Design and…

Experimental comparison of trauma in lateral (+Gy) rearward-facing (+Gx), and forward-facing (-Gx) body orientations when restrained by lap belt only.

DOT National Transportation Integrated Search

1969-07-01

In this study, 24 anesthetized Savannah Baboons (Papio cynocephalus) restrained with a lap belt were subjected to a controlled series of lateral impacts at entrance velocities ranging from 36.4 ft./sec. (15g.) to 88.2 ft./ sec. (44g.) 1,200 g./sec. t...

Shape memory-based actuators and release mechanisms therefrom

NASA Technical Reports Server (NTRS)

Vaidyanathan, Rajan (Inventor); Snyder, Daniel W. (Inventor); Schoenwald, David K. (Inventor); Lam, Nhin S. (Inventor); Watson, Daniel S. (Inventor); Krishnan, Vinu B. (Inventor); Noebe, Ronald D. (Inventor)

2012-01-01

SM-based actuators (110) and release mechanisms (100) therefrom and systems (500) including one or more release mechanisms (100). The actuators (110) comprise a SM member (118) and a deformable member (140) mechanically coupled to the SM member (118) which deforms upon a shape change of the SM member triggered by a phase transition of the SM member. A retaining element (160) is mechanically coupled to the deformable member (140), wherein the retaining element (160) moves upon the shape change. Release mechanism (100) include an actuator, a rotatable mechanism (120) including at least one restraining feature (178) for restraining rotational movement of the retaining element (160) before the shape change, and at least one spring (315) that provides at least one locked spring-loaded position when the retaining element is in the restraining feature and at least one released position that is reached when the retaining element is in a position beyond the restraining feature (178). The rotatable mechanism (120) includes at least one load-bearing protrusion (310). A hitch (400) is for mechanically coupling to the load, wherein the hitch is supported on the load bearing protrusion (310) when the rotatable mechanism is in the locked spring-loaded position.

Management of cervical spine injuries in young children: lessons learned.

PubMed

Smith, Jodi L; Ackerman, Laurie L

2009-07-01

Previous studies have shown that the correct use of car safety seats can protect infants and children from vehicular injury. Although child passenger devices are increasingly used in the US, motor vehicle crashes continue to be the leading cause of death and acquired disability in infants and children younger than 14 years of age. These events are likely related, at least in part, to the high percentage of children who are unrestrained or improperly restrained. The authors present 2 cases of severe cervical spine trauma in young children restrained in car safety seats during a motor vehicle crash: 1) a previously healthy 14-month-old girl who was improperly restrained in a forward-facing booster seat secured to the vehicle by a lap belt, and 2) a previously healthy 30-month-old girl who was a rear seat passenger restrained in a car safety seat. This study points out the unique challenges encountered in treating cervical spine injuries in infants and young children, as well as the lessons learned, and emphasizes the significance of continuing efforts to increase family and public awareness regarding the importance of appropriate child safety seat selection and use.

An investigation of child restraint/seatbelt usage in motor vehicles by Maori in Northland New Zealand.

PubMed

Brewin, M; Peters, T

2003-03-01

To investigate child restraint/seatbelt use by the indigenous (Maori) population in Northland New Zealand. Observational surveys were conducted at the two main car parks (McDonald's and the largest supermarket) to determine the number of passengers restrained, the type of restraints, and correct use. Observations were restricted to those who were obviously Maori, based upon the local knowledge of the observer. In addition, face to face questionnaires were administered to Maori whanau/caregivers involved in the care of two or more children for more than three days a week. A total of 788 participants were observed. Babies were those most likely to have all occupants restrained correctly (97%), followed by toddlers (66%), adults (56%), and school age children (48%); 138 interviews were conducted. Females (86%) were significantly more likely to ensure that all passengers were restrained on short journeys compared to males (67%; p<0.05). Respondents under 45 (80%) were significantly less likely to restrain child passengers compared to people aged 45 or older (91%; p<0.05). This study highlights the problem that larger families in this study had in providing correct child restraints for all their children.

Sudden death due to sickle cell crisis during law enforcement restraint.

PubMed

Channa Perera, S D; Pollanen, Michael S

2007-07-01

We report a case of vaso-occlusive sickle cell crisis in a young schizophrenic man with undiagnosed sickle cell trait who was restrained. Prior to being restrained he had locked himself in his apartment for two days without food or water. He was subsequently restrained, and transferred to hospital while handcuffed to the stretcher. He died suddenly during restraint. At autopsy, there was acute vaso-occlusive sickle cell crisis associated with hypernatremic dehydration. There were no injuries present. We conclude that the death was due to vaso-occlusive sickle cell crisis secondary to dehydration. It is important for the forensic pathologist to remember that death may occur suddenly during restraint from an unexpected mechanism other than excited delirium leading to cardiac arrhythmia or restraint asphyxia.

An implementation of the maximum-caliber principle by replica-averaged time-resolved restrained simulations

NASA Astrophysics Data System (ADS)

Capelli, Riccardo; Tiana, Guido; Camilloni, Carlo

2018-05-01

Inferential methods can be used to integrate experimental informations and molecular simulations. The maximum entropy principle provides a framework for using equilibrium experimental data, and it has been shown that replica-averaged simulations, restrained using a static potential, are a practical and powerful implementation of such a principle. Here we show that replica-averaged simulations restrained using a time-dependent potential are equivalent to the principle of maximum caliber, the dynamic version of the principle of maximum entropy, and thus may allow us to integrate time-resolved data in molecular dynamics simulations. We provide an analytical proof of the equivalence as well as a computational validation making use of simple models and synthetic data. Some limitations and possible solutions are also discussed.

Relationship of dieting and restrained eating to self-reported caloric intake in female college freshmen.

PubMed

Goldstein, Stephanie P; Katterman, Shawn N; Lowe, Michael R

2013-04-01

Evidence indicates that restrained eaters do not eat less than unrestrained eaters in the natural environment. However, no study has examined caloric intake in those who are currently dieting to lose, or avoid gaining, weight. The current study examined caloric intake using 24-hour food recalls among individuals dieting to lose weight, dieting to avoid weight gain, restrained nondieters, and unrestrained nondieters. Participants were 246 female college students participating in a weight gain prevention trial. The predicted significant difference in caloric intake across the four groups was found for beverage but not for food intake. Results reinforce past literature indicating that dieting/restraint status does not reflect hypo-caloric intake in naturalistic settings. Copyright © 2012 Elsevier Ltd. All rights reserved.

Ulcers in restrained rats: Study of protective substances

NASA Technical Reports Server (NTRS)

Buche, L.; Gallaire, D.

1980-01-01

The genesis of ulcers in restrained rats is discussed through an investigation of the relationship between the protective effects of nervous system effectual substances examined vis-a-vis ulcers in restrained rats and their elective or secondary pharmacologic effects. The substances used were capable of either peripheral parasympatholytic, sympatholytic, ganglioplegic, spasmolytic effects or central, hypnotic, tranquilizing, neuroleptic, analgesic effects. The regular and considerable protection observed with parasympatholytics (atropine sulfate, benzylonium bromide, dihexyverine, J.L. 1344) and a ganglioplegic (pentamethonium) is a function of their anticholinergic properties. It is of less importance with dibenamine, a sympatholytic action on the adrenergic receptors. Among the central depressive substances tested (hypnotics, tranquilizers, neuroleptics, analgesic), phenobarbital at a nonhypnotic dose, and dextromoramide at a nonanalgesic dose, show antiulcerous effects, which are found with chlorpromazine only at cataleptogenic doses.

An implementation of the maximum-caliber principle by replica-averaged time-resolved restrained simulations.

PubMed

Capelli, Riccardo; Tiana, Guido; Camilloni, Carlo

2018-05-14

Inferential methods can be used to integrate experimental informations and molecular simulations. The maximum entropy principle provides a framework for using equilibrium experimental data, and it has been shown that replica-averaged simulations, restrained using a static potential, are a practical and powerful implementation of such a principle. Here we show that replica-averaged simulations restrained using a time-dependent potential are equivalent to the principle of maximum caliber, the dynamic version of the principle of maximum entropy, and thus may allow us to integrate time-resolved data in molecular dynamics simulations. We provide an analytical proof of the equivalence as well as a computational validation making use of simple models and synthetic data. Some limitations and possible solutions are also discussed.

Structural and Antimicrobial Features of Peptides Related to Myticin C, a Special Defense Molecule from the Mediterranean Mussel Mytilus galloprovincialis.

PubMed

Domeneghetti, Stefania; Franzoi, Marco; Damiano, Nunzio; Norante, Rosa; El Halfawy, Nancy M; Mammi, Stefano; Marin, Oriano; Bellanda, Massimo; Venier, Paola

2015-10-28

Mussels (Mytilus spp.) have a large repertoire of cysteine-stabilized α,β peptides, and myticin C (MytC) was identified in some hundreds of transcript variants after in vivo immunostimulation. Using a sequence expressed in Italian mussels, we computed the MytC structure and synthesized the mature MytC and related peptide fragments (some of them also prepared in oxidized form) to accurately assess their antibacterial and antifungal activity. Only when tested at pH 5 was the reduced MytC as well as reduced and oxidized fragments including structural β-elements able to inhibit Gram-positive and -negative bacteria (MIC ranges of 4-32 and 8-32 μM, respectively). Such fragments caused selective Escherichia coli killing (MBC of 8-32 μM) but scarcely inhibited two fungal strains. In detail, the antimicrobial β-hairpin MytC[19-40]SOX caused membrane-disrupting effects in E. coli despite its partially ordered conformation in membrane-mimetic environments. In perspective, MytC-derived peptides could be employed to protect acidic mucosal tissues, in cosmetic and food products, and, possibly, as adjuvants in aquaculture.

Cloning and functional identification of moricins from the diamondback moth, Plutella xylostella (L.).

PubMed

Xia, X-F; Li, Y; Yu, X-Q; Lin, J-H; Li, S-Y; Li, Q; You, M-S

2017-10-01

Antimicrobial peptides (AMPs) are small-molecule peptides that play crucial roles in insect innate immune responses. To better understand the function of AMPs in Plutella xylostella, one of the main pests of cruciferous vegetables, three full-length cDNAs encoding moricins were cloned from Pl. xylostella. Two variants of the moricin named PxMor2 and PxMor3 were heterologously expressed and purified. A secondary structure analysis using circular dichroism demonstrated that the two peptides adopted an α-helical structure in the membrane-like environment, but in aqueous solution, they were present in random coiled conformation. Antimicrobial activity assays demonstrated that PxMor2 exhibited high activity against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli; however, PxMor3 only demonstrated high activity against E. coli. Scanning electron microscopy and confocal laser-scanning microscopy analyses suggest that PxMors can lead to the disruption of bacterial membrane, which might be the mechanism by which PxMors inhibit bacterial growth. This study contributes to the understanding of Pl. xylostella AMPs and immune responses, and also enriches the knowledge of insect moricin. © 2017 The Royal Entomological Society.

Kinematics of child volunteers and child anthropomorphic test devices during emergency braking events in real car environment.

PubMed

Stockman, Isabelle; Bohman, Katarina; Jakobsson, Lotta; Brolin, Karin

2013-01-01

The objective of this study was to present, compare, and discuss the kinematic response of children and child anthropomorphic test devices (ATDs) during emergency braking events in different restraint configurations in a passenger vehicle. A driving study was conducted on a closed-circuit test track comprising 16 children aged 4 to 12 years old and the Q3, Hybrid III (HIII) 3-year-old, 6-year-old, and 10-year-old ATDs restrained on the right rear seat of a modern passenger vehicle. The children were exposed to one braking event in each of the 2 restraint systems and the ATDs were exposed to 2 braking events in each restraint system. All events had a deceleration of 1.0 g. Short children (stature 107-123 cm) and the Q3, HIII 3-year-old, and 6-year-old were restrained on booster cushions as well as high-back booster seats. Tall children (stature 135-150 cm) and HIII 10-year-old were restrained on booster cushions or restrained by 3-point belts directly on the car seat. Vehicle data were collected and synchronized with video data. Forward trajectories for the forehead and external auditory canal (ear) were determined as well as head rotation and shoulder belt force. A total of 40 trials were analyzed. Child volunteers had greater maximum forward displacement of the head and greater head rotation compared to the ATDs. The average maximum displacement for children ranged from 165 to 210 mm and 155 to 195 mm for the forehead and ear target, respectively. Corresponding values for the ATDs were 55 to 165 mm and 50 to 160 mm. The change in head angle was greater for short children than for tall children. Shoulder belt force was within the same range for short children when restrained on booster cushions or high-back booster seats. For tall children, the shoulder belt force was greater when restrained on booster cushions compared to being restrained by seat belts directly on the car seat. The forward displacement was within the same range for all children regardless of stature and restraint system. However, the maximum forward position depended on the initial seated posture and shoulder belt position on the shoulder. Differences could also be seen in the curvature of the neck and spine. Short children exhibited a greater flexion motion of the head, whereas a more upright posture at maximum forward position was exhibited by the tall children. The ATDs displayed less forward displacement compared to the children.

Investigations of α-helix↔β-sheet transition pathways in a miniprotein using the finite-temperature string method

PubMed Central

Ovchinnikov, Victor; Karplus, Martin

2014-01-01

A parallel implementation of the finite-temperature string method is described, which takes into account the invariance of coordinates with respect to rigid-body motions. The method is applied to the complex α-helix↔β-sheet transition in a β-hairpin miniprotein in implicit solvent, which exhibits much of the complexity of conformational changes in proteins. Two transition paths are considered, one derived from a linear interpolant between the endpoint structures and the other derived from a targeted dynamics simulation. Two methods for computing the conformational free energy (FE) along the string are compared, a restrained method, and a tessellation method introduced by E. Vanden-Eijnden and M. Venturoli [J. Chem. Phys. 130, 194103 (2009)]. It is found that obtaining meaningful free energy profiles using the present atom-based coordinates requires restricting sampling to a vicinity of the converged path, where the hyperplanar approximation to the isocommittor surface is sufficiently accurate. This sampling restriction can be easily achieved using restraints or constraints. The endpoint FE differences computed from the FE profiles are validated by comparison with previous calculations using a path-independent confinement method. The FE profiles are decomposed into the enthalpic and entropic contributions, and it is shown that the entropy difference contribution can be as large as 10 kcal/mol for intermediate regions along the path, compared to 15–20 kcal/mol for the enthalpy contribution. This result demonstrates that enthalpic barriers for transitions are offset by entropic contributions arising from the existence of different paths across a barrier. The possibility of using systematically coarse-grained representations of amino acids, in the spirit of multiple interaction site residue models, is proposed as a means to avoid ad hoc sampling restrictions to narrow transition tubes. PMID:24811667

Calpha methylation in molecular recognition. Application to substance P and the two neurokinin-1 receptor binding sites.

PubMed

Sagan, S; Lequin, O; Frank, F; Convert, O; Ayoub, M; Lavielle, S; Chassaing, G

2001-05-01

Two binding sites NK-1M (major, more abundant) and NK-1m (minor) are associated with the neurokinin-1 receptor. For the first time with a bioactive peptide, the Calpha methylation constraint, shown to be a helix stabiliser in model peptides, was systematically used to probe the molecular requirements of NK-1M and NK-1m binding sites and the previously postulated bioactive helical conformation of substance P (SP). Seven Calpha methylated analogues of the undecapeptide SP (from position 5-11) have been assayed for their affinities and their potencies to stimulate second messenger production. The consequences of Calpha methylation on the structure of SP have been analysed by circular dichroism and nuclear magnetic resonance combined with restrained molecular dynamics. The decreased potencies of six out of these seven Calpha methylated SP analogues do not allow the identification of any clear-cut differences in the structural requirements between the two binding sites. Strikingly, the most active analogue, [alphaMeMet5]SP, leads to variable subnanomolar affinity and potency when interacting with the NK-1m binding site. The conformational analyses show that the structural consequences associated with Calpha methylation of SP are sequence dependent. Moreover, a single Calpha methylation is not sufficient by itself to drastically stabilize a helical structure even pre-existing in solution, except when Gly9 is substituted by an alpha-aminoisobutyric acid. Furthermore, Calpha methylation of residues 5 and 6 of SP in the middle of the postulated helix does not stabilize, but decreases (to different extents) the stability of the helical structure previously observed in the 4-8 domain of other potent SP analogues.

Investigations of α-helix↔β-sheet transition pathways in a miniprotein using the finite-temperature string method

NASA Astrophysics Data System (ADS)

Ovchinnikov, Victor; Karplus, Martin

2014-05-01

A parallel implementation of the finite-temperature string method is described, which takes into account the invariance of coordinates with respect to rigid-body motions. The method is applied to the complex α-helix↔β-sheet transition in a β-hairpin miniprotein in implicit solvent, which exhibits much of the complexity of conformational changes in proteins. Two transition paths are considered, one derived from a linear interpolant between the endpoint structures and the other derived from a targeted dynamics simulation. Two methods for computing the conformational free energy (FE) along the string are compared, a restrained method, and a tessellation method introduced by E. Vanden-Eijnden and M. Venturoli [J. Chem. Phys. 130, 194103 (2009)]. It is found that obtaining meaningful free energy profiles using the present atom-based coordinates requires restricting sampling to a vicinity of the converged path, where the hyperplanar approximation to the isocommittor surface is sufficiently accurate. This sampling restriction can be easily achieved using restraints or constraints. The endpoint FE differences computed from the FE profiles are validated by comparison with previous calculations using a path-independent confinement method. The FE profiles are decomposed into the enthalpic and entropic contributions, and it is shown that the entropy difference contribution can be as large as 10 kcal/mol for intermediate regions along the path, compared to 15-20 kcal/mol for the enthalpy contribution. This result demonstrates that enthalpic barriers for transitions are offset by entropic contributions arising from the existence of different paths across a barrier. The possibility of using systematically coarse-grained representations of amino acids, in the spirit of multiple interaction site residue models, is proposed as a means to avoid ad hoc sampling restrictions to narrow transition tubes.

Accelerating Convergence in Molecular Dynamics Simulations of Solutes in Lipid Membranes by Conducting a Random Walk along the Bilayer Normal.

PubMed

Neale, Chris; Madill, Chris; Rauscher, Sarah; Pomès, Régis

2013-08-13

All molecular dynamics simulations are susceptible to sampling errors, which degrade the accuracy and precision of observed values. The statistical convergence of simulations containing atomistic lipid bilayers is limited by the slow relaxation of the lipid phase, which can exceed hundreds of nanoseconds. These long conformational autocorrelation times are exacerbated in the presence of charged solutes, which can induce significant distortions of the bilayer structure. Such long relaxation times represent hidden barriers that induce systematic sampling errors in simulations of solute insertion. To identify optimal methods for enhancing sampling efficiency, we quantitatively evaluate convergence rates using generalized ensemble sampling algorithms in calculations of the potential of mean force for the insertion of the ionic side chain analog of arginine in a lipid bilayer. Umbrella sampling (US) is used to restrain solute insertion depth along the bilayer normal, the order parameter commonly used in simulations of molecular solutes in lipid bilayers. When US simulations are modified to conduct random walks along the bilayer normal using a Hamiltonian exchange algorithm, systematic sampling errors are eliminated more rapidly and the rate of statistical convergence of the standard free energy of binding of the solute to the lipid bilayer is increased 3-fold. We compute the ratio of the replica flux transmitted across a defined region of the order parameter to the replica flux that entered that region in Hamiltonian exchange simulations. We show that this quantity, the transmission factor, identifies sampling barriers in degrees of freedom orthogonal to the order parameter. The transmission factor is used to estimate the depth-dependent conformational autocorrelation times of the simulation system, some of which exceed the simulation time, and thereby identify solute insertion depths that are prone to systematic sampling errors and estimate the lower bound of the amount of sampling that is required to resolve these sampling errors. Finally, we extend our simulations and verify that the conformational autocorrelation times estimated by the transmission factor accurately predict correlation times that exceed the simulation time scale-something that, to our knowledge, has never before been achieved.

Structure, synthesis, and activity of dermaseptin b, a novel vertebrate defensive peptide from frog skin: relationship with adenoregulin.

PubMed

Mor, A; Amiche, M; Nicolas, P

1994-05-31

A novel antimicrobial peptide, designated dermaseptin b, was isolated from the skin of the arboreal frog Phyllomedusa bicolor. This 27-residue peptide amide is basic, containing 3 lysine residues that punctuate an alternating hydrophobic and hydrophilic sequence. In helix-inducing solvent, dermaseptin b adopts an amphipathic alpha-helical conformation that most closely resembles class L amphipathic helixes, with all lysine residues on the polar face of the helix. The peptide exhibits growth inhibition activity in vitro against a broad spectrum of pathogenic microorganisms including yeast and bacteria as well as various filamentous fungi that are responsible for severe opportunistic infections accompanying acquired immunodeficiency syndrome and the use of immunosuppressive agents. Maximized pairwise sequence alignment of dermaseptin b and dermaseptin s, a 34-residue antimicrobial peptide previously isolated from Phyllomedusa sauvagii, reveals 81% amino acid identity. No other significant similarity was found between dermaseptin b and any prokaryotic or eukaryotic protein, but similarity was found with adenoregulin (38% amino acid postional identity), a 33-residue peptide that enhances binding of agonists to the A1 adenosine receptor. The synthetic replicates of dermaseptin b and adenoregulin displayed similar but nonidentical spectra of antimicrobial activity, and both peptides were devoid of lytic effect on mammalian cells. Accordingly, the observation that adenoregulin enhances binding of agonists to the adenosine receptor may in fact be a consequence of its ability to alter the structure of biological membranes and to produce signal transduction via interactions with the lipid bilayer, bypassing cell surface receptor interactions.

Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism*

PubMed Central

Wei, Lin; Gao, Jiuxiang; Zhang, Shumin; Wu, Sijin; Xie, Zeping; Ling, Guiying; Kuang, Yi-Qun; Yang, Yongliang; Yu, Haining; Wang, Yipeng

2015-01-01

Cathelicidins are a family of gene-encoded peptide effectors of innate immunity found exclusively in vertebrates. They play pivotal roles in host immune defense against microbial invasions. Dozens of cathelicidins have been identified from several vertebrate species. However, no cathelicidin from marine reptiles has been characterized previously. Here we report the identification and characterization of a novel cathelicidin (Hc-CATH) from the sea snake Hydrophis cyanocinctus. Hc-CATH is composed of 30 amino acids, and the sequence is KFFKRLLKSVRRAVKKFRKKPRLIGLSTLL. Circular dichroism spectroscopy and structure modeling analysis indicated that Hc-CATH mainly assumes an amphipathic α-helical conformation in bacterial membrane-mimetic solutions. It possesses potent broad-spectrum and rapid antimicrobial activity. Meanwhile, it is highly stable and shows low cytotoxicity toward mammalian cells. The microbial killing activity of Hc-CATH is executed through the disruption of cell membrane and lysis of bacterial cells. In addition, Hc-CATH exhibited potent anti-inflammatory activity by inhibiting the LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Hc-CATH directly binds with LPS to neutralize its toxicity, and it also binds to Toll-like receptor 4 (TLR4/MD2 complex), which therefore inhibits the binding of LPS to TLR4/MD2 complex and the subsequent activation of LPS-induced inflammatory response pathways. Taken together, our study demonstrates that Hc-CATH, the first cathelicidin from sea snake discovered to have both antimicrobial and anti-inflammatory activity, is a potent candidate for the development of peptide antibiotics. PMID:26013823

Structural analysis as an alternative to identify and determine mode of action of antimicrobial peptides: proposition of a kinetic model based on molecular dynamics studies.

PubMed

Robles-Gomez, Edson Edinho; Flores-Villegas, Mirelle Citlali; Gonzalez-Manjarrez, Alicia; Soriano-Garcia, Manuel

2013-05-01

Antimicrobial peptides (AMPs) constitute an important alternative in the search for new treatments against pathogens. We analyzed the sequence variability in cytokine and chemokine proteins to investigate whether these molecules contain a sequence useful in the development of new AMPs. Cluster analysis allowed the identification of tracts, grouped in five categories showing structure and sequence homology. The structure and function relationship among these groups, was analyzed using physicochemical parameters such as length, sequence, charge, hydrophobicity and helicity, which allowed the selection of a candidate that could constitute an AMP. This peptide comprises the C-terminal alpha-helix of chemokines CXCL4/PF-457-70. Far-UV CD spectroscopy showed that this molecule adopts a random conformation in aqueous solution and the addition of 2, 2, 2 trifluoroethanol (TFE) is required to induce a helical secondary structure. The CXCL4/PF-457-70 peptide was found to have antimicrobial activity and very limited hemolytic activity. The mechanism of action was analyzed using model kinetics and molecular dynamics. The kinetic model led to a reasonable assumption about a rate constant and regulatory step on its mechanism of action. Using molecular dynamics simulations, the structural properties the CXCL4/PF-457-70 have been examined in a membrane environment. Our results show that this peptide has a strong preference for binding to the lipid head groups, consequently, increasing the surface density and decreasing the lateral mobility of the lipids alters its functionality.

Interaction of Gramicidin S and its Aromatic Amino-Acid Analog with Phospholipid Membranes

PubMed Central

Jelokhani-Niaraki, Masoud; Hodges, Robert S.; Meissner, Joseph E.; Hassenstein, Una E.; Wheaton, Laura

2008-01-01

To investigate the mechanism of interaction of gramicidin S-like antimicrobial peptides with biological membranes, a series of five decameric cyclic cationic β-sheet-β-turn peptides with all possible combinations of aromatic D-amino acids, Cyclo(Val-Lys-Leu-D-Ar1-Pro-Val-Lys-Leu-D-Ar2-Pro) (Ar ≡ Phe, Tyr, Trp), were synthesized. Conformations of these cyclic peptides were comparable in aqueous solutions and lipid vesicles. Isothermal titration calorimetry measurements revealed entropy-driven binding of cyclic peptides to POPC and POPE/POPG lipid vesicles. Binding of peptides to both vesicle systems was endothermic—exceptions were peptides containing the Trp-Trp and Tyr-Trp pairs with exothermic binding to POPC vesicles. Application of one- and two-site binding (partitioning) models to binding isotherms of exothermic and endothermic binding processes, respectively, resulted in determination of peptide-lipid membrane binding constants (Kb). The Kb1 and Kb2 values for endothermic two-step binding processes corresponded to high and low binding affinities (Kb1 ≥ 100 Kb2). Conformational change of cyclic peptides in transferring from buffer to lipid bilayer surfaces was estimated using fluorescence resonance energy transfer between the Tyr-Trp pair in one of the peptide constructs. The cyclic peptide conformation expands upon adsorption on lipid bilayer surface and interacts more deeply with the outer monolayer causing bilayer deformation, which may lead to formation of nonspecific transient peptide-lipid porelike zones causing membrane lysis. PMID:18621820

Car safety seats for children: rear facing for best protection

PubMed Central

Henary, B; Sherwood, C P; Crandall, J R; Kent, R W; Vaca, F E; Arbogast, K B; Bull, M J

2007-01-01

Objective To compare the injury risk between rear‐facing (RFCS) and forward‐facing (FFCS) car seats for children less than 2 years of age in the USA. Methods Data were extracted from a US National Highway Traffic Safety Administration vehicle crash database for the years 1988–2003. Children 0–23 months of age restrained in an RFCS or FFCS when riding in passenger cars, sport utility vehicles, or light trucks were included in the study. Logistic regression models and restraint effectiveness calculations were used to compare the risk of injury between children restrained in RFCSs and FFCSs. Results Children in FFCSs were significantly more likely to be seriously injured than children restrained in RFCSs in all crash types (OR = 1.76, 95% CI 1.40 to 2.20). When considering frontal crashes alone, children in FFCSs were more likely to be seriously injured (OR = 1.23), although this finding was not statistically significant (95% CI 0.95 to 1.59). In side crashes, however, children in FFCSs were much more likely to be injured (OR = 5.53, 95% CI 3.74 to 8.18). When 1 year olds were analyzed separately, these children were also more likely to be seriously injured when restrained in FFCSs (OR = 5.32, 95% CI 3.43 to 8.24). Effectiveness estimates for RFCSs (93%) were found to be 15% higher than those for FFCSs (78%). Conclusions RFCSs are more effective than FFCSs in protecting restrained children aged 0–23 months. The same findings apply when 1 year olds are analyzed separately. Use of an RFCS, in accordance with restraint recommendations for child size and weight, is an excellent choice for optimum protection up to a child's second birthday. PMID:18056317

Adolescent chronic restraint stress (aCRS) elicits robust depressive-like behavior in freely cycling, adult female rats without increasing anxiety-like behaviors.

PubMed

Hibicke, Meghan; Graham, Martha A; Hayslett, Renée L

2017-04-01

Stress during times of rapid development is a risk factor for Major Depressive Disorder, a mood disorder that disproportionately affects women. We developed an adolescent chronic restraint stress (aCRS) protocol using female rats to address the impact of adolescent stress on female adult depressive-like behavior. Animals were divided into 4 treatment groups: not restrained:saline (NRSAL), not restrained:desipramine (NRDES), restrained:saline (RSAL), and restrained:desipramine (RDES). NRSAL and NRDES rats were housed in a separate colony room from RSAL and RDES rats. All animals were weighed and handled daily. Beginning postnatal day (PND) 34(±1), RSAL and RDES rats were restrained for 1 hour daily for 14 consecutive days. Beginning PND 55(±1), NRDES and RDES rats were given subcutaneous desipramine (5 mg/kg), which served as a positive control, daily for 14 consecutive days. During that same time period, NRSAL and RSAL rats were given subcutaneous saline daily. aCRS (RSAL and RDES) rats showed significantly attenuated weight gain compared with nonrestrained (NRSAL and NRDES) rats during the restraint period. Weight gain normalized after the final restraint session. Behavioral testing took place PND 68-69(±1), and included open field testing, the elevated plus maze, locomotor activity, and the forced swim test (FST). RSAL rats showed significantly more immobility in the FST versus all other groups, indicating depressive-like behavior. No differences between groups were observed in the other behavioral measures. These results indicate that aCRS elicits depressive-like behavioral characteristics in adult female rats without increasing anxiety-like behaviors. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Restrained Differential Growth: The Initiating Event of Adolescent Idiopathic Scoliosis?

PubMed

Crijns, Tom Joris; Stadhouder, Agnita; Smit, Theodoor Henri

2017-06-15

An experimental model study and a short review of literature. The purpose of this study was to explore a new hypothesis suggesting that the curvatures seen in adolescent idiopathic scoliosis (AIS) originate from restrained differential growth between the vertebral column and the surrounding musculo-ligamentary structures. Despite decades of research, there is no generally accepted theory on the physical origin of the severe spinal deformations seen in AIS. The prevailing theories tend to focus on left-right asymmetry, rotational instability, or the sagittal spinal profile in idiopathic scoliosis. We test our hypothesis with a physical model of the spine that simulates growth, counteracted by ligaments and muscles, modeled by tethers and springs. Growth of the spine is further restrained by an anterior band representing the thorax, the linea alba, and abdominal musculature. We also explore literature in search of molecular mechanisms that may induce differential growth. Differential growth in the restrained spine model first induces hypokyphosis and mild lateral bending of the thoracic spine, but then suddenly escalates into a scoliotic deformity, consistent with clinical observations of AIS. The band simulating the ventral structures of the body had a pivotal effect on sagittal curvature and the initiation of lateral bending and rotation. In literature, several molecular mechanisms were found that may explain the occurrence of differential growth between the spine and the musculo-ligamentary structures. While AIS is a three-dimensional deformation of the spine, it appears that restrained differential growth in the sagittal plane can result in lateral bending and rotation without a pre-existing left-right asymmetry. This supports the concept that AIS may result from a growth imbalance rather than a local anatomical defect. N/A.

Investigation on frictional characteristics and drawbead restraining force of steel with/without coating

NASA Astrophysics Data System (ADS)

Chen, Lianfeng; Zheng, Tianran; Chen, Qing; Zhang, Jun

2013-12-01

Advanced high strength steels (AHSS) are used more and more in automotive industry for increasing crashworthiness and weight reduction. Improving metal flow and reduce friction are important to forming the part and decrease part reject rates of AHSS. The present study focused on friction characteristics and drawbead restraining force of Dual Phase (DP) steels with or without coating, such as DP980, DP780, DP590, DP780+Z, DP780+ZF, DP590+Z, using experimental approach. The effect of material properties, temperature, sliding velocity, surface roughness, dry and lubricant on friction behavior of DP steels is investigated. The contrast of DP steels with mild IF steel is carried out. The restraining force draw through different radius of drawbead is evaluated. This study is benefit to the set up of technique parameters during sheet metal forming simulation.

Photocatalytic, antimicrobial activities of biogenic silver nanoparticles and electrochemical degradation of water soluble dyes at glassy carbon/silver modified past electrode using buffer solution.

PubMed

Khan, Zia Ul Haq; Khan, Amjad; Shah, Afzal; Chen, Yongmei; Wan, Pingyu; Khan, Arif Ullah; Tahir, Kamran; Muhamma, Nawshad; Khan, Faheem Ullah; Shah, Hidayat Ullah

2016-03-01

In the present research work a novel, nontoxic and ecofriendly procedure was developed for the green synthesis of silver nano particle (AgNPs) using Caruluma edulis (C. edulis) extract act as reductant as well as stabilizer agents. The formation of AgNPs was confirmed by UV/Vis spectroscopy. The small and spherical sizes of AgNPs were conformed from high resolution transmission electron microscopy (HRTEM) analysis and were found in the range of 2-10nm, which were highly dispersion without any aggregation. The crystalline structure of AgNPs was conformed from X-ray diffraction (XRD) analysis. For the elemental composition EDX was used and FTIR helped to determine the type of organic compounds in the extract. The potential electrochemical property of modified silver electrode was also studied. The AgNPs showed prominent antibacterial motion with MIC values of 125 μg/mL against Bacillus subtilis and Staphylococcus aureus while 250 μg/mL against Escherichia coli. High cell constituents' release was exhibited by B. subtilis with 2 × MIC value of silver nanoparticles. Silver nanoparticles also showed significant DPPH free radical scavenging activity. This research would have an important implication for the synthesis of more efficient antimicrobial and antioxidant agent. The AgNP modified electrode (GC/AgNPs) exhibited an excellent electro-catalytic activity toward the redox reaction of phenolic compounds. The AgNPs were evaluated for electrochemical degradation of bromothymol blue (BTB) dyes which showed a significant activity. From the strong reductive properties it is obvious that AgNPs can be used in water sanitization and converting some organic perilous in to non-hazardous materials. The AgNPs showed potential applications in the field of electro chemistry, sensor, catalyst, nano-devices and medical. Copyright © 2016 Elsevier B.V. All rights reserved.

Compressive Membrane Capability Estimates in Laterally Edge Restrained Reinforced Concrete One-Way Slabs

DTIC Science & Technology

1999-05-01

by THE UNITED STATES ARMY, I DEPARTMENT OF CIVIL AND MECHANICAL ENGINEERINGI UNITED STATES MILITARY ACADEMY and DEPARTMENT OF CIVIL AND ENVIRONMENTAL ...SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSORING I MONITORING AG-ENCY REPORT NUMBER Department of Civil and Environmental ...LATERALLY EDGE RESTRAINED REINFORCED CONCRETE ONE-WAY SLABS Ronald Wayne Welch, Ph.D. Department of Civil and Environmental Engineering University of

Discovery of unexpected pain in intubated and sedated patients.

PubMed

Clukey, Lory; Weyant, Ruth A; Roberts, Melanie; Henderson, Ann

2014-05-01

The perceptions of patients who are restrained and sedated while being treated with mechanical ventilation in the intensive care unit are not well understood. The effectiveness of sedation used to aid in recovery and enhance comfort during intubation is unknown. To explore the perceptions of patients who were intubated and receiving pain medication while sedated and restrained in the intensive care unit, in particular, their experience and their memories of the experience. In a phenomenological study, 14 patients who were intubated and receiving pain medication while sedated and restrained were interviewed at the bedside. A semistructured interview guide was used. Data were analyzed by using an inductive method consistent with qualitative research. Three major themes were identified from the data: lack of memory of being restrained; a perception of being intubated as horrific; nursing behaviors that were helpful and comforting. An unexpected discovery was that sedation may be interfering with pain assessment and management. Being intubated can be painful and traumatic despite administration of sedatives and analgesics. Sedation may mask uncontrolled pain for intubated patients and prevent them from communicating this condition to a nurse. Nurses may need to evaluate current interventions in order to provide maximum comfort and promote optimal positive outcomes for intensive care patients who are intubated.

Effect of air bags and restraining devices on the pattern of facial fractures in motor vehicle crashes.

PubMed

Simoni, Payman; Ostendorf, Robert; Cox, Artemus J

2003-01-01

To examine the relationship between the use of restraining devices and the incidence of specific facial fractures in motor vehicle crashes. Retrospective analysis of patients with facial fractures following a motor vehicle crash. University of Alabama at Birmingham Hospital level I trauma center from 1996 to 2000. Of 3731 patients involved in motor vehicle crashes, a total of 497 patients were found to have facial fractures as determined by International Classification of Diseases, Ninth Revision (ICD-9) codes. Facial fractures were categorized as mandibular, orbital, zygomaticomaxillary complex (ZMC), and nasal. Use of seat belts alone was more effective in decreasing the chance of facial fractures in this population (from 17% to 8%) compared with the use of air bags alone (17% to 11%). The use of seat belts and air bags together decreased the incidence of facial fractures from 17% to 5%. Use of restraining devices in vehicles significantly reduces the chance of incurring facial fractures in a severe motor vehicle crash. However, use of air bags and seat belts does not change the pattern of facial fractures greatly except for ZMC fractures. Air bags are least effective in preventing ZMC fractures. Improving the mechanics of restraining devices might be needed to minimize facial fractures.

Stress and eating: the effects of ego-threat and cognitive demand on food intake in restrained and emotional eaters.

PubMed

Wallis, D J; Hetherington, M M

2004-08-01

Restrained and emotional eaters overeat in response to stress. To compare differential effects of cognitive demand and ego-threatening stressors on subsequent chocolate intake, 38 females completed a neutral (control), an ego threatening and an incongruent Stroop colour-naming task on three separate occasions. Participants were assigned to four groups based on median-split scores on the restrained and emotional eating scales of the Dutch Eating Behaviour Questionnaire-high restraint/high emotional, high restraint/low emotional, low restraint/high emotional and low restraint/low emotional. Higher response latencies were observed in the incongruent task, confirming its greater cognitive (attentional) demand. Overall intake was enhanced by 23% after ego-threat and 15% after the incongruent Stroop task relative to control. Restraint was associated with greater intake after both ego-threat and the incongruent task than in the control condition. In contrast, emotional eating was associated with greater intake after only the ego-threat, relative to control. A positive association between reaction time and subsequent intake in all conditions for high restraint/low emotional eaters provided support for the limited capacity hypothesis. Enhanced intake in emotional eaters is proposed to relate to escape from self-awareness. These findings demonstrate differential effects of threat and demand on stress-related eating in restrained and emotional eaters.

In-Situ-measurement of restraining forces during forming of rectangular cups

NASA Astrophysics Data System (ADS)

Singer, M.; Liewald, M.

2016-11-01

This contribution introduces a new method for evaluating the restraining forces during forming of rectangular cups with the goal of eliminating the disadvantages of the currently used scientifically established measurement procedures. With this method forming forces are measured indirectly by the elastic deformation of die structure caused by locally varying tribological system. Therefore, two sensors were integrated into the punch, which measure the restraining forces during the forming process. Furthermore, it was possible to evaluate the effects of different lubricants showing the time dependent trend as a function of stroke during the forming of the materials DP600 and DC04. A main advantage of this testing method is to get real friction corresponding data out of the physical deep drawing process as well as the measurement of real acting restraining forces at different areas of the deep drawing part by one single test. Measurement results gained by both sensors have been integrated into LS-Dyna simulation in which the coefficient of friction was regarded as a function of time. The simulated and deep drawn parts afterwards are analysed and compared to specific areas with regard to locally measured thickness of part. Results show an improvement of simulation quality when using locally varying, time dependent coefficients of friction compared to commonly used constant values.

Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.

PubMed

Tran, Hai L; Lexa, Katrina W; Julien, Olivier; Young, Travis S; Walsh, Christopher T; Jacobson, Matthew P; Wells, James A

2017-02-22

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.

Fabrication and characterization of curcumin-loaded silk fibroin/P(LLA-CL) nanofibrous scaffold

NASA Astrophysics Data System (ADS)

Lian, Yuan; Zhan, Jian-Chao; Zhang, Kui-Hua; Mo, Xiu-Mei

2014-12-01

Curcumin exhibited excellent properties including antioxidant, antiinflammatory, antiviral, antibacterial, antifungal, anticancer, and anticoagulant activities. In this study, curcumin was incorporated into silk fibroin (SF)/poly(L-lactic acid- co-e-caprolactone) (P(LLA-CL)) nanofibrous scaffolds via electrospinning, and changes brought about by raising the curcumin content were observed: SEM images showed that the average nanofibrous diameter decreased at the beginning and then increased, and the nanofibers became uniform; FTIR showed that the conformation of SF transforming from random coil form to β-sheet structure had not been induced, while SF conformation converted to β-sheet after being treated with 75% ethanol vapor; XRD results confirmed that the crystal structure of (P(LLA-CL)) had been destroyed; The mechanical test illustrated that nanofibrous scaffolds still maintained good mechanical properties. Further, curcumin-loaded nanofibrous scaffolds were evaluated for drug release, antioxidant and antimicrobial activities in vitro. The results showed that curcumin presented a sustained release behavior from nanofibrous scaffolds and maintained its free radical scavenging ability, and such scaffolds could effectively inhibit S. aureus growth (> 95%). Thus, curcumin-loaded SF/P(LLA-CL) nanofibrous scaffolds might be potential candidates for wound dressing and tissue engineering scaffolds.

Structure of a double-domain phosphagen kinase reveals an asymmetric arrangement of the tandem domains.

PubMed

Wang, Zhiming; Qiao, Zhu; Ye, Sheng; Zhang, Rongguang

2015-04-01

Tandem duplications and fusions of single genes have led to magnificent expansions in the divergence of protein structures and functions over evolutionary timescales. One of the possible results is polydomain enzymes with interdomain cooperativities, few examples of which have been structurally characterized at the full-length level to explore their innate synergistic mechanisms. This work reports the crystal structures of a double-domain phosphagen kinase in both apo and ligand-bound states, revealing a novel asymmetric L-shaped arrangement of the two domains. Unexpectedly, the interdomain connections are not based on a flexible hinge linker but on a rigid secondary-structure element: a long α-helix that tethers the tandem domains in relatively fixed positions. Besides the connective helix, the two domains also contact each other directly and form an interdomain interface in which hydrogen bonds and hydrophobic interactions further stabilize the L-shaped domain arrangement. Molecular-dynamics simulations show that the interface is generally stable, suggesting that the asymmetric domain arrangement crystallographically observed in the present study is not a conformational state simply restrained by crystal-packing forces. It is possible that the asymmetrically arranged tandem domains could provide a structural basis for further studies of the interdomain synergy.

Driving forces for adsorption of amphiphilic peptides to the air-water interface.

PubMed

Engin, Ozge; Villa, Alessandra; Sayar, Mehmet; Hess, Berk

2010-09-02

We have studied the partitioning of amphiphilic peptides at the air-water interface. The free energy of adsorption from bulk to interface was calculated by determining the potential of mean force via atomistic molecular dynamics simulations. To this end a method is introduced to restrain or constrain the center of mass of a group of molecules in a periodic system. The model amphiphilic peptides are composed of alternating valine and asparagine residues. The decomposition of the free energy difference between the bulk and interface is studied for different peptide block lengths. Our analysis revealed that for short amphiphilic peptides the surface driving force dominantly stems from the dehydration of hydrophobic side chains. The only opposing force is associated with the loss of orientational freedom of the peptide at the interface. For the peptides studied, the free energy difference scales linearly with the size of the molecule, since the peptides mainly adopt extended conformations both in bulk and at the interface. The free energy difference depends strongly on the water model, which can be rationalized through the hydration thermodynamics of hydrophobic solutes. Finally, we measured the reduction of the surface tension associated with complete coverage of the interface with peptides.

Computational study of some benzamidine-based inhibitors of thrombin-like snake venom proteinases

NASA Astrophysics Data System (ADS)

Henriques, Elsa S.; Nascimento, Marco A. C.; Ramos, Maria João

Pit viper venoms contain a number of serine proteinases that, despite their observed coagulant thrombin-like action in vitro, exhibit a paradoxical benign defibrinogenating (anticoagulant) action in vivo, with clinical applications in preventing thrombi and improved blood circulation. Considering that several benzamidine-based inhibitors, some highly selective to thrombin, also inhibit the enzymatic activity of such venombins, the modeling of their enzyme-inhibitor interactions could provide valuable information on the topological factors that determine the divergences in activity. The first step, and the object of the present study, was to derive the necessary set of parameters, consistent with the CHARMM force field, and to perform molecular dynamics (MD) simulations on a few selected representatives of the inhibitors in question under physiological conditions. Bonding and van der Waals parameters were derived by analogy to similar ones in the existing force field. Net atomic charges were obtained with a restrained fitting to the molecular electrostatic potential generated at B3LYP/6-31G(d) level. The parameters were refined to reproduce the available experimental geometries and crystal data, and the MD simulations of the free inhibitors in aqueous solution at 298 K provided an insightful description of their available conformational space.

Critical Compressive Stress for Flat Rectangular Plates Supported Along All Edges and Elastically Restrained Against Rotation along the Unloaded Edges

NASA Technical Reports Server (NTRS)

Lundquist, Eugene E; Stowell, Elbridge Z

1942-01-01

A chart is presented for the values of the coefficient in the formula for the critical compressive stress at which buckling may be expected to occur in flat rectangular plates supported along all edges and, in addition, elastically restrained against rotation along the unloaded edges. The mathematical derivations of the formulas required in the construction of the chart are given.

Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling.

PubMed

Artico, M; Di Santo, R; Costi, R; Novellino, E; Greco, G; Massa, S; Tramontano, E; Marongiu, M E; De Montis, A; La Colla, P

1998-10-08

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.

Eating styles and energy intake in young women.

PubMed

Anschutz, Doeschka J; Van Strien, Tatjana; Van De Ven, Monique O M; Engels, Rutger C M E

2009-08-01

The aim of the present study was to examine the relations between restrained, emotional, and external eating and total energy intake, and total fat and carbohydrate intake controlling for body mass index and physical activity. The sample consisted of 475 female students. Energy intake was measured over a 1-month period using the self-report Food Frequency Questionnaire and eating styles were assessed with the Dutch Eating Behaviour Questionnaire. Structural equation modelling was used to analyze the data. The results showed that restrained eating was consistently negatively related to energy intake and fat and carbohydrate intake, whereas external eating was positively related to all dependent variables. Emotional eating was not related to energy intake or fat and carbohydrate intake. Thus, restrained eaters seem to restrict their energy intake, while external eating was found to be associated with higher levels of energy intake, especially of fat intake.

Temperament Dispositions, Problematic Eating Behaviours and Overweight in Adolescents.

PubMed

Walther, Mireille; Hilbert, Anja

2016-01-01

Obesity, a common health condition in adolescence leading to severe medical complications, is assumed to be influenced by temperament factors. This paper investigates associations between reactive and regulative temperament, problematic eating behaviours and excess weight. Several self-report instruments were completed by 130 adolescents (mean age 14.13 ± 0.61 years), including 27 overweight and obese individuals (20.8%). Bootstrap analysis revealed a mediating effect of restrained eating on the relation between reactive temperament and body mass index percentile, which differed according to gender: Restrained eating, which predicted weight gain, was more present in girls having a higher sensitivity to reward and in boys showing a higher sensitivity to punishment. No effect of regulative temperament was found. These results have important implications for weight management programmes, as they suggest that reducing restrained eating by working on temperament may help to control weight. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

The health consequences of using physical restraints in nursing homes.

PubMed

Castle, Nicholas G; Engberg, John

2009-11-01

Using a national longitudinal sample of nursing homes residents (N = 264,068), we examine whether physical restraint use contributes to subsequent physical or psychological health decline. The minimum data set, the on-line survey certification and recording system, and the area resource file were the data sources used. This data represented the period of 2004 and 2005. To control for the difference in characteristics between residents who were subsequently physically restrained and who were not, we use a propensity score matching method. For all outcomes examined (except depression), that is, behavior issues, cognitive performance, falls, walking dependence, activities of daily living, pressure ulcers, and contractures, were all significantly worse for restrained residents compared with matched residents who were not restrained. Physical restraint use represents poor clinical practice, and the benefits to residents of further reducing physical restraint use in nursing homes are substantial.

Containers for use in a self supporting assembly

DOEpatents

Gillespie, Peter J.

1982-07-13

This invention is directed to a container having side walls and end walls forming a body having a generally rectangular cross-section. Means for restraining lateral and rotational movement of the container relative to an adjacent container while allowing relatively unhindered movement perpendicular to the side walls is also included. The lateral and rotational movement is restrained in a plane parallel to the side walls. The means include a projection connected to at least one of the side walls and extending outwardly therefrom to engage the adjacent container. Also part of this invention is an assembly of containers which includes a plurality of the above described containers arranged side by side with the end walls generally coplanar and the side walls generally parallel. Means for restraining movement perpendicular to the side walls of the plurality of containers is also included. Each of the containers may house a plurality of battery electrodes.

Incremental update of electrostatic interactions in adaptively restrained particle simulations.

PubMed

Edorh, Semeho Prince A; Redon, Stéphane

2018-04-06

The computation of long-range potentials is one of the demanding tasks in Molecular Dynamics. During the last decades, an inventive panoply of methods was developed to reduce the CPU time of this task. In this work, we propose a fast method dedicated to the computation of the electrostatic potential in adaptively restrained systems. We exploit the fact that, in such systems, only some particles are allowed to move at each timestep. We developed an incremental algorithm derived from a multigrid-based alternative to traditional Fourier-based methods. Our algorithm was implemented inside LAMMPS, a popular molecular dynamics simulation package. We evaluated the method on different systems. We showed that the new algorithm's computational complexity scales with the number of active particles in the simulated system, and is able to outperform the well-established Particle Particle Particle Mesh (P3M) for adaptively restrained simulations. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Development of high shrinkage polyethylene terephthalate (PET) shape memory polymer tendons for concrete crack closure

NASA Astrophysics Data System (ADS)

Teall, Oliver; Pilegis, Martins; Sweeney, John; Gough, Tim; Thompson, Glen; Jefferson, Anthony; Lark, Robert; Gardner, Diane

2017-04-01

The shrinkage force exerted by restrained shape memory polymers (SMPs) can potentially be used to close cracks in structural concrete. This paper describes the physical processing and experimental work undertaken to develop high shrinkage die-drawn polyethylene terephthalate (PET) SMP tendons for use within a crack closure system. The extrusion and die-drawing procedure used to manufacture a series of PET tendon samples is described. The results from a set of restrained shrinkage tests, undertaken at differing activation temperatures, are also presented along with the mechanical properties of the most promising samples. The stress developed within the tendons is found to be related to the activation temperature, the cross-sectional area and to the draw rate used during manufacture. Comparisons with commercially-available PET strip samples used in previous research are made, demonstrating an increase in restrained shrinkage stress by a factor of two for manufactured PET filament samples.

Compliant hydrodynamic fluid journal bearing

NASA Technical Reports Server (NTRS)

Warren, E. L. (Inventor)

1985-01-01

An air bearing structure is described that prevents destructive bending moments within the top foil. Welds are eliminated by mounting the top bearing foil in the bearing cartridge sleeve without using a space block. Tabs or pins at the end of the top bearing foil are restrained by slots or stops formed in the cartridge sleeve. These structural members are free to move in a direction normal to the shaft while being restrained from movement in the direction of shaft rotation.

Comparative activity and mechanism of action of three types of bovine antimicrobial peptides against pathogenic Prototheca spp.

PubMed

Tomasinsig, Linda; Skerlavaj, Barbara; Scarsini, Michele; Guida, Filomena; Piccinini, Renata; Tossi, Alessandro; Zanetti, Margherita

2012-02-01

The yeast-like algae of the genus Prototheca are ubiquitous saprophytes causing infections in immunocompromised patients and granulomatous mastitis in cattle. Few available therapies and the rapid spread of resistant strains worldwide support the need for novel drugs against protothecosis. Host defence antimicrobial peptides inactivate a wide array of pathogens and are a rich source of leads, with the advantage of being largely unaffected by microbial resistance mechanisms. Three structurally diverse bovine peptides [BMAP-28, Bac5 and lingual antimicrobial peptide (LAP)] have thus been tested for their capacity to inactivate Prototheca spp. In minimum inhibitory concentration (MIC) assays, they were all effective in the micromolar range against clinical mastitis isolates as well as a Prototheca wickerhamii reference strain. BMAP-28 sterilized Prototheca cultures within 30-60 min at its MIC, induced cell permeabilization with near 100% release of cellular adenosine triphosphate and resulted in extensive surface blebbing and release of intracellular material as observed by scanning electron microscopy. Bac5 and LAP inactivated Prototheca following 3-6 h incubation at fourfold their MIC and did not result in detectable surface damage despite 70-90% killing, suggesting they act via non-lytic mechanisms. In circular dichroism studies, the conformation of BMAP-28, but not that of Bac5 or LAP, was affected by interaction with liposomes mimicking algal membranes. Our results indicate that BMAP-28, Bac5 and LAP kill Prototheca with distinct potencies, killing kinetics, and modes of action and may be appropriate for protothecal mastitis treatment. In addition, the ability of Bac5 and LAP to act via non-lytic mechanisms may be exploited for the development of target-selective drugs. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.

TIME management by medicinal larvae.

PubMed

Pritchard, David I; Čeřovský, Václav; Nigam, Yamni; Pickles, Samantha F; Cazander, Gwendolyn; Nibbering, Peter H; Bültemann, Anke; Jung, Wilhelm

2016-08-01

Wound bed preparation (WBP) is an integral part of the care programme for chronic wounds. The acronym TIME is used in the context of WBP and describes four barriers to healing in chronic wounds; namely, dead Tissue, Infection and inflammation, Moisture imbalance and a non-migrating Edge. Larval debridement therapy (LDT) stems from observations that larvae of the blowfly Lucilia sericata clean wounds of debris. Subsequent clinical studies have proven debriding efficacy, which is likely to occur as a result of enzymatically active alimentary products released by the insect. The antimicrobial, anti-inflammatory and wound healing activities of LDT have also been investigated, predominantly in a pre-clinical context. This review summarises the findings of investigations into the molecular mechanisms of LDT and places these in context with the clinical concept of WBP and TIME. It is clear from these findings that biotherapy with L. sericata conforms with TIME, through the enzymatic removal of dead tissue and its associated biofilm, coupled with the secretion of defined antimicrobial peptides. This biotherapeutic impact on the wound serves to reduce inflammation, with an associated capacity for an indirect effect on moisture imbalance. Furthermore, larval serine proteinases have the capacity to alter fibroblast behaviour in a manner conducive to the formation of granulation tissue. © 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Identification of a moronecidin-like antimicrobial peptide in the venomous fish Pterois volitans: Functional and structural study of pteroicidin-α.

PubMed

Houyvet, Baptiste; Bouchon-Navaro, Yolande; Bouchon, Claude; Goux, Didier; Bernay, Benoît; Corre, Erwan; Zatylny-Gaudin, Céline

2018-01-01

The present study characterizes for the first time an antimicrobial peptide in lionfish (Pterois volitans), a venomous fish. Using a peptidomic approach, we identified a mature piscidin in lionfish and called it pteroicidin-α. We detected an amidated form (pteroicidin-α- CONH 2 ) and a non-amidated form (pteroicidin-α-COOH), and then performed their functional and structural study. Interestingly, the two peptides displayed different antibacterial and hemolytic activity levels. Pteroicidin-α-CONH 2 was bactericidal on human pathogens like Staphylococcus aureus or Escherichia coli, as well as on the fish pathogen Aeromonas salmonicida, while pteroicidin-α-COOH only inhibited their growth. Furthermore, the two peptides induced hemolysis of red blood cells from different vertebrates, namely humans, sea bass and lesser-spotted dogfish. Hemolysis occurred with low concentrations of pteroicidin-α-CONH 2 , indicating greater toxicity of the amidated form. Circular dichroism analysis showed that both peptides adopted a helical conformation, yet with a greater α-helix content in pteroicidin-α-CONH 2 . Overall, these results suggest that amidation strongly influences pteroicidin-α by modifying its structure and its physico-chemical characteristics and by increasing its hemolytic activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Elucidating the pH-Dependent Structural Transition of T7 Bacteriophage Endolysin.

PubMed

Sharma, Meenakshi; Kumar, Dinesh; Poluri, Krishna Mohan

2016-08-23

Bacteriophages are the most abundant and diverse biological entities on earth. Bacteriophage endolysins are unique peptidoglycan hydrolases and have huge potential as effective enzybiotics in various infectious models. T7 bacteriophage endolysin (T7L), also known as N-acetylmuramoyl-l-alanine amidase or T7 lysozyme, is a 17 kDa protein that lyses a range of Gram-negative bacteria by hydrolyzing the amide bond between N-acetylmuramoyl residues and the l-alanine of the peptidoglycan layer. Although the activity profiles of several of the T7 family members have been known for many years, the molecular basis for their pH-dependent differential activity is not clear. In this study, we explored the pH-induced structural, stability, and activity characteristics of T7L by applying a variety of biophysical techniques and protein nuclear magnetic resonance (NMR) spectroscopy. Our studies established a reversible structural transition of T7L below pH 6 and the formation of a partially denatured conformation at pH 3. This low-pH conformation is thermally stable and exposed its hydrophobic pockets. Further, NMR relaxation measurements and structural analysis unraveled that T7L is highly dynamic in its native state and a network of His residues are responsible for the observed pH-dependent conformational dynamics and transitions. As bacteriophage chimeric and engineered endolysins are being developed as novel therapeutics against multiple drug resistance pathogens, we believe that our results are of great help in designing these entities as broadband antimicrobial and/or antibacterial agents.

Motor Vehicle Crashes, Medical Outcomes, and Hospital Charges Among Children Aged 1-12 Years - Crash Outcome Data Evaluation System, 11 States, 2005-2008.

PubMed

Sauber-Schatz, Erin K; Thomas, Andrea M; Cook, Lawrence J

2015-10-02

Motor vehicle crashes are a leading cause of death among children. Age- and size-appropriate restraint use is an effective way to prevent motor vehicle-related injuries and deaths. However, children are not always properly restrained while riding in a motor vehicle, and some are not restrained at all, which increases their risk for injury and death in a crash. 2005-2008. The Crash Outcome Data Evaluation System (CODES) is a multistate program facilitated by the National Highway Traffic Safety Administration to probabilistically link police crash reports and hospital databases for traffic safety analyses. Eleven participating states (Connecticut, Georgia, Kentucky, Maryland, Minnesota, Missouri, Nebraska, New York, Ohio, South Carolina, and Utah) submitted data to CODES during the reporting period. Descriptive analysis was used to describe drivers and child passengers involved in motor vehicle crashes and to summarize crash and medical outcomes. Odds ratios and 95% confidence intervals were used to compare a child passenger's likelihood of sustaining specific types of injuries by restraint status (optimal, suboptimal, or unrestrained) and seating location (front or back seat). Because of data constraints, optimal restraint use was defined as a car seat or booster seat use for children aged 1-7 years and seat belt use for children aged 8-12 years. Suboptimal restraint use was defined as seat belt use for children aged 1-7 years. Unrestrained was defined as no use of car seat, booster seat, or seat belt for children aged 1-12 years. Optimal restraint use in the back seat declined with child's age (1 year: 95.9%, 5 years: 95.4%, 7 years: 94.7%, 8 years: 77.4%, 10 years: 67.5%, 12 years: 54.7%). Child restraint use was associated with driver restraint use; 41.3% of children riding with unrestrained drivers also were unrestrained compared with 2.2% of children riding with restrained drivers. Child restraint use also was associated with impaired driving due to alcohol or drug use; 16.4% children riding with drivers suspected of alcohol or drug use were unrestrained compared with 2.9% of children riding with drivers not suspected of such use. Optimally restrained and suboptimally restrained children were less likely to sustain a traumatic brain injury than unrestrained children. The 90th percentile hospital charges for children aged 4-7 years who were in motor vehicle crashes were $1,630.00 and $1,958.00 for those optimally restrained in a back seat and front seat, respectively; $2,035.91 and $3,696.00 for those suboptimally restrained in a back seat and front seat, respectively; and $9,956.60 and $11,143.85 for those unrestrained in a back seat and front seat, respectively. Proper car seat, booster seat, and seat belt use among children in the back seat prevents injuries and deaths, as well as averts hospital charges. However, the number, severity, and cost of injuries among children in crashes who were not optimally restrained or who were seated in a front seat indicates the need for improvements in proper use of age- and size-appropriate car seats, booster seats, and seat belts in the back seat. Effective interventions for increasing proper child restraint use could be universally implemented by states and communities to prevent motor vehicle-related injuries among children and their resulting costs.

Persistent rupture terminations at a restraining bend from slip rates on the eastern Altyn Tagh fault

NASA Astrophysics Data System (ADS)

Elliott, A. J.; Oskin, M. E.; Liu-zeng, J.; Shao, Y.-X.

2018-05-01

Restraining double-bends along strike-slip faults inhibit or permit throughgoing ruptures depending on bend angle, length, and prior rupture history. Modeling predicts that for mature strike-slip faults in a regional stress regime characterized by simple shear, a restraining bend of >18° and >4 km length impedes propagating rupture. Indeed, natural evidence shows that the most recent rupture(s) of the Xorkoli section (90°-93°E) of the eastern Altyn Tagh fault (ATF) ended at large restraining bends. However, when multiple seismic cycles are considered in numerical dynamic rupture modeling, heterogeneous residual stresses enable some ruptures to propagate further, modulating whether the bends persistently serve as barriers. These models remain to be tested using observations of the cumulative effects of multiple earthquake ruptures. Here we investigate whether a large restraining double-bend on the ATF serves consistently as a barrier to rupture by measuring long-term slip rates around the terminus of its most recent surface rupture at the Aksay bend. Our results show a W-E decline in slip as the SATF enters the bend, as would be predicted from repeated rupture terminations there. Prior work demonstrated no Holocene slip on the central, most misoriented portion of the bend, while 19-79 m offsets suggest that multiple ruptures have occurred on the west side of the bend during the Holocene. Thus we conclude the gradient in the SATF's slip rate results from the repeated termination of earthquake ruptures there. However, a finite slip rate east of the bend represents the transmission of some slip, suggesting that a small fraction of ruptures may fully traverse or jump the double-bend. This agreement between natural observations of slip accumulation and multi-cycle models of fault rupture enables us to translate observed slip rates into insight about the dynamic rupture process of individual earthquakes as they encounter geometric complexities along faults.

The Impact of Child Safety Restraint Status and Age in Motor Vehicle Collisions in Predicting Type and Severity of Bone Fractures and Traumatic Injuries.

PubMed

Loftis, Christopher M; Sawyer, Jeffrey R; Eubanks, James W; Kelly, Derek M

2017-12-01

Although morbidity and mortality in children increases in motor vehicle collisions (MVC) if child restraints are not used, no data exist correlating specific injuries with proper or improper use of safety restraints or age. The purpose of this study was to evaluate correlations between childhood MVC injuries, age, and restraint status. A medical record search for pediatric patients involved in a MVC was conducted at a pediatric hospital (level 1 trauma). Charts were reviewed for demographics and injury-specific information. Patients were grouped by age, restraint use, and injuries. Nine hundred sixty-seven patients ≤12 years (average age 6.39 y) were identified. Being properly restrained was most common in all age groups except the 4- to 8-year age group in which being improperly restrained was most common. Unrestrained patients were most commonly found in the 9- to 12-year age group. A statistically significant difference was not observed for orthopaedic injuries among the restraint groups, but internal thoracic injuries, open head wound, and open upper extremity wounds were significantly more common in improperly or unrestrained patients. Improperly restrained infants had a significantly higher rate of intracranial bleeds and abrasions than those properly restrained. Unrestrained and improperly restrained 9- to 12-year olds had significantly more open head, open upper extremity, and vascular injuries. When comparing injury types with age groups, upper extremity fractures, femoral fractures, dislocations, and spinal fractures were found to be significantly higher in older children. Preventing orthopaedic injuries in older children may be accomplished by changes in regulations or automotive safety equipment. Rear-facing child safety seats could possibly be improved to prevent head trauma in the youngest patients. There is a continued need to reinforce the importance of proper use of child safety devices to parents. Knowledge of the patient's age, along with restraint status, might aid in diagnosis of less obvious MCV injuries. Level III.

Weldability of High-tensile Steels from Experience in Airplane Construction, with Special Reference to Welding Crack Susceptibility

NASA Technical Reports Server (NTRS)

Muller, J

1935-01-01

The concept of welding crack tendency is explained and illustrated with practical examples. All pertinent causes are enumerated, and experimental measures are given through which the secondary effects can be removed and the principal causes analyzed: 1) welding stresses; and 2) material defects. The variations in length and stresses incident to welding a small bar as free weld, with restrained elongation and restrained elongation and contraction, are explored in three fundamental experiments.

The impact of caloric preloading on attempts at food and eating-related thought suppression in restrained and unrestrained eaters.

PubMed

O'Connell, Cara; Larkin, Kevin; Mizes, J Scott; Fremouw, William

2005-07-01

The current study examined the impact of dietary restraint and caloric preload on thought suppression in a sample of 64 college females classified as either restrained or unrestrained eaters. Participants engaged in a 60-min laboratory session. One half of the participants were preloaded with a high-calorie milkshake and all participants were randomly assigned to a food and eating-related thought suppression condition or a no suppression control condition. Food-related thoughts were assessed with a digital counter and verbal references to food were tracked with an audio recorder. Restrained participants instructed to suppress food-related thoughts demonstrated significantly more food and eating-related thoughts than unrestrained participants. Preloading was associated with an increase in the frequency of indirect mentions to food and eating. Although the hypothesized "rebound" effect did not occur for any study groups, these findings indicate that both restraint status and preloading impact food and eating-related thoughts. Copyright 2005 by Wiley Periodicals, Inc

Ergodicity and model quality in template-restrained canonical and temperature/Hamiltonian replica exchange coarse-grained molecular dynamics simulations of proteins.

PubMed

Karczyńska, Agnieszka S; Czaplewski, Cezary; Krupa, Paweł; Mozolewska, Magdalena A; Joo, Keehyoung; Lee, Jooyoung; Liwo, Adam

2017-12-05

Molecular simulations restrained to single or multiple templates are commonly used in protein-structure modeling. However, the restraints introduce additional barriers, thus impairing the ergodicity of simulations, which can affect the quality of the resulting models. In this work, the effect of restraint types and simulation schemes on ergodicity and model quality was investigated by performing template-restrained canonical molecular dynamics (MD), multiplexed replica-exchange molecular dynamics, and Hamiltonian replica exchange molecular dynamics (HREMD) simulations with the coarse-grained UNRES force field on nine selected proteins, with pseudo-harmonic log-Gaussian (unbounded) or Lorentzian (bounded) restraint functions. The best ergodicity was exhibited by HREMD. It has been found that non-ergodicity does not affect model quality if good templates are used to generate restraints. However, when poor-quality restraints not covering the entire protein are used, the improved ergodicity of HREMD can lead to significantly improved protein models. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Superconducting magnetic energy storage apparatus structural support system

DOEpatents

Withers, Gregory J.; Meier, Stephen W.; Walter, Robert J.; Child, Michael D.; DeGraaf, Douglas W.

1992-01-01

A superconducting magnetic energy storage apparatus comprising a cylindrical superconducting coil; a cylindrical coil containment vessel enclosing the coil and adapted to hold a liquid, such as liquefied helium; and a cylindrical vacuum vessel enclosing the coil containment vessel and located in a restraining structure having inner and outer circumferential walls and a floor; the apparatus being provided with horizontal compression members between (1) the coil and the coil containment vessel and (2) between the coil containment vessel and the vacuum vessel, compression bearing members between the vacuum vessel and the restraining structure inner and outer walls, vertical support members (1) between the coil bottom and the coil containment vessel bottom and (2) between the coil containment vessel bottom and the vacuum vessel bottom, and external supports between the vacuum vessel bottom and the restraining structure floor, whereby the loads developed by thermal and magnetic energy changes in the apparatus can be accommodated and the structural integrity of the apparatus be maintained.

Lateral restraint assembly for reactor core

DOEpatents

Gorholt, Wilhelm; Luci, Raymond K.

1986-01-01

A restraint assembly for use in restraining lateral movement of a reactor core relative to a reactor vessel wherein a plurality of restraint assemblies are interposed between the reactor core and the reactor vessel in circumferentially spaced relation about the core. Each lateral restraint assembly includes a face plate urged against the outer periphery of the core by a plurality of compression springs which enable radial preloading of outer reflector blocks about the core and resist low-level lateral motion of the core. A fixed radial key member cooperates with each face plate in a manner enabling vertical movement of the face plate relative to the key member but restraining movement of the face plate transverse to the key member in a plane transverse to the center axis of the core. In this manner, the key members which have their axes transverse to or subtending acute angles with the direction of a high energy force tending to move the core laterally relative to the reactor vessel restrain such lateral movement.

Antimicrobial and host cell-directed activities of Gly/Ser-rich peptides from salmonid cathelicidins.

PubMed

D'Este, Francesca; Benincasa, Monica; Cannone, Giuseppe; Furlan, Michela; Scarsini, Michele; Volpatti, Donatella; Gennaro, Renato; Tossi, Alessandro; Skerlavaj, Barbara; Scocchi, Marco

2016-12-01

Cathelicidins, a major family of vertebrate antimicrobial peptides (AMPs), have a recognized role in the first line of defense against infections. They have been identified in several salmonid species, where the putative mature peptides are unusually long and rich in serine and glycine residues, often arranged in short multiple repeats (RLGGGS/RPGGGS) intercalated by hydrophobic motifs. Fragments of 24-40 residues, spanning specific motifs and conserved sequences in grayling or brown, rainbow and brook trout, were chemically synthesized and examined for antimicrobial activity against relevant Gram-positive and Gram-negative salmonid pathogens, as well as laboratory reference strains. They were not active in complete medium, but showed varying potency and activity spectra in diluted media. Bacterial membrane permeabilization also occurred only under these conditions and was indicated by rapid propidium iodide uptake in peptide-treated bacteria. However, circular dichroism analyses indicated that they did not significantly adopt ordered conformations in membrane-like environments. The peptides were not hemolytic or cytotoxic to trout cells, including freshly purified head kidney leukocytes (HKL) and the fibroblastic RTG-2 cell line. Notably, when exposed to them, HKL showed increased metabolic activity, while a growth-promoting effect was observed on RTG-2 cells, suggesting a functional interaction of salmonid cathelicidins with host cells similar to that shown by mammalian ones. The three most active peptides produced a dose-dependent increase in phagocytic uptake by HKL simultaneously stimulated with bacterial particles. The peptide STF(1-37), selected for further analyses, also enhanced phagocytic uptake in the presence of autologous serum, and increased intracellular killing of live E. coli. Furthermore, when tested on HKL in combination with the immunostimulant β-glucan, it synergistically potentiated both phagocytic uptake and the respiratory burst response, activities that play a key role in fish immunity. Collectively, these data point to a role of salmonid cathelicidins as modulators of fish microbicidal mechanisms beyond a salt-sensitive antimicrobial activity, and encourage further studies also in view of potential applications in aquaculture. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural Characterization of an Alternative Mode of Tigecycline Binding to the Bacterial Ribosome

PubMed Central

Schedlbauer, Andreas; Kaminishi, Tatsuya; Ochoa-Lizarralde, Borja; Dhimole, Neha; Zhou, Shu; López-Alonso, Jorge P.

2015-01-01

Although both tetracycline and tigecycline inhibit protein synthesis by sterically hindering the binding of tRNA to the ribosomal A site, tigecycline shows increased efficacy in both in vitro and in vivo activity assays and escapes the most common resistance mechanisms associated with the tetracycline class of antibiotics. These differences in activities are attributed to the tert-butyl-glycylamido side chain found in tigecycline. Our structural analysis by X-ray crystallography shows that tigecycline binds the bacterial 30S ribosomal subunit with its tail in an extended conformation and makes extensive interactions with the 16S rRNA nucleotide C1054. These interactions restrict the mobility of C1054 and contribute to the antimicrobial activity of tigecycline, including its resistance to the ribosomal protection proteins. PMID:25753625

Comparison of biochemical stress indicators in juvenile captive estuarine crocodiles (Crocodylus porosus) following physical restraint or chemical restraint by midazolam injection.

PubMed

Olsson, Annabelle; Phalen, David

2013-07-01

Using a prospective, randomized study design we demonstrate that midazolam sedation minimizes acidosis compared with physical restraint in captive juvenile estuarine crocodiles during handling or noninvasive procedures at preferred body temperature. A dose of midazolam (5.0 mg/kg) was administered intramuscularly into the forelimb of 20 male estuarine crocodiles weighing 2-3.5 kg. Their heart and respiratory rate and degree of sedation were monitored until recovery and then daily for 7 subsequent days. Blood samples were taken at 30, 60, 90, 180, and 360 min. We recorded lactate, partial pressure of carbon dioxide (CO2), hematocrit, glucose, and blood pH. A second group (1.9-2.6 kg) was physically restrained for 5 min and the same parameters recorded. Physically restrained animals demonstrated elevated heart rate, respiratory rate, glucose, lactate, and anion gap compared with the midazolam-treated group. Physically restrained animals had lower pH, bicarbonate, and partial pressure of CO2 compared with the midazolam-treated group. Behavior in the physically restrained group in the days following the study was disrupted, with reluctance to feed and bask, compared with midazolam-treated animals whose behavior was normal. We conclude that midazolam administered in the forelimb of captive estuarine crocodiles of 2-3.5 kg provides predictable onset and duration of sedation enabling physical examination, sample collection, and translocation of the animals with minimal disturbance to lactate, pH, and CO2. Behavior following recovery appears normal.

Emotions and eating. Self-reported and experimentally induced changes in food intake under stress.

PubMed

Wallis, D J; Hetherington, M M

2009-04-01

Two studies investigated the stress-eating relationship. The first examined self-reported changes in intake of snack foods, whilst the second investigated stress-induced overconsumption in a laboratory setting comparing high (HF) and low-fat (LF) snacks. Eighty-nine females completed the Dutch Eating Behaviour Questionnaire (DEBQ) [Van Strien, T., Fritjers, J. E. R., Bergers, G. P. A., & Defares, P. B. (1986). Dutch Eating Behaviour Questionnaire for assessment of restrained, emotional and external eating behaviour. International Journal of Eating Disorders, 5, 295-315] and a self-report measure designed to evaluate changes in eating in response to stress. Increased intake of HF snacks was associated with high emotional eating but not with restraint. A laboratory-based experiment compared intake of HF and LF snacks after ego-threatening and neutral Stroop colour-naming tasks. Intake was suppressed by 31.8% in restrained compared to unrestrained eaters across tasks. Restrained eaters consumed significantly less after ego-threat than after the neutral manipulation, but this was associated only with intake of the LF snack. Restrained eaters' intake of dried fruit was suppressed by 33.2% after ego-threat relative to the neutral task, despite a significant increase in hunger for this group following ego-threat. These results suggest that the type and variety of foods offered influences the link between stress and eating in laboratory settings. Further research should aim to replicate and extend these findings, with a view to informing potential interventions for stress-related eating.

DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth

PubMed Central

Wu, Chunlai; Daniels, Richard W; DiAntonio, Aaron

2007-01-01

Background The growth of new synapses shapes the initial formation and subsequent rearrangement of neural circuitry. Genetic studies have demonstrated that the ubiquitin ligase Highwire restrains synaptic terminal growth by down-regulating the MAP kinase kinase kinase Wallenda/dual leucine zipper kinase (DLK). To investigate the mechanism of Highwire action, we have identified DFsn as a binding partner of Highwire and characterized the roles of DFsn in synapse development, synaptic transmission, and the regulation of Wallenda/DLK kinase abundance. Results We identified DFsn as an F-box protein that binds to the RING-domain ubiquitin ligase Highwire and that can localize to the Drosophila neuromuscular junction. Loss-of-function mutants for DFsn have a phenotype that is very similar to highwire mutants – there is a dramatic overgrowth of synaptic termini, with a large increase in the number of synaptic boutons and branches. In addition, synaptic transmission is impaired in DFsn mutants. Genetic interactions between DFsn and highwire mutants indicate that DFsn and Highwire collaborate to restrain synaptic terminal growth. Finally, DFsn regulates the levels of the Wallenda/DLK kinase, and wallenda is necessary for DFsn-dependent synaptic terminal overgrowth. Conclusion The F-box protein DFsn binds the ubiquitin ligase Highwire and is required to down-regulate the levels of the Wallenda/DLK kinase and restrain synaptic terminal growth. We propose that DFsn and Highwire participate in an evolutionarily conserved ubiquitin ligase complex whose substrates regulate the structure and function of synapses. PMID:17697379

Head impact contact points for restrained child occupants.

PubMed

Arbogast, Kristy B; Wozniak, Samantha; Locey, Caitlin M; Maltese, Matthew R; Zonfrillo, Mark R

2012-01-01

Head injuries are the most common injuries sustained by children in motor vehicle crashes regardless of age, restraint, and crash direction. For rear seat occupants, the interaction of the subject with the seat back and the vehicle side interior structures has been previously highlighted. In order to advance this knowledge to the development of countermeasures, a summary of vehicle components that contributed to these injuries is needed. Therefore, the objective of this study was to create a contact map of the vehicle interior for head and face injuries to rear-seated restrained children in front crashes. The Crash Injury Research and Engineering Network (CIREN) was queried for rear-seated, restrained child occupants (age 0-15 years) in forward-facing child restraints, booster seats, or lap and shoulder belts who sustained an AIS2+ head and/or face injury in a frontal motor vehicle crash. Cases were analyzed to describe injury patterns and injury causation scenarios. A contact point map was developed to summarize the vehicle components related to injury causation of the head/face injury. Twenty-one cases met the combined inclusion and exclusion criteria. Seven of the child occupants were restrained in forward-facing child restraints, 2 in belt-positioning booster seats, and 12 in lap and shoulder belts. There were 28 head and 17 facial injuries. For left rear occupants, the most common contact point was the pillar in front of the occupant's seat row; that is, B-pillar for second-row occupants, indicating a leftward kinematics. For right rear occupants, due to differences in crash dynamics, the most common contact point location was the passenger's seat back, suggesting that these occupants moved predominantly forward. Contact points associated with head/face injury for restrained children 0 to 15 years in frontal crashes have been delineated. In a majority of the cases, the head/face injury was the most severe injury and severe injuries to other body regions were uncommon, suggesting that efforts to mitigate head injuries for these occupants would greatly improve their overall safety. The majority of the head/face contact points were to the first row seat back and B-pillar. In these frontal crashes, the importance of head/face contact with the vehicle side structure suggests that deploying a curtain air bag in frontal impacts may help manage the energy of impact. These data advance the current understanding of injury patterns and causation in frontal crashes involving restrained rear-row occupants and can be used to develop solutions to mitigate the injuries sustained. Copyright © 2012 Taylor & Francis Group, LLC

Stroop interference and food intake.

PubMed

Overduin, J; Jansen, A; Louwerse, E

1995-11-01

The Stroop task is aimed at assessing attentional bias. Words are displayed one by one on a computer screen and subjects are instructed to name the color in which every word is printed. The attentional bias is supposed to be reflected in the extent to which the word meanings interfere with the speed of color naming: The longer the color naming latency, the larger the attentional bias. Experiments using this task have demonstrated attentional bias for eating and body shape-related words in bulimic, anorexic, and restrained subjects. Explanations of these results have generally been formulated in terms of restricted food intake or emotional concerns about food and body shape-related themes. In contrast, in the present article it was proposed that Stroop interference might reflect a tendency either to withdraw or approach food or body shape-related stimuli. Fifty-one subjects (25 unrestrained, 26 restrained) were administered a Stroop task containing neutral, food, and body shape-related words. There were two conditions to which subjects were randomly allocated: the "appetizer" and "no-appetizer" condition. The appetizer was a bit of pudding to be ingested by the subject just before the Stroop task. Following the Stroop task an ice cream taste test was presented in which the subjects were allowed to eat as much as they liked. The amount of ice cream eaten was registered secretly. The results show that in unrestrained subjects Stroop interference for food words was found only in the appetizer condition. Restrained subjects, however, showed a permanent interference for food words. A significant correlation of .58 between Stroop food-word interference and ice cream intake was found only in unrestrained subjects. In restrained eaters the correlation was near 0. No effect of condition or restraint was found on Stroop body shape-word interference. The findings indicate that (1) ingestion of an appetizer seems to have evoked an attentional bias for food words in nonrestraints that correlated with food intake; (2) restrained eaters showed continuous attentional bias. This appears to support the urge-to-act explanation of Stroop interference. The lack of correlation between restraints' attentional bias and ad lib food intake could have been caused by inhibition of approach which is one of the characteristics of restrained eating: The present procedure seems not to have triggered disinhibited eating in these subjects. Among other things it is concluded that Stroop interference, as a measure of "craving" triggered by food cue, might be a useful aid in assessing the risk of relapse in treated binge eating patients.

Self-interrupted synthesis of sterically hindered aliphatic polyamide dendrimers

PubMed Central

Jishkariani, Davit; Timsina, Yam N.; Grama, Silvia; Gillani, Syeda S.; Divar, Masoumeh; Yadavalli, Srujana S.; Moussodia, Ralph-Olivier; Leowanawat, Pawaret; Berrios Camacho, Angely M.; Walter, Ricardo; Goulian, Mark; Klein, Michael L.; Percec, Virgil

2017-01-01

2,2-Bis(azidomethyl)propionic acid was prepared in four steps and 85% yield from the commercially available 2,2-bis(hydroxymethyl)propionic acid and used as the starting building block for the divergent, convergent, and double-stage convergent–divergent iterative methods for the synthesis of dendrimers and dendrons containing ethylenediamine (EDA), piperazine (PPZ), and methyl 2,2-bis(aminomethyl)propionate (COOMe) cores. These cores have the same multiplicity but different conformations. A diversity of synthetic methods were used for the synthesis of dendrimers and dendrons. Regardless of the method used, a self-interruption of the synthesis was observed at generation 4 for the dendrimer with an EDA core and at generation 5 for the one with a PPZ core, whereas for the COOMe core, self-interruption was observed at generation 6 dendron, which is equivalent to generation 5 dendrimer. Molecular modeling and molecular-dynamics simulations demonstrated that the observed self-interruption is determined by the backfolding of the azide groups at the periphery of the dendrimer. The latter conformation inhibits completely the heterogeneous hydrogenation of the azide groups catalyzed by 10% Pd/carbon as well as homogeneous hydrogenation by the Staudinger method. These self-terminated polyamide dendrimers are enzymatically and hydrolytically stable and also exhibit antimicrobial activity. Thus, these nanoscale constructs open avenues for biomedical applications. PMID:28270599

Utilizing a Dynamical Description of IspH to Aid in the Development of Novel Antimicrobial Drugs

PubMed Central

Blachly, Patrick G.; de Oliveira, César A. F.; Williams, Sarah L.; McCammon, J. Andrew

2013-01-01

The nonmevalonate pathway is responsible for isoprenoid production in microbes, including H. pylori, M. tuberculosis and P. falciparum, but is nonexistent in humans, thus providing a desirable route for antibacterial and antimalarial drug discovery. We coordinate a structural study of IspH, a [4Fe-4S] protein responsible for converting HMBPP to IPP and DMAPP in the ultimate step in the nonmevalonate pathway. By performing accelerated molecular dynamics simulations on both substrate-free and HMBPP-bound [Fe4S4]2+ IspH, we elucidate how substrate binding alters the dynamics of the protein. Using principal component analysis, we note that while substrate-free IspH samples various open and closed conformations, the closed conformation observed experimentally for HMBPP-bound IspH is inaccessible in the absence of HMBPP. In contrast, simulations with HMBPP bound are restricted from accessing the open states sampled by the substrate-free simulations. Further investigation of the substrate-free simulations reveals large fluctuations in the HMBPP binding pocket, as well as allosteric pocket openings – both of which are achieved through the hinge motions of the individual domains in IspH. Coupling these findings with solvent mapping and various structural analyses reveals alternative druggable sites that may be exploited in future drug design efforts. PMID:24367248

Purification and Molecular Characterization of the Novel Highly Potent Bacteriocin TSU4 Produced by Lactobacillus animalis TSU4.

PubMed

Sahoo, Tapasa Kumar; Jena, Prasant Kumar; Patel, Amiya Kumar; Seshadri, Sriram

2015-09-01

Bacterial infections causing fish diseases and spoilage during fish food processing and storage are major concerns in aquaculture. Use of bacteriocins has recently been considered as an effective strategy for prevention of bacterial infections. A novel bacteriocin produced by Catla catla gut isolates, Lactobacillus animalis TSU4, designated as bacteriocin TSU4 was purified to homogeneity by a three-step protocol. The molecular mass of bacteriocin TSU4 was 4117 Da determined by Q-TOF LC/MS analysis. Its isoelectric point was ~9. Secondary conformation obtained by circular dichroism spectroscopy showed molecular conformation with significant proportions of the structure in α-helix (23.7 %) and β-sheets (17.1 %). N-terminal sequencing was carried out by the Edman degradation method; partial sequence identified was NH2-SMSGFSKPHD. Bacteriocin TSU4 exhibited a wide range of antimicrobial activity, pH and thermal stability. It showed a bacteriocidal mode of action against the indicator strain Aeromonas hydrophila MTCC 646. Bacteriocin TSU4 is the first reported bacteriocin produced by fish isolate Lactobacillus animalis. The characterization of bacteriocin TSU4 suggested that it is a novel bacteriocin with potential value against infections of bacteria such as A. hydrophila MTCC 646 and Pseudomonas aeruginosa MTCC 1688 and application to prevent spoilage during food preservation.

A Nuclease from Streptococcus mutans Facilitates Biofilm Dispersal and Escape from Killing by Neutrophil Extracellular Traps

PubMed Central

Liu, Jia; Sun, Luping; Liu, Wei; Guo, Lihong; Liu, Zhaohui; Wei, Xi; Ling, Junqi

2017-01-01

Streptococcus mutans is the primary etiologic agent of dental caries and occasionally infective endocarditis, with the ability to form biofilms and disperse cells into distal sites to exacerbate and spread infection. In this study, we identified a nuclease (DeoC) as a S. mutans biofilm dispersal modulating factor through microarray analysis. In vitro assays revealed a dispersal defect of a deoC deletion mutant, and functional studies with purified protein were indicative of the biofilm dispersal activity of DeoC. Neutrophils are a key host response factor restraining bacterial spreading through the formation of neutrophil extracellular traps (NETs), which consist of a nuclear DNA backbone associated with antimicrobial peptides. Therefore, we hypothesized that the dispersed S. mutans might utilize DeoC to degrade NETs and escape killing by the immune system. It was found that S. mutans induced NET formation upon contact with neutrophils, while the presence of NETs in turn enhanced the deoC expression of S. mutans. Fluorescence microscopy inspection showed that deoC deletion resulted in a decreased NET degradation ability of S. mutans and enhanced susceptibility to neutrophil killing. Data obtained from this study assigned two important roles for DeoC in S. mutans: contributing to the spread of infection through mediating biofilm dispersal, and facilitating the escape of S. mutans from neutrophil killing through NET degradation. PMID:28401067

A Nuclease from Streptococcus mutans Facilitates Biofilm Dispersal and Escape from Killing by Neutrophil Extracellular Traps.

PubMed

Liu, Jia; Sun, Luping; Liu, Wei; Guo, Lihong; Liu, Zhaohui; Wei, Xi; Ling, Junqi

2017-01-01

Streptococcus mutans is the primary etiologic agent of dental caries and occasionally infective endocarditis, with the ability to form biofilms and disperse cells into distal sites to exacerbate and spread infection. In this study, we identified a nuclease (DeoC) as a S. mutans biofilm dispersal modulating factor through microarray analysis. In vitro assays revealed a dispersal defect of a deoC deletion mutant, and functional studies with purified protein were indicative of the biofilm dispersal activity of DeoC. Neutrophils are a key host response factor restraining bacterial spreading through the formation of neutrophil extracellular traps (NETs), which consist of a nuclear DNA backbone associated with antimicrobial peptides. Therefore, we hypothesized that the dispersed S. mutans might utilize DeoC to degrade NETs and escape killing by the immune system. It was found that S. mutans induced NET formation upon contact with neutrophils, while the presence of NETs in turn enhanced the deoC expression of S. mutans . Fluorescence microscopy inspection showed that deoC deletion resulted in a decreased NET degradation ability of S. mutans and enhanced susceptibility to neutrophil killing. Data obtained from this study assigned two important roles for DeoC in S. mutans : contributing to the spread of infection through mediating biofilm dispersal, and facilitating the escape of S. mutans from neutrophil killing through NET degradation.

Perceptions regarding workplace hazards at a veterinary teaching hospital.

PubMed

Weaver, Dustin R; Newman, Lee S; Lezotte, Dennis C; Morley, Paul S

2010-07-01

To assess perceptions of personnel working at a veterinary teaching hospital regarding risks of occupational hazards and compare those perceptions with assessments made by occupational safety experts. Cross-sectional study. A representative sample of personnel (n = 90) working at the veterinary teaching hospital at Colorado State University and a panel of 3 occupational safety experts. Hospital personnel ranked perceptions of 14 physical, chemical, and biological workplace hazards and listed the injuries, illnesses, and near misses they had experienced. The expert panel provided consensus rankings of the same 14 hazards for 9 sections of the facility. Risk perceptions provided by the 2 sources were compared. Risk perceptions did not differ significantly between hospital personnel and the expert panel for most of the site-specific comparisons (94/126 [75%]). Personnel perceived greater risks for some physical hazards (loud noises, sharps injuries, and ionizing radiation) and some chemical or materials exposures (insecticides or pesticides and tissue digester emissions). In contrast, the expert panel perceived greater risks for physical hazards (bite or crush and restraining and moving animals), chemical exposures (anesthetic waste gas), and biological exposures (Toxoplasma gondii, antimicrobial-resistant bacteria, and allergens). Participants and safety experts had similar perceptions about occupational risks, but there were important differences where hospital personnel apparently overestimated or underappreciated the risks for workplace hazards. This type of study may be useful in guiding development of optimal workplace safety programs for veterinary hospitals.

Review of Research and Application of Reinforced Concrete Structures Strengthened by Braces

NASA Astrophysics Data System (ADS)

Gong, Jing; Zhu, Zezhong; Zeng, Cong

2017-06-01

Many of RC frame structures are urgently needed to be strengthened and maintained due to the increase of service life, the change of use function, and the impact of natural disasters. This paper reviews the research status of strengthening RC structures with braces; introduces the features and connection forms of joints connecting with braces; summarizes the engineering application of buckling-restrained braces, pointing out that buckling-restrained brace is an effective means to strengthen the RC frame structures with more reliable performance and broad application prospect.

Efficacy of 3D conforming nickel titanium rotary instruments in eliminating canal wall bacteria from oval-shaped root canals.

PubMed

Bortoluzzi, Eduardo A; Carlon, Daniel; Meghil, Mohamed M; El-Awady, Ahmed R; Niu, Lina; Bergeron, Brian E; Susin, Lisiane; Cutler, Christopher W; Pashley, David H; Tay, Franklin R

2015-05-01

To evaluate the effectiveness of TRUShape® 3D Conforming Files, compared with Twisted Files, in reducing bacteria load from root canal walls, in the presence or absence of irrigant agitation. Extracted human premolars with single oval-shaped canals were infected with Enterococcus faecalis. Teeth in Group I (N=10; NaOCl and QMix® 2in1 as respective initial and final irrigants) were subdivided into 4 subgroups: (A) TRUShape® instrumentation without irrigant activation; (B) TRUShape® instrumentation with sonic irrigant agitation; (C) Twisted Files without irrigant agitation; (D) Twisted Files with sonic irrigant agitation. To remove confounding factor (antimicrobial irrigants), teeth in Group II (N=10) were irrigated with sterile saline, using the same subgroup designations. Specimens before and after chemomechanical débridement were cultured for quantification of colony-forming units (CFUs). Data from each group were analyzed separately using two-factor ANOVA and Holm-Sidak multiple comparison (α=0.05). Canal wall bacteria were qualitatively examined using scanning electron microscopy (SEM) and light microscopy of Taylor-modified Brown and Brenn-stained demineralised sections. CFUs from subgroups in Group I were not significantly different (P=0.935). For Group II, both file type (P<0.001) and irrigant agitation (P<0.001) significantly affected log-reduction in CFU concentrations. The interaction of these two factors was not significant (P=0.601). Although SEM showed reduced canal wall bacteria, bacteria were present within dentinal tubules after rotary instrumentation, as revealed by light microscopy of longitudinal root sections. TRUShape® files removed significantly more canal wall bacteria than Twisted Files when used without an antibacterial irrigant; the latter is required to decontaminate dentinal tubules. Root canal disinfection should not be focused only on a mechanistic approach. Rather, the rational choice of a rotary instrumentation system should be combined with the use of well-tested antimicrobial irrigants and delivery/agitation techniques to establish a clinically realistic chemomechanical débridement protocol. Published by Elsevier Ltd.

Conformation of the Phosphate D-alanine Zwitterion in Bacterial Teichoic Acid from Nuclear Magnetic Resonance Spectroscopy

PubMed Central

Garimella, Ravindranath; Halye, Jeffrey L.; Harrison, William; Klebba, Phillip E.; Rice, Charles V.

2009-01-01

The conformation of D-alanine (D-Ala) groups of bacterial teichoic acid is a central, yet untested, paradigm of microbiology. The D-Ala binds via the C-terminus, thereby allowing the amine to exist as a free cationic NH3+ group with the ability to form a contact-ion-pair with the nearby anionic phosphate group. This conformation hinders metal chelation by the phosphate because the zwitterion pair is charge neutral. To the contrary, the repulsion of cationic antimicrobial peptides (CAMPs) is attributed to the presence of the D-Ala cation; thus the ion-pair does not form in this model. Solid-state nuclear magnetic resonance (NMR) spectroscopy has been used to measure the distance between amine and phosphate groups within cell wall fragments of Bacillus subtilis. The bacteria were grown on media containing 15N D-Ala and β-chloroalanine racemase inhibitor. The rotational-echo double-resonance (REDOR) pulse sequence was used to measure the internuclear dipolar coupling and the results demonstrate: 1) the metal-free amine-to-phosphate distance is 4.4 Å and 2) the amine-to-phosphate distance increases to 5.4 Å in the presence of Mg2+ ions. As a result, the zwitterion exists in a nitrogen-oxygen ion-pair configuration providing teichoic acid with a positive charge to repel CAMPs. Additionally, the amine of D-Ala does not prevent magnesium chelation in contradiction to the prevailing view of teichoic acids in metal binding. Thus, the NMR-based description of teichoic acid structure resolves the contradictory models, advances the basic understanding of cell wall biochemistry, and provides possible insight into the creation of new antibiotic therapies. PMID:19746945

The Structure of the Antibiotic Deactivating, N-hydroxylating Rifampicin Monooxygenase*

PubMed Central

Liu, Li-Kai; Abdelwahab, Heba; Martin Del Campo, Julia S.; Mehra-Chaudhary, Ritcha; Sobrado, Pablo; Tanner, John J.

2016-01-01

Rifampicin monooxygenase (RIFMO) catalyzes the N-hydroxylation of the natural product antibiotic rifampicin (RIF) to 2′-N-hydroxy-4-oxo-rifampicin, a metabolite with much lower antimicrobial activity. RIFMO shares moderate sequence similarity with well characterized flavoprotein monooxygenases, but the protein has not been isolated and characterized at the molecular level. Herein, we report crystal structures of RIFMO from Nocardia farcinica, the determination of the oligomeric state in solution with small angle x-ray scattering, and the spectrophotometric characterization of substrate binding. The structure identifies RIFMO as a class A flavoprotein monooxygenase and is similar in fold and quaternary structure to MtmOIV and OxyS, which are enzymes in the mithramycin and oxytetracycline biosynthetic pathways, respectively. RIFMO is distinguished from other class A flavoprotein monooxygenases by its unique middle domain, which is involved in binding RIF. Small angle x-ray scattering analysis shows that RIFMO dimerizes via the FAD-binding domain to form a bell-shaped homodimer in solution with a maximal dimension of 110 Å. RIF binding was monitored using absorbance at 525 nm to determine a dissociation constant of 13 μm. Steady-state oxygen consumption assays show that NADPH efficiently reduces the FAD only when RIF is present, implying that RIF binds before NADPH in the catalytic scheme. The 1.8 Å resolution structure of RIFMO complexed with RIF represents the precatalytic conformation that occurs before formation of the ternary E-RIF-NADPH complex. The RIF naphthoquinone blocks access to the FAD N5 atom, implying that large conformational changes are required for NADPH to reduce the FAD. A model for these conformational changes is proposed. PMID:27557658

Rapid exhumation of Cretaceous arc-rocks along the Blue Mountains restraining bend of the Enriquillo-Plantain Garden fault, Jamaica, using thermochronometry from multiple closure systems

NASA Astrophysics Data System (ADS)

Cochran, William J.; Spotila, James A.; Prince, Philip S.; McAleer, Ryan J.

2017-11-01

The effect of rapid erosion on kinematic partitioning along transpressional plate margins is not well understood, particularly in highly erosive climates. The Blue Mountains restraining bend (BMRB) of eastern Jamaica, bound to the south by the left-lateral Enriquillo-Plantain Garden fault (EPGF), offers an opportunity to test the effects of highly erosive climatic conditions on a 30-km-wide restraining bend system. No previous thermochronometric data exists in Jamaica to describe the spatial or temporal pattern of rock uplift and how oblique (> 20°) plate motion is partitioned into vertical strain. To define the exhumation history, we measured apatite (n = 10) and zircon (n = 6) (U-Th)/He ages, 40Ar/39Ar (n = 2; amphibole and K-spar) ages, and U/Pb zircon (n = 2) crystallization ages. Late Cretaceous U/Pb and 40Ar/39Ar ages (74-68 Ma) indicate rapid cooling following shallow emplacement of plutons during north-south subduction along the Great Caribbean Arc. Early to middle Miocene zircon helium ages (19-14 Ma) along a vertical transect suggest exhumation and island emergence at 0.2 mm/yr. Older zircon ages 10-15 km to the north (44-35 Ma) imply less rock uplift. Apatite helium ages are young (6-1 Ma) across the entire orogen, suggesting rapid exhumation of the BMRB since the late Miocene. These constraints are consistent with previous reports of restraining bend formation and early emergence of eastern Jamaica. An age-elevation relationship from a vertical transect implies an exhumation rate of 0.8 mm/yr, while calculated closure depths and thermal modeling suggests exhumation as rapid as 2 mm/yr. The rapid rock uplift rates in Jamaica are comparable to the most intense transpressive zones worldwide, despite the relatively slow (5-7 mm/yr) strike-slip rate. We hypothesize highly erosive conditions in Jamaica enable a higher fraction of plate motion to be accommodated by vertical deformation. Thus, strike-slip restraining bends may evolve differently depending on erosivity and local climate.

Rapid exhumation of Cretaceous arc-rocks along the Blue Mountains restraining bend of the Enriquillo-Plantain Garden fault, Jamaica, using thermochronometry from multiple closure systems

USGS Publications Warehouse

Cochran, William J.; Spotila, James A.; Prince, Philip S.; McAleer, Ryan J.

2017-01-01

The effect of rapid erosion on kinematic partitioning along transpressional plate margins is not well understood, particularly in highly erosive climates. The Blue Mountains restraining bend (BMRB) of eastern Jamaica, bound to the south by the left-lateral Enriquillo-Plantain Garden fault (EPGF), offers an opportunity to test the effects of highly erosive climatic conditions on a 30-km-wide restraining bend system. No previous thermochronometric data exists in Jamaica to describe the spatial or temporal pattern of rock uplift and how oblique (> 20°) plate motion is partitioned into vertical strain. To define the exhumation history, we measured apatite (n = 10) and zircon (n = 6) (U-Th)/He ages, 40Ar/39Ar (n = 2; amphibole and K-spar) ages, and U/Pb zircon (n = 2) crystallization ages. Late Cretaceous U/Pb and 40Ar/39Ar ages (74–68 Ma) indicate rapid cooling following shallow emplacement of plutons during north-south subduction along the Great Caribbean Arc. Early to middle Miocene zircon helium ages (19–14 Ma) along a vertical transect suggest exhumation and island emergence at ~ 0.2 mm/yr. Older zircon ages 10–15 km to the north (44–35 Ma) imply less rock uplift. Apatite helium ages are young (6–1 Ma) across the entire orogen, suggesting rapid exhumation of the BMRB since the late Miocene. These constraints are consistent with previous reports of restraining bend formation and early emergence of eastern Jamaica. An age-elevation relationship from a vertical transect implies an exhumation rate of 0.8 mm/yr, while calculated closure depths and thermal modeling suggests exhumation as rapid as 2 mm/yr. The rapid rock uplift rates in Jamaica are comparable to the most intense transpressive zones worldwide, despite the relatively slow (5–7 mm/yr) strike-slip rate. We hypothesize highly erosive conditions in Jamaica enable a higher fraction of plate motion to be accommodated by vertical deformation. Thus, strike-slip restraining bends may evolve differently depending on erosivity and local climate.

A dual RF resonator system for high-field functional magnetic resonance imaging of small animals.

PubMed

Ludwig, R; Bodgdanov, G; King, J; Allard, A; Ferris, C F

2004-01-30

A new apparatus has been developed that integrates an animal restrainer arrangement for small animals with an actively tunable/detunable dual radio-frequency (RF) coil system for in vivo anatomical and functional magnetic resonance imaging of small animals at 4.7 T. The radio-frequency coil features an eight-element microstrip line configuration that, in conjunction with a segmented outer copper shield, forms a transversal electromagnetic (TEM) resonator structure. Matching and active tuning/detuning is achieved through fixed/variable capacitors and a PIN diode for each resonator element. These components along with radio-frequency chokes (RFCs) and blocking capacitors are placed on two printed circuit boards (PCBs) whose copper coated ground planes form the front and back of the volume coil and are therefore an integral part of the resonator structure. The magnetic resonance signal response is received with a dome-shaped single-loop surface coil that can be height-adjustable with respect to the animal's head. The conscious animal is immobilized through a mechanical arrangement that consists of a Plexiglas body tube and a head restrainer. This restrainer has a cylindrical holder with a mouthpiece and position screws to receive and restrain the head of the animal. The apparatus is intended to perform anatomical and functional magnetic resonance imaging in conscious animals such as mice, rats, hamsters, and marmosets. Cranial images acquired from fully conscious rats in a 4.7 T Bruker 40 cm bore animal scanner underscore the feasibility of this approach and bode well to extend this system to the imaging of other animals.

Worry or craving? A selective review of evidence for food-related attention biases in obese individuals, eating-disorder patients, restrained eaters and healthy samples.

PubMed

Werthmann, Jessica; Jansen, Anita; Roefs, Anne

2015-05-01

Living in an 'obesogenic' environment poses a serious challenge for weight maintenance. However, many people are able to maintain a healthy weight indicating that not everybody is equally susceptible to the temptations of this food environment. The way in which someone perceives and reacts to food cues, that is, cognitive processes, could underlie differences in susceptibility. An attention bias for food could be such a cognitive factor that contributes to overeating. However, an attention bias for food has also been implicated with restrained eating and eating-disorder symptomatology. The primary aim of the present review was to determine whether an attention bias for food is specifically related to obesity while also reviewing evidence for attention biases in eating-disorder patients, restrained eaters and healthy-weight individuals. Another aim was to systematically examine how selective attention for food relates (causally) to eating behaviour. Current empirical evidence on attention bias for food within obese samples, eating-disorder patients, and, even though to a lesser extent, in restrained eaters is contradictory. However, present experimental studies provide relatively consistent evidence that an attention bias for food contributes to subsequent food intake. This review highlights the need to distinguish not only between different (temporal) attention bias components, but also to take different motivations (craving v. worry) and their impact on attentional processing into account. Overall, the current state of research suggests that biased attention could be one important cognitive mechanism by which the food environment tempts us into overeating.

Structure and geometry of the Aksay restraining double bend along the Altyn Tagh Fault, northern Tibet, imaged using magnetotelluric method

NASA Astrophysics Data System (ADS)

Xiao, Qibin; Yu, Guo; Liu-Zeng, Jing; Oskin, Michael E.; Shao, Guihang

2017-05-01

Large restraining bends along active strike-slip faults locally enhance the accumulation of clamping tectonic normal stresses that may limit the size of major earthquakes. In such settings, uncertain fault geometry at depth limits understanding of how effectively a bend arrests earthquake ruptures. Here we demonstrate fault imaging within a major restraining bend along the Altyn Tagh Fault of western China using the magnetotelluric (MT) method. The new MT data were collected along two profiles across the Aksay restraining double bend, which is bounded by two subparallel strands of the Altyn Tagh Fault: Northern (NATF) and Southern (SATF). Both two-dimensional (2-D) and three-dimensional (3-D) inversion models show that the Aksay bend may be the center of a positive flower structure, imaged as a high-resistivity body extending to an 40 km depth and bounded by subvertical resistivity discontinuities corresponding to the NATF and SATF. In the western section of the Aksay bend, both the NATF and SATF show similar low-resistivity structure, whereas in the eastern part of the bend, the low-resistivity anomaly below the SATF is wider and more prominent than that below the NATF. This observation indicates that the SATF shear zone may be wider and host more fluid than the NATF, lending structural support to the contention that fault slip at depth is asymmetrically focused on the SATF, even though surface slip is focused on the NATF. A south dipping, low-resistivity interface branching upward from the SATF toward the NATF indicates a fault link between these strands at depth.

Simultaneous in- and out-of-plane Mitral Valve Annular Force Measurements.

PubMed

Skov, Søren N; Røpcke, Diana M; Telling, Kristine; Ilkjær, Christine; Tjørnild, Marcell J; Nygaard, Hans; Nielsen, Sten L; Jensen, Morten O

2015-06-01

Mitral valve repair with annuloplasty is often favoured over total valve replacement. In order to develop and optimize new annuloplasty ring designs, it is important to study the complex biomechanical behaviour of the valve annulus and the subvalvular apparatus with simultaneous in- and out-of-plane restraining force measurements. A new flat D-shaped mitral valve annular force transducer was developed. The transducer was mounted with strain gauges to measure strain and calibrated to provide simultaneous restraining forces in- and out of the mitral annular plane. The force transducer was implanted and evaluated in an 80 kg porcine experimental model. Accumulation of out-of-plane restraining forces, creating strain in the anterior segment were 0.7 ± 0.0 N (towards apex) and an average force accumulation of 1.5 ± 0.3 N, creating strain in the commissural segments (away from apex). The accumulations of in-plane restraining forces, creating strain on the inner side of the ring were 1.7 ± 0.2 N (away from ring center). A new mitral annular force transducer was successfully developed and evaluated in vivo. The transducer was able to measure forces simultaneously in different planes. Initial indications point towards overall agreement with previous individual force measurements in- and out-of the mitral annular plane. This can provide more detailed insight into the annular force distribution, and could potentially improve the level of evidence based mitral valve repair and support the development of future mitral annuloplasty devices.

Molecular dynamics simulation of cytochrome c3: studying the reduction processes using free energy calculations.

PubMed Central

Soares, C M; Martel, P J; Mendes, J; Carrondo, M A

1998-01-01

The tetraheme cytochrome c3 from Desulfovibrio vulgaris Hildenborough is studied using molecular dynamics simulation studies in explicit solvent. The high heme content of the protein, which has its core almost entirely made up of c-type heme, presents specific problems in the simulation. Instability in the structure is observed in long simulations above 1 ns, something that does not occur in a monoheme cytochrome, suggesting problems in heme parametrization. Given these stability problems, a partially restrained model, which avoids destruction of the structure, was created with the objective of performing free energy calculations of heme reduction, studies that require long simulations. With this model, the free energy of reduction of each individual heme was calculated. A correction in the long-range electrostatic interactions of charge groups belonging to the redox centers had to be made in order to make the system physically meaningful. Correlation is obtained between the calculated free energies and the experimental data for three of four hemes. However, the relative scale of the calculated energies is different from the scale of the experimental free energies. Reasons for this are discussed. In addition to the free energy calculations, this model allows the study of conformational changes upon reduction. Even if the precise details of the structural changes that take place in this system upon individual heme reduction are probably out of the reach of this study, it appears that these structural changes are small, similarly to what is observed for other redox proteins. This does not mean that their effect is minor, and one example is the conformational change observed in propionate D from heme I when heme II becomes reduced. A motion of this kind could be the basis of the experimentally observed cooperativity effects between heme reduction, namely positive cooperativity. PMID:9545034

Steric Effects on the Binding of Phosphate and Polyphosphate Anions by Zinc(II) and Copper(II) Dinuclear Complexes of m-Xylyl-bis-cyclen.

PubMed

Esteves, Catarina V; Esteban-Gómez, David; Platas-Iglesias, Carlos; Tripier, Raphaël; Delgado, Rita

2018-05-11

The triethylbenzene-bis-cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) compound (tbmce) was designed with an imposed structural rigidity at the m-xylyl spacer to be compared to a less restrained and known parent compound (bmce). The framework of both compounds differs only in the substituents of the m-xylyl spacer. The study was centered in the differences observed in the acid-base reactions of both compounds, their copper(II) and zinc(II) complexation behaviors, as well as in the uptake of phosphate and polyphosphate anions (HPPi 3- , ATP 4- , ADP 3- , AMP 2- , PhPO 4 2- , and HPO 4 2- ). On the one hand, the acid-base reactions showed lower values for the third and fourth protonation constants of tbmce than for bmce, suggesting that the ethyl groups of the spacer in tbmce force the two cyclen units to more conformational restricted positions. On the other hand, the stability constant values for copper(II) and zinc(II) complexes revealed that bmce is a better chelator than tbmce pointing out to additional conformational restraints imposed by the triethylbenzene spacer. The binding studies of phosphates by the dinuclear copper(II) and zinc(II) complexes showed much smaller effective association constants for the dicopper complexes. Single-crystal X-ray and computational (density functional theory) studies suggest that anion binding promotes the formation of tetranuclear entities in which anions are bridging the metal centers. Our studies also revealed the dinuclear zinc(II) complex of bmce as a promising receptor for phosphate anions, with the largest effective association constant of 5.94 log units being observed for the formation of [Zn 2 bmce(HPPi)] + . Accordingly, a colorimetric study via an indicator displacement assay to detect phosphates in aqueous solution found that the [Zn 2 bmce] 4+ complex acts as the best receptor for pyrophosphate displaying a detection limit of 2.5 nM by changes visible to naked eye.

Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity

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

She, Fengyu; Nimmagadda, Alekhya; Teng, Peng

As one of the greatest threats facing in 21st century, antibiotic resistance is now a major public health concern. Host-defense peptides (HDPs) offer an alternative approach to combat emerging multidrug-resistant bacteria. It is known that helical HDPs such as magainin 2 and its analogs adopt cationic amphipathic conformations upon interaction with bacterial membranes, leading to membrane disruption and subsequent bacterial cell death. We have previously shown that amphipathic sulfono-γ-AApeptides could mimic magainin 2 and exhibit bactericidal activity. In this article, we demonstrate for the first time that amphipathic helical 1:1 α/sulfono-γ-AA heterogeneous peptides, in which regular amino acids and sulfono-γ-AApeptidemore » building blocks are alternatively present in a 1:1 pattern, display potent antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens. Small Angle X-ray Scattering (SAXS) suggests that the lead sequences adopt defined helical structures. The subsequent studies including 2 fluorescence microscopy and time-kill experiments indicate that these hybrid peptides exert antimicrobial activity by mimicking the mechanism of HDPs. Our findings may lead to the development of HDP-mimicking antimicrobial peptidomimetics that combat drug-resistant bacterial pathogens. In addition, our results also demonstrate the effective design of a new class of helical foldamer, which could be employed to interrogate other important biological targets such as protein-protein interactions in the future.« less

Green Tea Catechins Quench the Fluorescence of Bacteria-Conjugated Alexa Fluor Dyes

PubMed Central

Zhao, Lin; Li, Wei; Zhu, Shu; Tsai, Sheena; Li, Jianhua; Tracey, Kevin J.; Wang, Ping; Fan, Saijun; Sama, Andrew E.; Wang, Haichao

2013-01-01

Accumulating evidence suggests that Green tea polyphenolic catechins, especially the (-)-epigallocatechin gallate (EGCG), can be cross-linked to many proteins, and confer a wide range of anti-bacterial activities possibly by damaging microbial cytoplasmic lipids and proteins. At the doses that conferred protection against lethal polymicrobial infection (induced by cecal ligation and puncture), EGCG significantly reduced bacterial loads particularly in the liver and lung. To elucidate its bactericidal mechanisms, we determined whether EGCG affected the fluorescence intensities of bacteria-conjugated Alexa Fluor 488 or 594 dyes. When mixed with unconjugated Alexa Fluor 488 or 594 dyes, EGCG or analogs did not affect the fluorescence intensity of these dyes. In a sharp contrast, EGCG and some analogs (e.g., Catechin Gallate, CG), markedly reduced the fluorescence intensity of Gram-positive Staphylococcus aureus-conjugated Alexa 594 and Gram-negative Escherichia coli-conjugated Alexa 488. Interestingly, co-treatment with ethanol impaired the EGCG-mediated fluorescence quenching of the G+ S. aureus, but not of the G- E. coli-conjugated Alexa Flour dyes. In light of the notion that Alexa Fluor dyes can be quenched by aromatic amino acids, it is plausible that EGCG exerts anti-microbial activities possibly by altering microbial protein conformations and functions. This possibility can now be explored by screening other fluorescence-quenching agents for possible antimicrobial activities. PMID:24011199

Identifying armed respondents to domestic violence restraining orders and recovering their firearms: process evaluation of an initiative in California.

PubMed

Wintemute, Garen J; Frattaroli, Shannon; Claire, Barbara E; Vittes, Katherine A; Webster, Daniel W

2014-02-01

We evaluated a law enforcement initiative to screen respondents to domestic violence restraining orders for firearm ownership or possession and recover their firearms. The initiative was implemented in San Mateo and Butte counties in California from 2007 through 2010. We used descriptive methods to evaluate the screening process and recovery effort in each county, relying on records for individual cases. Screening relied on an archive of firearm transactions, court records, and petitioner interviews; no single source was adequate. Screening linked 525 respondents (17.7%) in San Mateo County to firearms; 405 firearms were recovered from 119 (22.7%) of them. In Butte County, 88 (31.1%) respondents were linked to firearms; 260 firearms were recovered from 45 (51.1%) of them. Nonrecovery occurred most often when orders were never served or respondents denied having firearms. There were no reports of serious violence or injury. Recovering firearms from persons subject to domestic violence restraining orders is possible. We have identified design and implementation changes that may improve the screening process and the yield from recovery efforts. Larger implementation trials are needed.

Effects of exposure to unrealistic promises about dieting: are unrealistic expectations about dieting inspirational?

PubMed

Trottier, Kathryn; Polivy, Janet; Herman, C Peter

2005-03-01

The false-hope syndrome suggests that unrealistic expectations about dieting set dieters up for failure and then promote renewed efforts at weight loss. Many dieters believe the inflated promises typical of diet advertisements, which may be the source of at least some of their unrealistic expectations. Diet advertisements promoting unrealistic expectations were expected to inspire restrained eaters to diet and lead to enhanced self-perceptions, relative to more circumspect advertisements. Female undergraduates rated their expectations in response to a control advertisement or to advertisements containing realistic, moderately unrealistic, or highly unrealistic promises of dieting. Participants then rated their self-perceptions and participated in an apparent "taste-test". Restrained eaters had higher expectations for themselves than did unrestrained eaters, and restrained and unrestrained eaters had similar expectations concerning dieting for others. Those who viewed the advertisements containing unrealistic expectations ate fewer cookies ad libitum than did those who viewed the realistic or control advertisements. This finding is consistent with the suggestion that unrealistic expectations contribute to the decision to change oneself. (c) 2005 by Wiley Periodicals, Inc.

Effects of Tangential Edge Constraints on the Postbuckling Behavior of Flat and Curved Panels Subjected to Thermal and Mechanical Loads

NASA Technical Reports Server (NTRS)

Lin, W.; Librescu, L.; Nemeth, M. P.; Starnes, J. H. , Jr.

1994-01-01

A parametric study of the effects of tangential edge constraints on the postbuckling response of flat and shallow curved panels subjected to thermal and mechanical loads is presented. The mechanical loads investigated are uniform compressive edge loads and transverse lateral pressure. The temperature fields considered are associated with spatially nonuniform heating over the panels, and a linear through-the-thickness temperature gradient. The structural model is based on a higher-order transverse-shear-deformation theory of shallow shells that incorporates the effects of geometric nonlinearities, initial geometric imperfections, and tangential edge motion constraints. Results are presented for three-layer sandwich panels made from transversely isotropic materials. Simply supported panels are considered in which the tangential motion of the unloaded edges is either unrestrained, partially restrained, or fully restrained. These results focus on the effects of the tangential edge restraint on the postbuckling response. The results of this study indicate that tangentially restraining the edges of a curved panel can make the panel insensitive to initial geometric imperfections in some cases.

A study of Quaternary structures in the Qom region, West Central Iran

NASA Astrophysics Data System (ADS)

Babaahmadi, A.; Safaei, H.; Yassaghi, A.; Vafa, H.; Naeimi, A.; Madanipour, S.; Ahmadi, M.

2010-12-01

West Central Iran comprises numerous Quaternary faults. Having either strike-slip or thrust mechanisms, these faults are potentially active and therefore capable of creating destructive earthquakes. In this paper, we use satellite images as well as field trips to identify these active faults in the Qom region. The Qom and Indes faults are the main NW-trending faults along which a Quaternary restraining step-over zone has formed. Kamarkuh, Mohsen Abad, and Ferdows anticlines are potentially active structures that formed in this restraining step-over zone. There are some thrusts and anticlines, such as the Alborz anticline and Alborz fault, which are parallel to strike-slip faults such as the Qom fault, indicating deformation partitioning in the area. In addition to NW-trending structures, there is an important NE-trending fault known as the Qomrud fault that has deformed Quaternary deposits and affected Kushk-e-Nosrat fault, Alborz anticline, and Qomrud River. The results of this study imply that the major Quaternary faults of West Central Iran and their restraining step-over zones are potentially active.

Research on liquid sloshing performance in vane type tank under microgravity

NASA Astrophysics Data System (ADS)

Hu, Q.; Li, Y.; Liu, J. T.; Liang, J. Q.

2016-05-01

Propellant management device (PMD) in vane type tank mainly comprises of vane type structure parts, whose performance of restraining liquid sloshing should satisfy spacecraft requirements of high stabilization and fast orbital maneuver. Aiming at liquid sloshing performance in vane type tank under microgravity environment, gas-liquid flow model based on the volume of fluid (VOF) method was put forward, and via numerical simulation liquid sloshing performances of vane type PMD with anti-sloshing baffles and without anti-sloshing baffles in microgravity were analyzed and compared. Simulation results reveal that liquid sloshing performance of vane type PMD with anti-sloshing baffles is markedly superior vane type PMD without anti-sloshing baffles and the baffles make liquid surface become stable fast. Then by comparing between results of microgravity experiments and results of numerical simulations, they are very similar. According to present research, vane type PMD with antisloshing baffles has better effects on restraining liquid sloshing and is able to restrain observably propellant sloshing in tanks in order to satisfy spacecraft requirements of high stabilization and fast orbital maneuver.

Personality, emotion-related variables, and media pressure predict eating disorders via disordered eating in Lebanese university students.

PubMed

Sanchez-Ruiz, Maria Jose; El-Jor, Claire; Abi Kharma, Joelle; Bassil, Maya; Zeeni, Nadine

2017-04-18

Disordered eating behaviors are on the rise among youth. The present study investigates psychosocial and weight-related variables as predictors of eating disorders (ED) through disordered eating (DE) dimensions (namely restrained, external, and emotional eating) in Lebanese university students. The sample consisted of 244 undergraduates (143 female) aged from 18 to 31 years (M = 20.06; SD = 1.67). Using path analysis, two statistical models were built separately with restrained and emotional eating as dependent variables, and all possible direct and indirect pathways were tested for mediating effects. The variables tested for were media influence, perfectionism, trait emotional intelligence, and the Big Five dimensions. In the first model, media pressure, self-control, and extraversion predicted eating disorders via emotional eating. In the second model, media pressure and perfectionism predicted eating disorders via restrained eating. Findings from this study provide an understanding of the dynamics between DE, ED, and key personality, emotion-related, and social factors in youth. Lastly, implications and recommendations for future studies are advanced.

Enhanced isoprene biosynthesis in Saccharomyces cerevisiae by engineering of the native acetyl-CoA and mevalonic acid pathways with a push-pull-restrain strategy.

PubMed

Lv, Xiaomei; Xie, Wenping; Lu, Wenqiang; Guo, Fei; Gu, Jiali; Yu, Hongwei; Ye, Lidan

2014-09-30

To explore the capacity of isoprene production in Saccharomyces cerevisiae, a rational push-pull-restrain strategy was proposed to engineer the mevalonic acid (MVA) and acetyl-CoA pathways. The strategy can be decomposed into the up-regulation of precursor supply in the acetyl-CoA module and the MVA pathway (push-strategy), increase of the isoprene branch flux (pull-strategy), and down-regulation of the competing pathway (restrain-strategy). Furthermore, to reduce the production cost arising from galactose addition and meanwhile maintain the high expression of Gal promoters, the galactose regulatory network was modulated by Gal80p deletion. Finally, the engineered strain YXM10-ispS-ispS could accumulate up to 37 mg/L isoprene (about 782-fold increase compared to the parental strain) under aerobic conditions with glycerol-sucrose as carbon source. In this way, a new potential platform for isoprene production was established via metabolic engineering of the yeast native pathways. Copyright © 2014 Elsevier B.V. All rights reserved.

Strategy of restraining ripple error on surface for optical fabrication.

PubMed

Wang, Tan; Cheng, Haobo; Feng, Yunpeng; Tam, Honyuen

2014-09-10

The influence from the ripple error to the high imaging quality is effectively reduced by restraining the ripple height. A method based on the process parameters and the surface error distribution is designed to suppress the ripple height in this paper. The generating mechanism of the ripple error is analyzed by polishing theory with uniform removal character. The relation between the processing parameters (removal functions, pitch of path, and dwell time) and the ripple error is discussed through simulations. With these, the strategy for diminishing the error is presented. A final process is designed and demonstrated on K9 work-pieces using the optimizing strategy with magnetorheological jet polishing. The form error on the surface is decreased from 0.216λ PV (λ=632.8  nm) and 0.039λ RMS to 0.03λ PV and 0.004λ RMS. And the ripple error is restrained well at the same time, because the ripple height is less than 6 nm on the final surface. Results indicate that these strategies are suitable for high-precision optical manufacturing.

Cognitive load, stress, and disinhibited eating.

PubMed

Lattimore, Paul; Maxwell, Linda

2004-11-01

The impact of cognitive distraction on eating behaviour was examined in restrained and unrestrained eaters. It was predicted that restrained eaters would eat more than unrestrained eaters following high cognitive load when it involves processing of ego-threat information independent of self-reported anxiety. There were 119 female participants randomly allocated to one of four experimental conditions whereby cognitive load and ego threat were manipulated using modified colour-naming Stroop (CNS) tasks. Anxiety ratings were made prior to and following experimental tasks. After performing Stroop tasks, participants consumed snack foods ad libitum. Restrained eaters consumed significantly more food when high cognitive load was ego threatening than when it involved processing and memorisation of colour nouns and consumed significantly more than unrestrained eaters in a high cognitive load ego-threat condition. Posttask anxiety was greater than baseline across all conditions. Task difficulty was greater under high cognitive load than low cognitive load as indicated by Stroop response times. These results indicated that the escape theory of disinhibited eating is conceptually subsumed by a more generalisable limited cognitive capacity model.

Rear seat safety: Variation in protection by occupant, crash and vehicle characteristics.

PubMed

Durbin, Dennis R; Jermakian, Jessica S; Kallan, Michael J; McCartt, Anne T; Arbogast, Kristy B; Zonfrillo, Mark R; Myers, Rachel K

2015-07-01

Current information on the safety of rear row occupants of all ages is needed to inform further advances in rear seat restraint system design and testing. The objectives of this study were to describe characteristics of occupants in the front and rear rows of model year 2000 and newer vehicles involved in crashes and determine the risk of serious injury for restrained crash-involved rear row occupants and the relative risk of fatal injury for restrained rear row vs. front passenger seat occupants by age group, impact direction, and vehicle model year. Data from the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) and Fatality Analysis Reporting System (FARS) were queried for all crashes during 2007-2012 involving model year 2000 and newer passenger vehicles. Data from NASS-CDS were used to describe characteristics of occupants in the front and rear rows and to determine the risk of serious injury (AIS 3+) for restrained rear row occupants by occupant age, vehicle model year, and impact direction. Using a combined data set containing data on fatalities from FARS and estimates of the total population of occupants in crashes from NASS-CDS, logistic regression modeling was used to compute the relative risk (RR) of death for restrained occupants in the rear vs. front passenger seat by occupant age, impact direction, and vehicle model year. Among all vehicle occupants in tow-away crashes during 2007-2012, 12.3% were in the rear row where the overall risk of serious injury was 1.3%. Among restrained rear row occupants, the risk of serious injury varied by occupant age, with older adults at the highest risk of serious injury (2.9%); by impact direction, with rollover crashes associated with the highest risk (1.5%); and by vehicle model year, with model year 2007 and newer vehicles having the lowest risk of serious injury (0.3%). Relative risk of death was lower for restrained children up to age 8 in the rear compared with passengers in the right front seat (RR=0.27, 95% CI 0.12-0.58 for 0-3 years, RR=0.55, 95% CI 0.30-0.98 for 4-8 years) but was higher for restrained 9-12-year-old children (RR=1.83, 95% CI 1.18-2.84). There was no evidence for a difference in risk of death in the rear vs. front seat for occupants ages 13-54, but there was some evidence for an increased relative risk of death for adults age 55 and older in the rear vs. passengers in the right front seat (RR=1.41, 95% CI 0.94-2.13), though we could not exclude the possibility of no difference. After controlling for occupant age and gender, the relative risk of death for restrained rear row occupants was significantly higher than that of front seat occupants in model year 2007 and newer vehicles and significantly higher in rear and right side impact crashes. Results of this study extend prior research on the relative safety of the rear seat compared with the front by examining a more contemporary fleet of vehicles. The rear row is primarily occupied by children and adolescents, but the variable relative risk of death in the rear compared with the front seat for occupants of different age groups highlights the challenges in providing optimal protection to a wide range of rear seat occupants. Findings of an elevated risk of death for rear row occupants, as compared with front row passengers, in the newest model year vehicles provides further evidence that rear seat safety is not keeping pace with advances in the front seat. Copyright © 2015 Elsevier Ltd. All rights reserved.

Therapeutic index of gramicidin S is strongly modulated by D-phenylalanine analogues at the beta-turn.

PubMed

Solanas, Concepción; de la Torre, Beatriz G; Fernández-Reyes, María; Santiveri, Clara M; Jiménez, M Angeles; Rivas, Luis; Jiménez, Ana I; Andreu, David; Cativiela, Carlos

2009-02-12

Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo(Val-Orn-Leu-D-Phe-Pro)2, with d-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several pathogenic bacteria. While all D-Phe substitutions are shown by NMR to preserve the overall beta-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biological activity. In particular, the analogue incorporating D-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) shows a modest but significant increase in therapeutic index, mostly due to a sharp decrease in hemolytic effect. The fact that NMR data show a shortened distance between the D-Tic aromatic ring and the Orn delta-amino group may help explain the improved antibiotic profile of this analogue.

Therapeutic index of gramicidin S is strongly modulated by d-phenylalanine analogues at the β-turn

PubMed Central

Solanas, Concepción; de la Torre, Beatriz G.; Fernández-Reyes, María; Santiveri, Clara M.; Jiménez, M. Ángeles; Rivas, Luis; Jiménez, Ana I.; Andreu, David; Cativiela, Carlos

2009-01-01

Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo(Val-Orn-Leu-d-Phe-Pro)2, with d-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several pathogenic bacteria. While all d-Phe substitutions are shown by NMR to preserve the overall β-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biological activity. In particular, the analogue incorporating d-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) shows a modest but significant increase in therapeutic index, mostly due to a sharp decrease in hemolytic effect. The fact that NMR data show a shortened distance between the d-Tic aromatic ring and the Orn δ-amino group may help explain the improved antibiotic profile of this analogue. PMID:19132829

Column strength of tubes elastically restrained against rotation at the ends

NASA Technical Reports Server (NTRS)

Osgood, William R

1938-01-01

Report presents the results of a study made of the effects of known end restraint on commercially available round and streamline tubing of chromium-molybdenum steel, duralumin, stainless steel, and heat-treated chromium-molybdenum steel; and a more accurate method than any previously available, but still a practical method, was developed for designing compression members in riveted or welded structures, particularly aircraft. Two hundred specimens were tested as short, medium-length, and long columns with freely supported ends or elastically restrained ends. Tensile and compressive tests were made on each piece of original tubing from which column specimens were cut.

Research on motion model for the hypersonic boost-glide aircraft

NASA Astrophysics Data System (ADS)

Xu, Shenda; Wu, Jing; Wang, Xueying

2015-11-01

A motion model for the hypersonic boost-glide aircraft(HBG) was proposed in this paper, which also analyzed the precision of model through simulation. Firstly the trajectory of HBG was analyzed, and a scheme which divide the trajectory into two parts then build the motion model on each part. Secondly a restrained model of boosting stage and a restrained model of J2 perturbation were established, and set up the observe model. Finally the analysis of simulation results show the feasible and high-accuracy of the model, and raise a expectation for intensive research.

Large deflection random response of cross-ply laminated plates with elastically restrained edges and initial imperfections

NASA Technical Reports Server (NTRS)

Prasad, C. B.; Mei, Chuh

1988-01-01

The large deflection random response of symmetrically laminated cross-ply rectangular thin plates subjected to random excitation is studied. The out-of-plane boundary conditions are such that all the edges are rigidly supported against translation, but elastically restrained against rotation. The plate is also assumed to have a small initial imperfection. The assumed membrane boundary conditions are such that all the edges are free from normal and tangential forces in the plane of the plate. Mean-square deflections and mean-square strains are determined for a three-layered cross-ply laminate.

Association Between NCAP Ratings and Real-World Rear Seat Occupant Risk of Injury.

PubMed

Metzger, Kristina B; Gruschow, Siobhan; Durbin, Dennis R; Curry, Allison E

2015-01-01

Several studies have evaluated the correlation between U.S. or Euro New Car Assessment Program (NCAP) ratings and injury risk to front seat occupants, in particular driver injuries. Conversely, little is known about whether NCAP 5-star ratings predict real-world risk of injury to restrained rear seat occupants. The NHTSA has identified rear seat occupant protection as a specific area under consideration for improvements to its NCAP. In order to inform NHTSA's efforts, we examined how NCAP's current 5-star rating system predicts risk of moderate or greater injury among restrained rear seat occupants in real-world crashes. We identified crash-involved vehicles, model year 2004-2013, in NASS-CDS (2003-2012) with known make and model and nonmissing occupant information. We manually matched these vehicles to their NCAP star ratings using data on make, model, model year, body type, and other identifying information. The resultant linked NASS-CDS and NCAP database was analyzed to examine associations between vehicle ratings and rear seat occupant injury risk; risk to front seat occupants was also estimated for comparison. Data were limited to restrained occupants and occupant injuries were defined as any injury with a maximum Abbreviated Injury Scale (AIS) score of 2 or greater. We linked 95% of vehicles in NASS-CDS to a specific vehicle in NCAP. The 18,218 vehicles represented an estimated 6 million vehicles with over 9 million occupants. Rear seat passengers accounted for 12.4% of restrained occupants. The risk of injury in all crashes for restrained rear seat occupants was lower in vehicles with a 5-star driver rating in frontal impact tests (1.4%) than with 4 or fewer stars (2.6%, P =.015); results were similar for the frontal impact passenger rating (1.3% vs. 2.4%, P =.024). Conversely, side impact driver and passenger crash tests were not associated with rear seat occupant injury risk (driver test: 1.7% for 5-star vs. 1.8% for 1-4 stars; passenger test: 1.6% for 5 stars vs 1.8% for 1-4 stars). Current frontal impact test procedures provide some degree of discrimination in real-world rear seat injury risk among vehicles with 5 compared to fewer than 5 stars. However, there is no evidence that vehicles with a 5-star side impact passenger rating, which is the only crash test procedure to include an anthropomorphic test dummy (ATD) in the rear, demonstrate lower risks of injury in the rear than vehicles with fewer than 5 stars. These results support prioritizing modifications to the NCAP program that specifically evaluate rear seat injury risk to restrained occupants of all ages.

An ultrastable conjugate of silver nanoparticles and protein formed through weak interactions

NASA Astrophysics Data System (ADS)

Brahmkhatri, Varsha P.; Chandra, Kousik; Dubey, Abhinav; Atreya, Hanudatta S.

2015-07-01

In recent years, silver nanoparticles (AgNPs) have attracted significant attention owing to their unique physicochemical, optical, conductive and antimicrobial properties. One of the properties of AgNPs which is crucial for all applications is their stability. In the present study we unravel a mechanism through which silver nanoparticles are rendered ultrastable in an aqueous solution in complex with the protein ubiquitin (Ubq). This involves a dynamic and reversible association and dissociation of ubiquitin from the surface of AgNP. The exchange occurs at a rate much greater than 25 s-1 implying a residence time of <40 ms for the protein. The AgNP-Ubq complex remains stable for months due to steric stabilization over a wide pH range compared to unconjugated AgNPs. NMR studies reveal that the protein molecules bind reversibly to AgNP with an approximate dissociation constant of 55 μM and undergo fast exchange. At pH > 4 the positively charged surface of the protein comes in contact with the citrate capped AgNP surface. Further, NMR relaxation-based experiments suggest that in addition to the dynamic exchange, a conformational rearrangement of the protein takes place upon binding to AgNP. The ultrastability of the AgNP-Ubq complex was found to be useful for its anti-microbial activity, which allowed the recycling of this complex multiple times without the loss of stability. Altogether, the study provides new insights into the mechanism of protein-silver nanoparticle interactions and opens up new avenues for its application in a wide range of systems.In recent years, silver nanoparticles (AgNPs) have attracted significant attention owing to their unique physicochemical, optical, conductive and antimicrobial properties. One of the properties of AgNPs which is crucial for all applications is their stability. In the present study we unravel a mechanism through which silver nanoparticles are rendered ultrastable in an aqueous solution in complex with the protein ubiquitin (Ubq). This involves a dynamic and reversible association and dissociation of ubiquitin from the surface of AgNP. The exchange occurs at a rate much greater than 25 s-1 implying a residence time of <40 ms for the protein. The AgNP-Ubq complex remains stable for months due to steric stabilization over a wide pH range compared to unconjugated AgNPs. NMR studies reveal that the protein molecules bind reversibly to AgNP with an approximate dissociation constant of 55 μM and undergo fast exchange. At pH > 4 the positively charged surface of the protein comes in contact with the citrate capped AgNP surface. Further, NMR relaxation-based experiments suggest that in addition to the dynamic exchange, a conformational rearrangement of the protein takes place upon binding to AgNP. The ultrastability of the AgNP-Ubq complex was found to be useful for its anti-microbial activity, which allowed the recycling of this complex multiple times without the loss of stability. Altogether, the study provides new insights into the mechanism of protein-silver nanoparticle interactions and opens up new avenues for its application in a wide range of systems. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03047a

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

Vendeix, Franck A.P.; Murphy, IV, Frank V.; Cantara, William A.

Human tRNA Lys3 UUU (htRNA Lys3 UUU) decodes the lysine codons AAA and AAG during translation and also plays a crucial role as the primer for HIV-1 (human immunodeficiency virus type 1) reverse transcription. The posttranscriptional modifications 5-methoxycarbonylmethyl-2-thiouridine (mcm 5s 2U 34), 2-methylthio-N 6-threonylcarbamoyladenosine (ms 2t 6A 37), and pseudouridine (Ψ 39) in the tRNA's anticodon domain are critical for ribosomal binding and HIV-1 reverse transcription. To understand the importance of modified nucleoside contributions, we determined the structure and function of this tRNA's anticodon stem and loop (ASL) domain with these modifications at positions 34, 37, and 39, respectively (hASLmore » Lys3 UUU-mcm 5s 2U 34;ms 2t 6A 37;Ψ 39). Ribosome binding assays in vitro revealed that the hASL Lys3 UUU-mcm 5s 2U 34;ms 2t 6A 37;Ψ 39 bound AAA and AAG codons, whereas binding of the unmodified ASL Lys3 UUU was barely detectable. The UV hyperchromicity, the circular dichroism, and the structural analyses indicated that Ψ 39 enhanced the thermodynamic stability of the ASL through base stacking while ms 2t 6A 37 restrained the anticodon to adopt an open loop conformation that is required for ribosomal binding. The NMR-restrained molecular-dynamics-derived solution structure revealed that the modifications provided an open, ordered loop for codon binding. The crystal structures of the hASL Lys3 UUU-mcm 5s 2U 34;ms 2t 6A 37;Ψ 39 bound to the 30S ribosomal subunit with each codon in the A site showed that the modified nucleotides mcm 5s 2U 34 and ms 2t 6A 37 participate in the stability of the anticodon–codon interaction. Importantly, the mcm 5s 2U 34·G 3 wobble base pair is in the Watson–Crick geometry, requiring unusual hydrogen bonding to G in which mcm 5s 2U 34 must shift from the keto to the enol form. The results unambiguously demonstrate that modifications pre-structure the anticodon as a key prerequisite for efficient and accurate recognition of cognate and wobble codons.« less

The effects of the dopamine D₃ receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects.

PubMed

Nathan, Pradeep J; O'Neill, Barry V; Mogg, Karin; Bradley, Brendan P; Beaver, John; Bani, Massimo; Merlo-Pich, Emilio; Fletcher, Paul C; Swirski, Bridget; Koch, Annelize; Dodds, Chris M; Bullmore, Edward T

2012-03-01

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D₃ receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D₃ receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m²) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D₃ receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.

Response, thermal regulatory threshold and thermal breakdown threshold of restrained RF-exposed mice at 905 MHz

NASA Astrophysics Data System (ADS)

Ebert, S.; Eom, S. J.; Schuderer, J.; Apostel, U.; Tillmann, T.; Dasenbrock, C.; Kuster, N.

2005-11-01

The objective of this study was the determination of the thermal regulatory and the thermal breakdown thresholds for in-tube restrained B6C3F1 and NMRI mice exposed to radiofrequency electromagnetic fields at 905 MHz. Different levels of the whole-body averaged specific absorption rate (SAR = 0, 2, 5, 7.2, 10, 12.6 and 20 W kg-1) have been applied to the mice inside the 'Ferris Wheel' exposure setup at 22 ± 2 °C and 30-70% humidity. The thermal responses were assessed by measurement of the rectal temperature prior, during and after the 2 h exposure session. For B6C3F1 mice, the thermal response was examined for three different weight groups (20 g, 24 g, 29 g), both genders and for pregnant mice. Additionally, NMRI mice with a weight of 36 g were investigated for an interstrain comparison. The thermal regulatory threshold of in-tube restrained mice was found at SAR levels between 2 W kg-1 and 5 W kg-1, whereas the breakdown of regulation was determined at 10.1 ± 4.0 W kg-1(K = 2) for B6C3F1 mice and 7.7 ± 1.6 W kg-1(K = 2) for NMRI mice. Based on a simplified power balance equation, the thresholds show a clear dependence upon the metabolic rate and weight. NMRI mice were more sensitive to thermal stress and respond at lower SAR values with regulation and breakdown. The presented data suggest that the thermal breakdown for in-tube restrained mice, whole-body exposed to radiofrequency fields, may occur at SAR levels of 6 W kg-1(K = 2) at laboratory conditions.

Distributed and Localized Deformation Along the Lebanese Restraining Bend from Geomorphic Observations and Modeling

NASA Astrophysics Data System (ADS)

Goren, L.; Castelltort, S.; Klinger, Y.

2014-12-01

The Dead Sea Fault System changes its orientation across Lebanon and forms a restraining bend. The oblique deformation along the Lebanese restraining bend is characterized by a complex suite of tectonic structures, among which, the Yammouneh Fault (YF), is believed to be the main strand that relays deformation from the southern section to the northern section of the Dead Sea Fault System. However, uncertainties regarding slip rates and strain partitioning in Lebanon still prevail. Here, we use morphometric analysis together with analytical and numerical models to constrain rates and modes of distributed and localized deformation along the Lebanese restraining bend.The rivers that drain the western flank of Mount Lebanon show a consistent counterclockwise rotation with respect to an expected orogen perpendicular orientation. Moreover, a pattern of divide disequilibrium in between these rivers emerges from an application of the χ mapping technique, which aims at estimating the degree of geometrical and topological disequilibrium in river networks. These geometrical patterns are compatible with simulation results using a landscape evolution model, which imposes a distributed velocity field along a domain that represents the western flank of Mount Lebanon. We further develop an analytical model that relates the river orientation to a set of kinematic parameters that represents a combined pure and simple shear strain field, and we find the parameters that best explain the present orientation of the western Lebanon rivers. Our results indicate that distributed deformation to the west of the YF takes as much as 30% of the relative Arabia-Sinai plate velocity since the late Miocene, and that the average slip rate along the YF during the same time interval has been 3.8-4.4 mm/yr. The theoretical model can further explain the inferred rotation from Paleomagnetic measurements.

A prime a day keeps calories away: The effects of supraliminal priming on food consumption and the moderating role of gender and eating restraint.

PubMed

Minas, Randall K; Poor, Morgan; Dennis, Alan R; Bartelt, Valerie L

2016-10-01

The link between intentions and action in weight control is weaker than previously thought, so recent research has called for further investigation of ways to improve weight control that bypass conscious intentions. Priming has been shown to have effects on individual behavior in a variety of contexts by influencing subconscious cognition. This paper investigates the effects of semantic priming using healthy body image, goal-oriented words on food consumption. The moderating role of both restrained eating and gender is investigated. 161 participants were involved in an experiment using a novel version of a scrambled sentence priming game. The outcome measure was the number of kilocalories consumed, examined using a between subjects ANCOVA with priming, gender, restrained eating index, self-reported BMI, and two interaction terms (primingxgender, and primingxrestrained eating index). There was no main effect of priming but there was an interaction of priming with gender. Females consumed significantly fewer kilocalories after being exposed to priming words related to a healthy body image (i.e. "slim", "fit,") compared to females receiving the neutral prime, with a medium effect size (d = 0.58). The body image prime did not significantly affect food intake for males, nor did it have a differential effect on restrained eaters. This study shows that priming can be an effective method for influencing females to reduce food intake, regardless of whether they are restrained or unrestrained eaters. Future studies could investigate whether different priming words related to a male's healthy body image goal (i.e. "buff," "muscles," etc.) would similarly reduce food intake for males. Copyright © 2016. Published by Elsevier Ltd.

Surface modification for interaction study with bacteria and preosteoblast cells

NASA Astrophysics Data System (ADS)

Song, Qing

Surface modification plays a pivotal role in bioengineering. Polymer coatings can provide biocompatibility and biofunctionalities to biomaterials through surface modification. In this dissertation, initiated chemical vapor deposition (iCVD) was utilized to coat two-dimensional (2D) and three-dimensional (3D) substrates with differently charged polyelectrolytes in order to generate antimicrobial and osteocompatible biomaterials. ICVD is a modified CVD technique that enables surface modification in an all-dry condition without substrate damage and solvent contamination. The free-radical polymerization allows the vinyl polymers to conformally coat on various micro- and nano-structured substrates and maintains the delicate structure of the functional groups. The vapor deposition of polycations provided antimicrobial activity to planar and porous substrates through destroying the negatively charged bacterial membrane and brought about high contact-killing efficiency (99.99%) against Gram-positive Bacillus subtilis and Gram-negative Escherichia coli. Additionally, the polyampholytes synthesized by iCVD exhibited excellent antifouling performance against the adhesion of Gram-positive Listeria innocua and Gram-negative E. coli in phosphate buffered saline (PBS). Their antifouling activities were attributed to the electrostatic interaction and hydration layers that served as physical and energetic barriers to prevent bacterial adhesion. The contact-killing and antifouling polymers synthesized by iCVD can be applied to surface modification of food processing equipment and medical devices with the aim of reducing foodborne diseases and medical infections. Moreover, the charged polyelectrolyte modified 2D polystyrene surfaces displayed good osteocompatibility and enhanced osteogenesis of preosteoblast cells than the un-modified polystyrene surface. In order to promote osteoinduction of hydroxyapatite (HA) scaffolds, bioinspired polymer-controlled mineralization was conducted on the polyelectrolyte modified HA scaffolds. The mineralized scaffolds stimulated osteogenesis of preosteoblast cells compared with the control HA scaffolds. Therefore, the surface modification through vapor deposition of polyelectrolytes and polymer-controlled mineralization can improve osteoinduction of bone materials. In summary, the iCVD-mediated surface modification is a simple and promising approach to biofunctionalizing various structured substrates and generating antimicrobial and biocompatible biomaterials.

Key Residues of Outer Membrane Protein OprI Involved in Hexamer Formation and Bacterial Susceptibility to Cationic Antimicrobial Peptides.

PubMed

Chang, Ting-Wei; Wang, Chiu-Feng; Huang, Hsin-Jye; Wang, Iren; Hsu, Shang-Te Danny; Liao, You-Di

2015-10-01

Antimicrobial peptides (AMPs) are important components of the host innate defense mechanism against invading pathogens. Our previous studies have shown that the outer membrane protein, OprI from Pseudomonas aeruginosa or its homologue, plays a vital role in the susceptibility of Gram-negative bacteria to cationic α-helical AMPs (Y. M. Lin, S. J. Wu, T. W. Chang, C. F. Wang, C. S. Suen, M. J. Hwang, M. D. Chang, Y. T. Chen, Y. D. Liao, J Biol Chem 285:8985-8994, 2010, http://dx.doi.org/10.1074/jbc.M109.078725; T. W. Chang, Y. M. Lin, C. F. Wang, Y. D. Liao, J Biol Chem 287:418-428, 2012, http://dx.doi.org/10.1074/jbc.M111.290361). Here, we obtained two forms of recombinant OprI: rOprI-F, a hexamer composed of three disulfide-bridged dimers, was active in AMP binding, while rOprI-R, a trimer, was not. All the subunits predominantly consisted of α-helices and exhibited rigid structures with a melting point centered around 76°C. Interestingly, OprI tagged with Escherichia coli signal peptide was expressed in a hexamer, which was anchored on the surface of E. coli, possibly through lipid acids added at the N terminus of OprI and involved in the binding and susceptibility to AMP as native P. aeruginosa OprI. Deletion and mutation studies showed that Cys1 and Asp27 played a key role in hexamer formation and AMP binding, respectively. The increase of OprI hydrophobicity upon AMP binding revealed that it undergoes conformational changes for membrane fusion. Our results showed that OprI on bacterial surfaces is responsible for the recruitment and susceptibility to amphipathic α-helical AMPs and may be used to screen antimicrobials. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A natural food ingredient based on ergosterol: optimization of the extraction from Agaricus blazei, evaluation of bioactive properties and incorporation in yogurts.

PubMed

Corrêa, Rúbia C G; Barros, Lillian; Fernandes, Ângela; Sokovic, Marina; Bracht, Adelar; Peralta, Rosane M; Ferreira, Isabel C F R

2018-03-01

In recent years, mycosterols have emerged as potential functional ingredients for the development of sterol-enriched food products and dietary supplements. Agaricus blazei is a mushroom rich in bioactive compounds. For commercial purposes, their fruiting bodies must obey rigid morphological criteria. Those not conforming to these criteria are usually discarded, although this does not mean impairment of their content in bioactives. The aim of the present work was to propose the use of commercially discarded A. blazei fruiting bodies for obtaining an extract rich in ergosterol as a fortifier ingredient for yogurts. For extraction, the Soxhlet technology was used and the highest ergosterol yield (around 12%) was achieved in the 5 th cycle, yielding 58.53 ± 1.72 µg of ergosterol per 100 g of mushroom (dry weight). The ergosterol rich extract presented notable antioxidant and antimicrobial properties, besides showing no hepatotoxicity. When added to the yogurts it significantly enhanced their antioxidant properties. Furthermore, it did not significantly alter the nutritional or the individual fatty acid profiles of the final dairy products. Thus, A. blazei fruiting bodies that do not conform to the commercial requirements of the market and are normally discarded could be exploited for obtaining a natural high added-value food additive, following the circular bioeconomy concept.

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

Effect of TFE on the Helical Content of AK17 and HAL-1 Peptides: Theoretical Insights into the Mechanism of Helix Stabilization.

PubMed

Vymětal, Jiří; Bednárová, Lucie; Vondrášek, Jiří

2016-02-18

Fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) are among the most frequently used cosolvents in experiment studies of peptides. They have significant effects on secondary structure and a particularly strong promotion of α-helix is induced by TFE. In this study we validated recently proposed force field parameters for TFE in molecular dynamics simulations with two model peptides-alanine-rich AK-17 and antimicrobial peptide halictine-1 (HAL-1). In the case of HAL-1, we characterized the effect of TFE on this peptide experimentally by ECD spectroscopy. Our TFE model in question reproduced the helix-promoting effect of TFE and provided insight into the mechanisms of TFE action on peptides. Our simulations confirmed the preferential interaction of TFE molecules with α-helices, although the TFE molecules accumulate in the vicinity of the peptides in various conformations. Moreover, we observed a significant effect of TFE on the thermodynamics of the helix-coil transition and a change in local conformational preferences in the unfolded (coil) state induced by TFE. In addition, our simulation-based analysis suggests that different mechanisms participate in helix stabilization in both model peptides in water and TFE solution. Our results thus support the picture of complex TFE action on peptides that is further diversified by the identity and intrinsic properties of the peptide.

Fourier transform infrared spectroscopic study of the interactions of a strongly antimicrobial but weakly hemolytic analogue of gramicidin S with lipid micelles and lipid bilayer membranes.

PubMed

Lewis, Ruthven N A H; Kiricsi, Monika; Prenner, Elmar J; Hodges, Robert S; McElhaney, Ronald N

2003-01-21

Cyclo[VKLdKVdYPLKVKLdYP] (GS14dK(4)), a synthetic tetradecameric ring-size analogue of the naturally occurring antimicrobial peptide gramicidin S (GS), retains the strong antimicrobial activity of GS but is 15-20 times less hemolytic. To characterize its interaction with lipid membranes and to understand the molecular basis of its capacity to lyse bacterial cells, in preference to erythrocytes, we have investigated the interactions of GS14dK(4) with detergent micelles and with lipid bilayer model membranes by Fourier transform infrared spectroscopy and compared our results with those of a similar study of GS [Lewis, R. N. A. H., et al. (1999) Biochemistry 38, 15193-15203]. In both aqueous and organic solvent solutions, GS14dK(4) adopts a beta-sheet conformation that is somewhat distorted and more sensitive to the polarity of its environment than GS. Like GS, GS14dK(4) is completely or partially excluded from gel-state lipid bilayers but interacts strongly with liquid-crystalline lipid bilayers and detergent micelle, and interacts more strongly with more fluid liquid-crystalline lipid systems. However, its interactions are more strongly influenced by membrane lipid order and fluidity, and unlike GS, it is essentially excluded from cholesterol-containing phospholipid bilayers. Also, GS14dK(4) is excluded from cationic lipid bilayers, but partitions more strongly and/or penetrates more deeply into anionic lipid bilayers than into those composed of either zwitterionic or nonionic lipids. Anionic lipids also facilitate GS14dK(4) interactions with multicomponent lipid bilayers which are predominantly zwitterionic or nonionic. Although GS14dK(4) generally penetrates and/or partitions into zwitterionic or uncharged lipid bilayers less strongly than does GS, its greater size and altered distribution of positive charges make it intrinsically more perturbing with regard to membrane organization once associated with lipid bilayers. This fact, combined with its relatively strong interactions with anionic phospholipids, may explain why GS14dK(4) retains relatively high antimicrobial activity. However, its low hemolytic activity is probably largely attributable to its low propensity to penetrate and/or partition into cholesterol-containing zwitterionic lipid membranes.

The use of music to release the ties that bind.

PubMed

Janelli, L; Kanski, G

2000-01-01

The purpose of this descriptive pilot study was to determine the effect of a musical intervention on the behavioural reactions of physically restrained patients. Forty patients, of whom 23 were female and 17 were males with a mean age of 77, participated in the study. Patients listened to their preferred musical selection for a period of 30 minutes while they were out of their restraining device. The findings indicated that there was an increase in observed positive behaviours while patients listened to music as compared to the pre- or post-intervention phase. Music intervention may be appropriate for some patients as an alternative to physical restraints.

Weight loss in rats exposed to repeated acute restraint stress is independent of energy or leptin status.

PubMed

Harris, Ruth B S; Mitchell, Tiffany D; Simpson, Jacob; Redmann, Stephen M; Youngblood, Bradley D; Ryan, Donna H

2002-01-01

Acute release of corticotropin-releasing factor (CRF) during repeated restraint (3-h restraint on each of 3 days) causes temporary hypophagia but chronic suppression of body weight in rats. Here we demonstrated that a second bout of repeated restraint caused additional weight loss, but continuing restraint daily for 10 days did not increase weight loss because the rats adapted to the stress. In these two studies serum leptin, which suppresses the endocrine response to stress, was reduced in restrained rats. Peripheral infusion of leptin before and during restraint did not prevent stress-induced weight loss, although stress-induced corticosterone release was suppressed. Restrained rats were hyperthermic during restraint, but there was no evidence that fever or elevated free interleukin-6 caused the sustained reduction in weight. Restraining food-restricted rats caused a small but significant weight loss. Food-restricted rats fed ad libitum after the end of restraint showed a blunted hyperphagia and slower rate of weight regain than their controls. These results indicate that repeated acute stress induces a chronic change in weight independent of stress-induced hypophagia and may represent a change in homeostasis initiated by repeated acute activation of the central CRF system.

Chloroplast downsizing under nitrate nutrition restrained mesophyll conductance and photosynthesis in rice (Oryza sativa L.) under drought conditions.

PubMed

Li, Yong; Ren, Binbin; Yang, Xiuxia; Xu, Guohua; Shen, Qirong; Guo, Shiwei

2012-05-01

The phenomenon whereby ammonium enhances the tolerance of rice seedlings (Oryza sativa L., cv. 'Shanyou 63' hybrid indica China) to water stress has been reported in previous studies. To study the intrinsic mechanism of biomass synthesis related to photosynthesis, hydroponic experiments supplying different nitrogen (N) forms were conducted; water stress was simulated by the addition of polyethylene glycol. Water stress decreased leaf water potential (Ψ(leaf)) under nitrate nutrition, while it had no negative effect under ammonium nutrition. The decreased Ψ(leaf) under nitrate nutrition resulted in chloroplast downsizing and subsequently decreased mesophyll conductance to CO(2) (g(m)). The decreased g(m) and stomatal conductance (g(s)) under nitrate nutrition with water stress restrained the CO(2) supply to the chloroplast and Rubisco. The relatively higher distribution of leaf N to Rubisco under ammonium nutrition might also be of benefit for photosynthesis under water stress. In conclusion, chloroplast downsizing induced a decline in g(m), a relatively higher decrease in g(s) under nitrate nutrition with water stress, restrained the CO(2) supply to Rubisco and finally decreased the photosynthetic rate.

Identifying Armed Respondents to Domestic Violence Restraining Orders and Recovering Their Firearms: Process Evaluation of an Initiative in California

PubMed Central

Frattaroli, Shannon; Claire, Barbara E.; Vittes, Katherine A.; Webster, Daniel W.

2014-01-01

Objectives. We evaluated a law enforcement initiative to screen respondents to domestic violence restraining orders for firearm ownership or possession and recover their firearms. Methods. The initiative was implemented in San Mateo and Butte counties in California from 2007 through 2010. We used descriptive methods to evaluate the screening process and recovery effort in each county, relying on records for individual cases. Results. Screening relied on an archive of firearm transactions, court records, and petitioner interviews; no single source was adequate. Screening linked 525 respondents (17.7%) in San Mateo County to firearms; 405 firearms were recovered from 119 (22.7%) of them. In Butte County, 88 (31.1%) respondents were linked to firearms; 260 firearms were recovered from 45 (51.1%) of them. Nonrecovery occurred most often when orders were never served or respondents denied having firearms. There were no reports of serious violence or injury. Conclusions. Recovering firearms from persons subject to domestic violence restraining orders is possible. We have identified design and implementation changes that may improve the screening process and the yield from recovery efforts. Larger implementation trials are needed. PMID:24328660

The effects of emotion regulation on the desire to overeat in restrained eaters.

PubMed

Svaldi, Jennifer; Tuschen-Caffier, Brunna; Lackner, Helmut K; Zimmermann, Sabine; Naumann, Eva

2012-10-01

The aim of the present study was to test whether emotion regulation (ER) strategies are underlying processes in the link between negative emotions and the desire to overeat (DTE) in high restrained eaters (HR). Forty-eight female HR and 46 female low restrained eaters (LR) watched three sadness inducing film clips. Thereby, participants were randomly assigned to and trained in one of three conditions while watching the first two clips: to suppress upcoming emotions, to accept upcoming emotions or to reappraise the situation. After that, they participated in an experiment in which the learned ER strategy was implemented while watching the third sadness inducing film clip. DTE and sadness were assessed prior to and at the end of each clip. Additionally, physiological measures of the sympathetic and parasympathetic branch were obtained. In the HR group emotion acceptance and suppression lead to a significant increase of the DTE from baseline to post-film, while there was no change in DTE in the reappraisal condition. However, psychophysiological measures were not moderated by ER strategies. The results are discussed in terms of the limited resource model. Copyright © 2012 Elsevier Ltd. All rights reserved.

How Farm Animals React and Perceive Stressful Situations Such As Handling, Restraint, and Transport

PubMed Central

Grandin, Temple; Shivley, Chelsey

2015-01-01

Simple Summary A common animal welfare question is: how stressful is handling and restraining farm animals for veterinary procedures even when no surgical or invasive procedures are done? It depends on how a particular animal perceives it. For one animal, restraint for an injection may be a positive experience associated with food treats and a different animal may be highly fearful and actively resist being restrained. The animal’s response is highly dependent on both its previous experiences and inherited traits such as temperament. Abstract An animal that has been carefully acclimated to handling may willingly re-enter a restrainer. Another animal may have an intense agitated behavioral reaction or refuse to re-enter the handling facility. Physiological measures of stress such as cortisol may be very low in the animal that re-enters willingly and higher in animals that actively resist restraint. Carefully acclimating young animals to handling and restraint can help improve both productivity and welfare by reducing fear stress. Some of the topics covered in this review are: How an animal perceives handling and restraint, the detrimental effects of a sudden novel event, descriptions of temperament and aversion tests and the importance of good stockmanship. PMID:26633523

The Effect of Manual Restraint on Physiological Parameters in Barred Owls ( Strix varia ).

PubMed

Doss, Grayson A; Mans, Christoph

2017-03-01

Manual restraint is commonly necessary when working with avian species in medical, laboratory, and field settings. Despite their prevalence, little is known about the stress response in raptorial bird species. To further understand the effect of restraint on the stress response in birds of prey, 12 barred owls ( Strix varia ) were manually restrained for 15 minutes. Physiological parameters (cloacal temperature, respiratory rate, heart rate) were followed over time and recorded at defined points during the restraint period. Heart rate decreased significantly over the restraint period by a mean ± SD of -73 ± 46 beats/min. Respiratory rate also decreased significantly (median: -11 breaths/min, interquartile range: -8 to -18). Cloacal temperature increased significantly over time in manually restrained owls (median: +1.5°C [+2.7°F], interquartile range: 1.3°C-2.1°C [2.3°F-3.8°F]). This study is the first to document stress hyperthermia in an owl species. Similar to another raptorial bird, the red-tailed hawk ( Buteo jamaicensis ), both heart rate and respiratory rate decreased and cloacal temperature increased over time in restrained barred owls. Barred owls appear to cope differently to restraint stress when compared to psittacine species.

Thoracic injuries to contained and restrained occupants in single-vehicle pure rollover crashes.

PubMed

Bambach, M R; Grzebieta, R H; McIntosh, A S

2013-01-01

Around one in three contained and restrained seriously injured occupants in single-vehicle pure rollover crashes receive a serious injury to the thorax. With dynamic rollover test protocols currently under development, there is a need to understand the nature and cause of serious thoracic injuries incurred in rollover events. This will allow decisions to be made with regards to adoption of a suitable crash test dummy and appropriate thoracic injury criteria in such protocols. Valid rollover occupant protection test protocols will lead to vehicle improvements that will reduce the high trauma burden of vehicle rollover crashes. This paper presents an analysis of contained and restrained occupants involved in single-vehicle pure rollover crashes that occurred in the United States between 2000 and 2009 (inclusive). Serious thoracic injury typology and causality are determined. A logistic regression model is developed to determine associations between the incidence of serious thoracic injury and the human, vehicle and environmental characteristics of the crashes. Recommendations are made with regards to the appropriate assessment of potential thoracic injury in dynamic rollover occupant protection crash test protocols. Copyright © 2012 Elsevier Ltd. All rights reserved.

PLASTIC SHRINKAGE CONTROLLING EFFECT BY POLYPROPYLENE SHORT FIBER WITH HYDROPHILY

NASA Astrophysics Data System (ADS)

Hosoda, Akira; Sadatsuki, Yoshitomo; Oshima, Akihiro; Ishii, Akina; Tsubaki, Tatsuya

The aim of this research is to clarify the mechanism of controlling plastic shrinkage crack by adding small amout of synthetic short fiber, and to propose optimum polypropylene short fiber to control plastic shrinkage crack. In this research, the effect of the hydrophily of polypropylene fiber was investigated in the amount of plastic shrinkage of mortar, total area of plastic shrinkage crack, and bond properties between fiber and mortar. The plastic shrinkage test of morar was conducted under high temperature, low relative humidity, and constant wind velocity. When polypropylene fiber had hydrophily, the amount of plastic shrinkage of mortar was restrained, which was because cement paste in morar was captured by hydrophilic fiber and then bleeding of mortar was restrained. With hydrophily, plastic shrinkage of mortar was restrained and bridging effect was improved due to better bond, which led to remarkable reduction of plastic shrinkage crack. Based on experimental results, the way of developing optimum polypropylene short fiber for actual construction was proposed. The fiber should have large hydrophily and small diameter, and should be used in as small amount as possible in order not to disturb workability of concrete.

Pediatric restraint use in motor vehicle collisions: reduction of deaths without contribution to injury.

PubMed

Tyroch, A H; Kaups, K L; Sue, L P; O'Donnell-Nicol, S

2000-10-01

Restraint use for children in automobiles is mandated in every state, but injury patterns are unknown. Although use of pediatric retraints is associated with reducing morbidity and mortality, the injury distribution for specific anatomic sites may be altered in restrained vs unrestrained children. Review of trauma registry data, medical records, and autopsy findings. Urban level I trauma center and tertiary care children's hospital. All children aged 6 years or younger who were in motor vehicle collisions from June 1, 1990, through March 31, 1997. Age, weight, restraint use and type, collision data, Injury Severity Score (ISS), injury type, and outcome. We included 600 children. The restrained group showed a reduction in severe injuries for every anatomic site and had a lower mean ISS, fewer injuries, and more uninjured children. The restrained group also had a reduction in the incidence of hollow- and solid-organ abdominal injuries. Age-appropriate restraint devices decrease mortality and reduce the incidence of significant injury in motor vehicle collisions for all anatomic sites in young children. In contrast to injuries attributed to restraint use in adults, specific restraint-related injury patterns were not seen in children.

Residual Strength Analyses of Riveted Lap-Splice Joints

NASA Technical Reports Server (NTRS)

Seshadri, B. R.; Newman, J. C., Jr.

2000-01-01

The objective of this paper was to analyze the crack-linkup behavior in riveted-stiffened lap-splice joint panels with small multiple-site damage (MSD) cracks at several adjacent rivet holes. Analyses are based on the STAGS (STructural Analysis of General Shells) code with the critical crack-tip-opening angle (CTOA) fracture criterion. To account for high constraint around a crack front, the "plane strain core" option in STAGS was used. The importance of modeling rivet flexibility with fastener elements that accurately model load transfer across the joint is discussed. Fastener holes are not modeled but rivet connectivity is accounted for by attaching rivets to the sheet on one side of the cracks that simulated both the rivet diameter and MSD cracks. Residual strength analyses made on 2024-T3 alloy (1.6-mm thick) riveted-lap-splice joints with a lead crack and various size MSD cracks were compared with test data from Boeing Airplane Company. Analyses were conducted for both restrained and unrestrained buckling conditions. Comparison of results from these analyses and results from lap-splice-joint test panels, which were partially restrained against buckling indicate that the test results were bounded by the failure loads predicted by the analyses with restrained and unrestrained conditions.

Thermal behavior of cylindrical buckling restrained braces at elevated temperatures.

PubMed

Talebi, Elnaz; Tahir, Mahmood Md; Zahmatkesh, Farshad; Yasreen, Airil; Mirza, Jahangir

2014-01-01

The primary focus of this investigation was to analyze sequentially coupled nonlinear thermal stress, using a three-dimensional model. It was meant to shed light on the behavior of Buckling Restraint Brace (BRB) elements with circular cross section, at elevated temperature. Such bracing systems were comprised of a cylindrical steel core encased in a strong concrete-filled steel hollow casing. A debonding agent was rubbed on the core's surface to avoid shear stress transition to the restraining system. The numerical model was verified by the analytical solutions developed by the other researchers. Performance of BRB system under seismic loading at ambient temperature has been well documented. However, its performance in case of fire has yet to be explored. This study showed that the failure of brace may be attributed to material strength reduction and high compressive forces, both due to temperature rise. Furthermore, limiting temperatures in the linear behavior of steel casing and concrete in BRB element for both numerical and analytical simulations were about 196°C and 225°C, respectively. Finally it is concluded that the performance of BRB at elevated temperatures was the same as that seen at room temperature; that is, the steel core yields prior to the restraining system.

Collision-avoidance behaviors of minimally restrained flying locusts to looming stimuli

PubMed Central

Chan, R. WM.; Gabbiani, F.

2013-01-01

SUMMARY Visually guided collision avoidance is of paramount importance in flight, for instance to allow escape from potential predators. Yet, little is known about the types of collision-avoidance behaviors that may be generated by flying animals in response to an impending visual threat. We studied the behavior of minimally restrained locusts flying in a wind tunnel as they were subjected to looming stimuli presented to the side of the animal, simulating the approach of an object on a collision course. Using high-speed movie recordings, we observed a wide variety of collision-avoidance behaviors including climbs and dives away from – but also towards – the stimulus. In a more restrained setting, we were able to relate kinematic parameters of the flapping wings with yaw changes in the trajectory of the animal. Asymmetric wing flapping was most strongly correlated with changes in yaw, but we also observed a substantial effect of wing deformations. Additionally, the effect of wing deformations on yaw was relatively independent of that of wing asymmetries. Thus, flying locusts exhibit a rich range of collision-avoidance behaviors that depend on several distinct aerodynamic characteristics of wing flapping flight. PMID:23364572

Theoretical analysis of the cost of antagonistic activity for aquatic bacteria in oligotrophic environments.

PubMed

Aguirre-von-Wobeser, Eneas; Eguiarte, Luis E; Souza, Valeria; Soberón-Chávez, Gloria

2015-01-01

Many strains of bacteria produce antagonistic substances that restrain the growth of others, and potentially give them a competitive advantage. These substances are commonly released to the surrounding environment, involving metabolic costs in terms of energy and nutrients. The rate at which these molecules need to be produced to maintain a certain amount of them close to the producing cell before they are diluted into the environment has not been explored so far. To understand the potential cost of production of antagonistic substances in water environments, we used two different theoretical approaches. Using a probabilistic model, we determined the rate at which a cell needs to produce individual molecules in order to keep on average a single molecule in its vicinity at all times. For this minimum protection, a cell would need to invest 3.92 × 10(-22) kg s(-1) of organic matter, which is 9 orders of magnitude lower than the estimated expense for growth. Next, we used a continuous model, based on Fick's laws, to explore the production rate needed to sustain minimum inhibitory concentrations around a cell, which would provide much more protection from competitors. In this scenario, cells would need to invest 1.20 × 10(-11) kg s(-1), which is 2 orders of magnitude higher than the estimated expense for growth, and thus not sustainable. We hypothesize that the production of antimicrobial compounds by bacteria in aquatic environments lies between these two extremes.

Investigation on the interaction between an antimicrobial in aquaculture, malachite green and hemocyanin from Mud Crab Scylla paramamosain

NASA Astrophysics Data System (ADS)

Li, Zhenxing; Tang, Boping; Zhang, Hongmei

2015-01-01

Interaction between malachite green and hemocyanin of crab plays a crucial role in the metabolism, distribution, and efficacy of toxic dyes in aquaculture. The mechanism of interaction between malachite green and Hc from mud crab was studied by using multi-spectral methods and molecular modeling in this work. The spectroscopic and thermodynamic data show that the interaction is a spontaneous process with the estimated enthalpy and entropy changes of -14.85(±1.86) kJ mol-1 and 30.38(±5.21) J mol-1 K-1, respectively. The binding sites of malachite green in hemocyanin mainly locate in the interface of protein. The hydrophobic and electrostatic forces are the primary contributors to the interaction between hemocyanin and malachite green. The results of ultraviolet-vis absorbance, circular dichroism, and synchronous fluorescence spectroscopy suggest that the binding of malachite green to hemocyanin induces some conformational changes of protein.

BSA binding and antimicrobial studies of branched polyethyleneimine-copper(II)bipyridine/phenanthroline complexes

NASA Astrophysics Data System (ADS)

Vignesh, Gopalaswamy; Arunachalam, Sankaralingam; Vignesh, Sivanandham; James, Rathinam Arthur

2012-10-01

The interaction of two water soluble branched polyethyleneimine-copper(II) complexes containing bipyridine/phenanthroline with bovine serum albumin (BSA) was studied by, UV-Visible absorption, fluorescence, lifetime measurements and circular dichroism spectroscopic techniques. The polymer-copper(II) complexes strongly quench the intrinsic fluorescence of BSA is the static quenching mechanism through hydrogen bonds and van der Waal's attraction. The distance r, between the BSA and the complexes seems to be less than 2 nm indicating that the energy transfer between the donor and acceptor occurs with high probability. Synchronous fluorescence studies indicate the binding of polymer-copper(II) complexes with BSA mostly changes the polarity around tryptophan residues rather than tyrosine residues. The circular dichroism studies indicate that the binding has induced considerable amount of conformational changes in the protein. The complexes also show some antibacterial and antifungal properties.

Biological and protein-binding studies of newly synthesized polymer-cobalt(III) complexes.

PubMed

Vignesh, G; Pradeep, I; Arunachalam, S; Vignesh, S; Arthur James, R; Arun, R; Premkumar, K

2016-03-01

The polymer-cobalt(III) complexes, [Co(bpy)(dien)BPEI]Cl3 · 4H2O (bpy = 2,2'-bipyridine, dien = diethylentriamine, BPEI = branched polyethyleneimine) were synthesized and characterized. The interaction of these complexes with human serum albumin (HSA) and bovine serum albumin (BSA) was investigated under physiological conditions using various physico-chemical techniques. The results reveal that the fluorescence quenching of serum albumins by polymer-cobalt(III) complexes took place through static quenching. The binding of these complexes changed the molecular conformation of the protein considerably. The polymer-cobalt(III) complex with x = 0.365 shows antimicrobial activity against several human pathogens. This complex also induces cytotoxicity against MCF-7 through apoptotic induction. However, further studies are needed to decipher the molecular mode of action of polymer-cobalt(III) complex and for its possible utilization in anticancer therapy. Copyright © 2015 John Wiley & Sons, Ltd.

Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule

PubMed Central

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; Tollefsen, Douglas M.; Malmsten, Martin; Mörgelin, Matthias

2013-01-01

The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity. PMID:23656734

Proteolytic activation transforms heparin cofactor II into a host defense molecule.

PubMed

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; Tollefsen, Douglas M; Malmsten, Martin; Mörgelin, Matthias; Schmidtchen, Artur

2013-06-15

The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.

Tissue factor pathway inhibitor 2 is found in skin and its C-terminal region encodes for antibacterial activity.

PubMed

Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E; Lundqvist, Katarina; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur

2012-01-01

Tissue factor pathway inhibitor 2 (TFPI-2) is a matrix-associated serine protease inhibitor with an enigmatic function in vivo. Here, we describe that TFPI-2 is present in fibrin of wounds and also expressed in skin, where it is up-regulated upon wounding. Neutrophil elastase cleaved TFPI-2, and a C-terminal fragment was found to bind to bacteria. Similarly, a prototypic peptide representing this C-terminal part, EDC34, bound to bacteria and bacterial lipopolysaccharide, and induced bacterial permeabilization. The peptide also induced leakage in artificial liposomes, and displayed a random coil conformation upon interactions with liposomes as well as lipopolysaccharide. EDC34 was antibacterial against both Gram-negative and Gram-positive bacteria in physiological buffer conditions. The results demonstrate that the C-terminus of TFPI-2 encodes for antimicrobial activity, and may be released during wounding.

Probing Membrane Order and Topography in Supported Lipid Bilayers by Combined Polarized Total Internal Reflection Fluorescence-Atomic Force Microscopy

PubMed Central

Oreopoulos, John; Yip, Christopher M.

2009-01-01

Determining the local structure, dynamics, and conformational requirements for protein-protein and protein-lipid interactions in membranes is critical to understanding biological processes ranging from signaling to the translocating and membranolytic action of antimicrobial peptides. We report here the application of a combined polarized total internal reflection fluorescence microscopy-in situ atomic force microscopy platform. This platform's ability to image membrane orientational order was demonstrated on DOPC/DSPC/cholesterol model membranes containing the fluorescent membrane probe, DiI-C20 or BODIPY-PC. Spatially resolved order parameters and fluorophore tilt angles extracted from the polarized total internal reflection fluorescence microscopy images were in good agreement with the topographical details resolved by in situ atomic force microscopy, portending use of this technique for high-resolution characterization of membrane domain structures and peptide-membrane interactions. PMID:19254557

D-Cateslytin: a new antifungal agent for the treatment of oral Candida albicans associated infections.

PubMed

Dartevelle, Pauline; Ehlinger, Claire; Zaet, Abdurraouf; Boehler, Christian; Rabineau, Morgane; Westermann, Benoit; Strub, Jean-Marc; Cianferani, Sarah; Haïkel, Youssef; Metz-Boutigue, Marie-Hélène; Marban, Céline

2018-06-18

The excessive use of antifungal agents, compounded by the shortage of new drugs being introduced into the market, is causing the accumulation of multi-resistance phenotypes in many fungal strains. Consequently, new alternative molecules to conventional antifungal agents are urgently needed to prevent the emergence of fungal resistance. In this context, Cateslytin (Ctl), a natural peptide derived from the processing of Chromogranin A, has already been described as an effective antimicrobial agent against several pathogens including Candida albicans. In the present study, we compared the antimicrobial activity of two conformations of Ctl, L-Ctl and D-Ctl against Candida albicans. Our results show that both D-Ctl and L-Ctl were potent and safe antifungal agents. However, in contrast to L-Ctl, D-Ctl was not degraded by proteases secreted by Candida albicans and was also stable in saliva. Using video microscopy, we also demonstrated that D-Ctl can rapidly enter C. albicans, but is unable to spread within a yeast colony unless from a mother cell to a daughter cell during cellular division. Besides, we revealed that the antifungal activity of D-Ctl could be synergized by voriconazole, an antifungal of reference in the treatment of Candida albicans related infections. In conclusion, D-Ctl can be considered as an effective, safe and stable antifungal and could be used alone or in a combination therapy with voriconazole to treat Candida albicans related diseases including oral candidosis.

Protein nanopore-based, single-molecule exploration of copper binding to an antimicrobial-derived, histidine-containing chimera peptide.

PubMed

Mereuta, Loredana; Schiopu, Irina; Asandei, Alina; Park, Yoonkyung; Hahm, Kyung-Soo; Luchian, Tudor

2012-12-11

Metal ions binding exert a crucial influence upon the aggregation properties and stability of peptides, and the propensity of folding in various substates. Herein, we demonstrate the use of the α-HL protein as a powerful nanoscopic tool to probe Cu(2+)-triggered physicochemical changes of a 20 aminoacids long, antimicrobial-derived chimera peptide with a His residue as metal-binding site, and simultaneously dissect the kinetics of the free- and Cu(2+)-bound peptide interaction to the α-HL pore. Combining single-molecule electrophysiology on reconstituted lipid membranes and fluorescence spectroscopy, we show that the association rate constant between the α-HL pore and a Cu(2+)-free peptide is higher than that of a Cu(2+)-complexed peptide. We posit that mainly due to conformational changes induced by the bound Cu(2+) on the peptide, the resulting complex encounters a higher energy barrier toward its association with the protein pore, stemming most likely from an extra entropy cost needed to fit the Cu(2+)-complexed peptide within the α-HL lumen region. The lower dissociation rate constant of the Cu(2+)-complexed peptide from α-HL pore, as compared to that of Cu(2+)-free peptide, supports the existence of a deeper free energy well for the protein interaction with a Cu(2+)-complexed peptide, which may be indicative of specific Cu(2+)-mediated contributions to the binding of the Cu(2+)-complexed peptide within the pore lumen.

Recognition of DNA/RNA bulges by antimicrobial and antitumor metallohelices.

PubMed

Malina, Jaroslav; Scott, Peter; Brabec, Viktor

2015-09-07

Bulged structures have been identified in nucleic acids and have been shown to be linked to biomolecular processes involved in numerous diseases. Thus, chemical agents with affinity for bulged nucleic acids are of general biological significance. Herein, the mechanism of specific recognition and stabilization of bulged DNA and RNA by helical bimetallic species was established through detailed molecular biophysics and biochemistry assays. These agents, known as 'flexicates', are potential mimetics of α-helical peptides in cancer treatment, exhibiting antimicrobial and antitumor effects. The flexicates have positive impacts on the thermal stability of DNA duplexes containing bulges, which means that the flexicates interact with the duplexes containing bulges, and that these interactions stabilize the secondary structures of these duplexes. Notably, the stabilising effect of the flexicates increases with the size of the bulge, the maximal stabilization is observed for the duplexes containing a bulge composed of at least three bases. The flexicates bind most preferentially to the bulges composed of pyrimidines flanked on both sides also by pyrimidines. It is suggested that it is so because these bulges exhibit greatest conformational variability in comparison with other combinations of bases in the bulge loop and bases flanking the bulge. Finally, the results indicate that there is only one dominant binding site for the flexicates on the DNA and RNA bulges and that the flexicates bind directly to the bulge or in its close proximity. It is also shown that the flexicates effectively bind to RNA duplexes containing the bulged region of HIV-1 TAR RNA.

Solution structure and stability of the DNA undecamer duplexes containing oxanine mismatch

PubMed Central

Pack, Seung Pil; Morimoto, Hirohisa; Makino, Keisuke; Tajima, Kunihiko; Kanaori, Kenji

2012-01-01

Solution structures of DNA duplexes containing oxanine (Oxa, O) opposite a cytosine (O:C duplex) and opposite a thymine (O:T duplex) have been solved by the combined use of 1H NMR and restrained molecular dynamics calculation. One mismatch pair was introduced into the center of the 11-mer duplex of [d(GTGACO6CACTG)/d(CAGTGX17GTCAC), X = C or T]. 1H NMR chemical shifts and nuclear Overhauser enhancement (NOE) intensities indicate that both the duplexes adopt an overall right-handed B-type conformation. Exchangeable resonances of C17 4-amino proton of the O:C duplex and of T17 imino proton of O:T duplex showed unusual chemical shifts, and disappeared with temperature increasing up to 30°C, although the melting temperatures were >50°C. The O:C mismatch takes a wobble geometry with positive shear parameter where the Oxa ring shifted toward the major groove and the paired C17 toward the minor groove, while, in the O:T mismatch pair with the negative shear, the Oxa ring slightly shifted toward the minor groove and the paired T17 toward the major groove. The Oxa mismatch pairs can be wobbled largely because of no hydrogen bond to the O1 position of the Oxa base, and may occupy positions in the strands that optimize the stacking with adjacent bases. PMID:22039100

Enhanced cyclic stability of SnS microplates with conformal carbon coating derived from ethanol vapor deposition for sodium-ion batteries

NASA Astrophysics Data System (ADS)

Li, Xiang; Liu, Jiangwen; Ouyang, Liuzhang; Yuan, Bin; Yang, Lichun; Zhu, Min

2018-04-01

Carbon coated SnS microplates (SnS@C MPs) were prepared via a facile chemical vapor deposition method using SnS2 nanoflakes as precursor and ethanol vapor as carbon source. The carbon coating restrains the growth of SnS during the heat treatment. Furthermore, it improves the electronic conductivity as well as accommodates volume variations of SnS during the sodiation and desodiation processes. Therefore, the rate capability and cycle performance of the SnS@C MPs as anode materials for sodium-ion batteries are remarkably enhanced compared with the bare SnS and the SnS2 precursor. At current densities of 0.1, 0.2, 0.5, 1 and 2 A g-1, the optimized SnS@C MPs exhibit stable capacities of 602.9, 532.1, 512.2, 465.9 and 427.2 mAh g-1, respectively. At 1 A g-1, they show a reversible capacity of 528.8 mAh g-1 in the first cycle, and maintain 444.7 mAh g-1 after 50 cycles, with capacity retention of 84.1%. The carbon coating through chemical vapor deposition using ethanol vapor as carbon sources is green, simple and cost-effective, which shows great promise to improve the reversible Na+ storage of electrode materials.

Theory and simulation of ion conduction in the pentameric GLIC channel.

PubMed

Zhu, Fangqiang; Hummer, Gerhard

2012-10-09

GLIC is a bacterial member of the large family of pentameric ligand-gated ion channels. To study ion conduction through GLIC and other membrane channels, we combine the one-dimensional potential of mean force for ion passage with a Smoluchowski diffusion model, making it possible to calculate single-channel conductance in the regime of low ion concentrations from all-atom molecular dynamics (MD) simulations. We then perform MD simulations to examine sodium ion conduction through the GLIC transmembrane pore in two systems with different bulk ion concentrations. The ion potentials of mean force, calculated from umbrella sampling simulations with Hamiltonian replica exchange, reveal a major barrier at the hydrophobic constriction of the pore. The relevance of this barrier for ion transport is confirmed by a committor function that rises sharply in the barrier region. From the free evolution of Na(+) ions starting at the barrier top, we estimate the effective diffusion coefficient in the barrier region, and subsequently calculate the conductance of the pore. The resulting diffusivity compares well with the position-dependent ion diffusion coefficient obtained from restrained simulations. The ion conductance obtained from the diffusion model agrees with the value determined via a reactive-flux rate calculation. Our results show that the conformation in the GLIC crystal structure, with an estimated conductance of ~1 picosiemens at 140 mM ion concentration, is consistent with a physiologically open state of the channel.

Investigations of Crashes Involving Pregnant Occupants

PubMed Central

Klinich, Kathleen DeSantis; Schneider, Lawrence W.; Moore, Jamie L.; Pearlman, Mark D.

2000-01-01

Case reports of 16 crashes involving pregnant occupants are presented that illustrate the main conclusions of a crash-investigation program that includes 42 crashes investigated to date. Some unusual cases that are exceptions to the overall trends are also described. The study indicates a strong association between adverse fetal outcome and both crash severity and maternal injury. Proper restraint use, with and without airbag deployment, generally leads to acceptable fetal outcomes in lower severity crashes, while it does not affect fetal outcome in high-severity crashes. Compared to properly restrained pregnant occupants, improperly restrained occupants have a higher risk of adverse fetal outcome in lower severity crashes, which comprise the majority of all motor-vehicle collisions. PMID:11558095

Some cable suspension systems and their effects on the flexural frequencies of slender aerospace structures

NASA Technical Reports Server (NTRS)

Herr, R. W.

1974-01-01

The effects of several cable suspension configurations on the first free-free flexural frequency of uniform beams have been determined by experiment and analysis. The results of this study confirm that in general the larger the test vehicle the larger is the flexural frequency measurement error attributable to a given cable suspension configuration. For horizontally oriented beams representing modern aerospace vehicles of average size and flexibility, the restraining effects of all but the shortest support cables were minor. The restraining effects of support cables of moderate length attached near the base of vertically oriented vehicles were overshadowed by the effects of beam compression due to gravity.

The two populations’ cellular automata model with predation based on the Penna model

NASA Astrophysics Data System (ADS)

He, Mingfeng; Lin, Jing; Jiang, Heng; Liu, Xin

2002-09-01

In Penna's single-species asexual bit-string model of biological ageing, the Verhulst factor has too strong a restraining effect on the development of the population. Danuta Makowiec gave an improved model based on the lattice, where the restraining factor of the four neighbours take the place of the Verhulst factor. Here, we discuss the two populations’ Penna model with predation on the planar lattice of two dimensions. A cellular automata model containing movable wolves and sheep has been built. The results show that both the quantity of the wolves and the sheep fluctuate in accordance with the law that one quantity increases while the other one decreases.

Payload Launch Lock Mechanism

NASA Technical Reports Server (NTRS)

Young, Ken (Inventor); Hindle, Timothy (Inventor)

2014-01-01

A payload launch lock mechanism includes a base, a preload clamp, a fastener, and a shape memory alloy (SMA) actuator. The preload clamp is configured to releasibly restrain a payload. The fastener extends, along an axis, through the preload clamp and into the base, and supplies a force to the preload clamp sufficient to restrain the payload. The SMA actuator is disposed between the base and the clamp. The SMA actuator is adapted to receive electrical current and is configured, upon receipt of the electrical current, to supply a force that causes the fastener to elongate without fracturing. The preload clamp, in response to the fastener elongation, either rotates or pivots to thereby release the payload.

Study of The Effect of Draw-bead Geometry on Stretch Flange Formability

NASA Astrophysics Data System (ADS)

Orlov, O. S.; Winkler, S. L.; Worswick, M. J.; Lloyd, D. J.; Finn, M. J.

2004-06-01

A fully instrumented stretch flange press equipped with a back-up punch and draw-beads near the specimen cutout area is simulated. The utilization of different draw-bead geometries is examined numerically to determine the restraining forces, strains and amount of damage generated in stretch flanges during forming. Simulations of the forming process are conducted for 1mm AA5182 sheets with circular cutouts. The damage evolution with the deformed specimens is investigated using the explicit dynamic finite element code, LS-DYNA, with a modified Gurson-based material model. It was found that double draw-beads can provide the same amount of restraining force as single draw-beads, but at reduced levels of damage.

Operation bandwidth optimization of photonic differentiators.

PubMed

Yan, Siqi; Zhang, Yong; Dong, Jianji; Zheng, Aoling; Liao, Shasha; Zhou, Hailong; Wu, Zhao; Xia, Jinsong; Zhang, Xinliang

2015-07-27

We theoretically investigate the operation bandwidth limitation of the photonic differentiator including the upper limitation, which is restrained by the device operation bandwidth and the lower limitation, which is restrained by the energy efficiency (EE) and detecting noise level. Taking the silicon photonic crystal L3 nano-cavity (PCN) as an example, for the first time, we experimentally demonstrate that the lower limitation of the operation bandwidth does exist and differentiators with different bandwidths have significantly different acceptable pulse width range of input signals, which are consistent to the theoretical prediction. Furthermore, we put forward a novel photonic differentiator scheme employing cascaded PCNs with different Q factors, which is likely to expand the operation bandwidth range of photonic differentiator dramatically.

The relation of hedonic hunger and restrained eating to lateralized frontal activation.

PubMed

Winter, S R; Feig, E H; Kounios, J; Erickson, B; Berkowitz, S; Lowe, M R

2016-09-01

Asymmetrical alpha activation in the prefrontal cortex (frontal asymmetry) in electroencephalography (EEG) has been related to eating behavior. Prior studies linked dietary restraint with right frontal asymmetry [1] and disinhibition with left frontal asymmetry [2]. The current study simultaneously assessed restrained eating and hedonic hunger (drive for food reward in the absence of hunger) in relation to frontal asymmetry. Resting-state EEG and measures of restrained eating (Revised Restraint Scale; RRS) and hedonic hunger (Power of Food Scale; PFS) were assessed in 61 non-obese adults. Individually, hedonic hunger predicted left asymmetry. However, PFS and RRS were correlated (r=0.48, p<0.05) and there was a significant interaction between PFS and RRS on frontal asymmetry, p<0.01. Results indicated that those high in hedonic hunger exhibited left asymmetry irrespective of RRS scores; among those low in PFS, only those high in RRS showed right asymmetry. Results were consistent with literature linking avoidant behaviors (restraint) with right-frontal asymmetry and approach behaviors (binge eating) with left-frontal asymmetry. It appears that a strong drive toward palatable foods predominates at a neural level even when restraint is high. Findings suggest that lateralized frontal activity is an indicator of motivation both to consume and to avoid consuming highly palatable foods. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular-biological analysis of the effect of methamphetamine on the heart in restrained mice.

PubMed

Shinone, Kotaro; Tomita, Masafumi; Inoue, Hiromasa; Nakagawa, Yasuhisa; Ikemura, Mayumi; Nata, Masayuki

2010-03-01

In order to investigate the interaction in the heart between the administration of methamphetamine (MAP) and restraint of the body following it, we administrated MAP intraperitoneally to mice and restrained them, and then determined the level of mRNA expression of 22 genes in the heart using quantitative RT-PCR method. The mRNA expressions of Nfkbiz, Nr4a1 and Dusp1 changed significantly after the administration of MAP, suggesting the induction of an inflammatory condition such as damage to the myocardium. Moreover, the serum concentrations of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1 beta and IL-6 were significantly increased by the administration of MAP. On the other hand, the mRNA expressions of Rgs2 and Rasd1 were changed by both the administration of MAP and body restraint without interaction, which indicated that these insults affected the circulatory system additively or synergistically. From these results, it is likely that the administration of MAP, followed by body restraint, might cause acute myocardial damage due to the direct myocardial toxic effect of MAP, myocardial hypoxia and/or severe hypertension, which is one of the mechanisms for sudden death in MAP abusers who were restrained due to their excited state. (c) 2010. Published by Elsevier Ireland Ltd.

Non-restraining EEG Radiotelemetry: Epidural and Deep Intracerebral Stereotaxic EEG Electrode Placement.

PubMed

Papazoglou, Anna; Lundt, Andreas; Wormuth, Carola; Ehninger, Dan; Henseler, Christina; Soós, Julien; Broich, Karl; Weiergräber, Marco

2016-06-25

Implantable EEG radiotelemetry is of central relevance in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies. This powerful technique does not only provide valuable insights into the underlying pathophysiological mechanisms, i.e., the etiopathogenesis of CNS related diseases, it also facilitates the development of new translational, i.e., therapeutic approaches. Whereas competing techniques that make use of recorder systems used in jackets or tethered systems suffer from their unphysiological restraining to semi-restraining character, radiotelemetric EEG recordings overcome these disadvantages. Technically, implantable EEG radiotelemetry allows for precise and highly sensitive measurement of epidural and deep, intracerebral EEGs under various physiological and pathophysiological conditions. First, we present a detailed protocol of a straight forward, successful, quick and efficient technique for epidural (surface) EEG recordings resulting in high-quality electrocorticograms. Second, we demonstrate how to implant deep, intracerebral EEG electrodes, e.g., in the hippocampus (electrohippocampogram). For both approaches, a computerized 3D stereotaxic electrode implantation system is used. The radiofrequency transmitter itself is implanted into a subcutaneous pouch in both mice and rats. Special attention also has to be paid to pre-, peri- and postoperative treatment of the experimental animals. Preoperative preparation of mice and rats, suitable anesthesia as well as postoperative treatment and pain management are described in detail.

Seating positions and children's risk of dying in motor vehicle crashes

PubMed Central

Braver, E.; Whitfield, R.; Ferguson, S.

1998-01-01

Objectives—To determine the effects of seating position, combined with restraint use and airbag status, on children's risk of dying in crashes. Methods—Using 1988–95 data from the United States Fatality Analysis Reporting System, risk of death was compared among front and rear seated passengers aged 12 and younger who were involved in fatal crashes for different categories of restraint use and in vehicles with and without passenger airbags. Results—Restrained children in rear seats had the lowest risk of dying in fatal crashes. Among children seated in the rear, risk of death was reduced 35% in vehicles without any airbags, 31% in vehicles equipped only with driver airbags, and 46% in vehicles with passenger airbags. Both restrained and unrestrained children aged 0–12 were at lower risk of dying in rear seats. Rear seats also afforded additional protection to children aged 5–12 restrained only with lap belts compared with lap/shoulder belted children in front seats. Children were about 10–20% less likely to die in rear center than in rear outboard positions. Conclusions—Parents and others who transport children should be strongly encouraged to place infants and children in rear seats whether or not vehicles have airbags. Existing laws requiring restraint use by children should be strengthened and actively enforced. PMID:9788087

Improvements in passive car safety led to decreased injury severity--a comparison between the 1970s and 1990s.

PubMed

Richter, Martinus; Pape, Hans-Christoph; Otte, Dietmar; Krettek, Christian

2005-04-01

The purpose of this study was to characterize changes in the mechanism and pattern of injury for vehicular trauma victims with modern vehicle design. Crash and injury severity were specifically investigated to isolate the influence of these improvements in vehicle design. Since 1972, a local, prospective, assessment of vehicular trauma victims on-scene and at medical institutions providing care has been performed including the following parameters: delta-v, collision speed, type of road using, abbreviated injury scale (AIS), injury severity score (ISS), incidence of polytrauma or death. Victims (for restrained car occupants, bicyclists, pedestrians) injured between 1973 and 1978, and between 1994 and 1999 were compared. Lower crash severity (delta-v, collision speed) and injury severity (AIS, ISS, incidence of polytrauma or death) were measured for restrained car occupants, bicyclists and pedestrians during the later period. The correlation coefficient between delta-v or vehicle collision speed and ISS was higher in the earlier period for car occupants, cyclists and pedestrians. This study suggests that the observed reduction in injury severity in restrained car occupants, bicyclists and pedestrians is not only linked to the reduction of crash severity, but also related to improvements in vehicle design beyond seat-belt use. Passive car safety led to decreased injury severity--a comparison.

"Just looking at food makes me gain weight": experimental induction of thought-shape fusion in eating-disordered and non-eating-disordered women.

PubMed

Coelho, Jennifer S; Carter, Jacqueline C; McFarlane, Traci; Polivy, Janet

2008-02-01

Thought-shape fusion (TSF) is a cognitive distortion that can be induced experimentally and is associated with eating pathology. The current study was conducted in order to elucidate the effects of TSF induction in females with eating disorders (n=35), as well as in restrained eaters (n=38) and unrestrained eaters (n=39). It was hypothesized that TSF induction would result in anxiety, guilt, increased feelings of fatness, perceived weight gain and feelings of moral wrong-doing relative to an anxiety and control induction. It was further hypothesized that restrained eaters and individuals with eating disorders would exhibit a stronger reaction to a TSF induction than would unrestrained eaters. The results indicated that, as predicted, TSF can be induced in individuals both with and without eating disorders, and individuals with eating disorders reported the highest levels of "state" TSF after the induction relative to the non-clinical controls. However, contrary to expectations, restrained eaters reported higher levels of perceived weight gain and moral wrong-doing after the anxiety induction (but not the TSF induction) relative to the control induction. Potential mechanisms for this pattern of results are discussed, and the clinical implications of research on TSF are also considered.

The inhibiting effect of dislocation helices on the stress-induced orientation of S' precipitates in Al–Cu–Mg alloy

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

Guo, Xiaobin; Deng, Yunlai, E-mail: luckdeng@csu.edu.cn; State Key Laboratory of High Performance and Complex Manufacturing, Central South University, Changsha

The phenomenon of restrained stress-induced preferential orientation of S′ precipitates is investigated using a single-crystal of Al–1.23Cu–0.43 Mg alloy. Al–1.23Cu–0.43 Mg single-crystal specimens are subjected to stress aging, and the microstructure is analyzed by transmission electron microscopy (TEM). It is found that the stress-induced preferential orientation of S′ precipitates is restrained owing to the dislocations produced by a higher stress. The effect of dislocations on the oriented precipitates depends on the total length of the intersection lines for precipitate habit planes and dislocation glide planes. This investigation not only provides important insight into solving the anisotropy problem attributed to precipitationmore » strengthening, but also offers a benchmark for choosing the appropriate stress range in manufacturing of Al–Cu–Mg alloys. - Highlights: • Single crystals of an Al–Cu–Mg alloy were prepared for the investigations. • A phenomenon of restrained stress-induced preferential orientation of S′ precipitates was found. • The influence of dislocation helices on precipitation during stress-aging was studied. • Difference of orientation degree of S′ precipitates and θ′ precipitates was explained. • A basis for choosing the appropriate stress range in manufacturing of Al–Cu–Mg alloys is provided.« less

Neurofeedback reduces overeating episodes in female restrained eaters: a randomized controlled pilot-study.

PubMed

Schmidt, Jennifer; Martin, Alexandra

2015-12-01

Overeating episodes, despite of intentions to control weight, are a common problem among women. Recurring episodes of overeating and dietary failure have been reported to result in higher Body Mass Indexes and to induce severe distress even in non-clinical groups. Based on findings from physiological research on eating behavior and craving, as well as previous biofeedback studies, we derived a cue exposure based EEG neurofeedback protocol to target overeating episodes. The treatment was evaluated in a randomized controlled trial, comparing a neurofeedback group (NFG; n = 14) with a waiting list control group (WLG; n = 13) in a sub-clinical sample of female restrained eaters. At post-treatment, the number of weekly overeating episodes and subsequent distress were significantly reduced in the NFG compared to the WLG (p < .01; r > .50). In a 3 month follow-up, effects in the NFG remained stable. As secondary outcomes, perceived dieting success was enhanced after the treatment. At follow-up, additional beneficial effects on trait food craving were observed. Altogether, we found preliminary evidence for the cue exposure neurofeedback against overeating episodes in female restrained eaters, although specific effects and underlying mechanisms still have to be explored in future research.

Influence of Nutrition Claims on Appetite Sensations according to Sex, Weight Status, and Restrained Eating

PubMed Central

Doucet, Éric; Pomerleau, Sonia

2016-01-01

Nutrition claims may help people to adopt healthier eating habits, but little is known about the potential cognitive effects of such claims on appetite sensations. The main purpose of this study was to evaluate the impact of nutrition claims and individual factors on perceived appetite sensations. According to a three (“healthy” versus “diet” (i.e., satiating) versus “hedonic”) by two (restrained or not restrained) by two (normal-weight or overweight/obese) by two (men versus women) factorial design, 164 males and 188 females aged 18–65 were invited to taste an oatmeal-raisin snack in a blinded and ad libitum context. Visual analog scales (150 mm) were used to evaluate appetite sensations before and over 1 h after consumption period. BMI and Restraint Scale were used to categorize participants according to their weight and restraint status. No main condition effect was observed for any of the four appetite sensations. However, subgroups analysis revealed significant differences among specific subgroups. A main effect of sex was also observed for all appetite sensations with men reporting higher levels of desire to eat, hunger and prospective food consumption, and lower levels of fullness than women. These findings highlight the importance of considering individual characteristics in interaction when studying appetite sensations. PMID:27725885

Buckling Behavior of Long Anisotropic Plates Subjected to Elastically Restrained Thermal Expansion

NASA Technical Reports Server (NTRS)

Nemeth, Michael P.

2002-01-01

An approach for synthesizing buckling results for, and behavior of, thin balanced and unbalanced symmetric laminates that are subjected to uniform heating or cooling and elastically restrained against thermal expansion or contraction is presented. This approach uses a nondimensional analysis for infinitely long, flexurally anisotropic plates that are subjected to combined mechanical loads and is based on useful nondimensional parameters. In addition, stiffness-weighted laminate thermal-expansion parameters and compliance coefficients are derived that are used to determine critical temperatures in terms of physically intuitive mechanical-buckling coefficients. The effects of membrane orthotropy and membrane anisotropy are included in the general formulation. Many results are presented for some common laminates that are intended to facilitate a structural designer's transition to the use of generic buckling design curves. Several curves that illustrate the fundamental parameters used in the analysis are presented, for nine contemporary material systems, that provide physical insight into the buckling response in addition to providing useful design data. Examples are presented that demonstrate the use of generic design curves. The analysis approach and generic results indicate the effects and characteristics of elastically restrained laminate thermal expansion or contraction, membrane orthotropy and anisotropy, and flexural orthotropy and anisotropy in a very general and unifying manner.

Effects of biaxial strain on the improper multiferroicity in h – LuFe O 3 films studied using the restrained thermal expansion method

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

Sinha, Kishan; Zhang, Yubo; Jiang, Xuanyuan

Elastic strain is potentially an important approach in tuning the properties of the improperly multiferroic hexagonal ferrites, the details of which have however been elusive due to the experimental difficulties. Employing the method of restrained thermal expansion, we have studied the effect of isothermal biaxial strain in the basal plane of h-LuFeO 3 (001) films. The results indicate that a compressive biaxial strain significantly enhances the K 3 structural distortion (the order parameter of the improper ferroelectricity), and the effect is larger at higher temperatures. The compressive biaxial strain and the enhanced K 3 structural distortion together, cause an increasemore » in the electric polarization and a reduction in the canting of the weak ferromagnetic moments in h-LuFeO 3, according to our first principle calculations. These findings are important for understanding the strain effect as well as the coupling between the lattice and the improper multiferroicity in h-LuFeO 3. Finally, the experimental elucidation of the strain effect in h-LuFeO 3 films also suggests that the restrained thermal expansion can be a viable method to unravel the strain effect in many other thin film materials.« less

Effects of biaxial strain on the improper multiferroicity in h – LuFe O 3 films studied using the restrained thermal expansion method

DOE PAGES

Sinha, Kishan; Zhang, Yubo; Jiang, Xuanyuan; ...

2017-03-14

Elastic strain is potentially an important approach in tuning the properties of the improperly multiferroic hexagonal ferrites, the details of which have however been elusive due to the experimental difficulties. Employing the method of restrained thermal expansion, we have studied the effect of isothermal biaxial strain in the basal plane of h-LuFeO 3 (001) films. The results indicate that a compressive biaxial strain significantly enhances the K 3 structural distortion (the order parameter of the improper ferroelectricity), and the effect is larger at higher temperatures. The compressive biaxial strain and the enhanced K 3 structural distortion together, cause an increasemore » in the electric polarization and a reduction in the canting of the weak ferromagnetic moments in h-LuFeO 3, according to our first principle calculations. These findings are important for understanding the strain effect as well as the coupling between the lattice and the improper multiferroicity in h-LuFeO 3. Finally, the experimental elucidation of the strain effect in h-LuFeO 3 films also suggests that the restrained thermal expansion can be a viable method to unravel the strain effect in many other thin film materials.« less

The choice of fat-free vs. regular-fat fudge: the effects of liking for the alternative and the restraint status.

PubMed

Tuorila, H; Kramer, F M; Engell, D

2001-08-01

Non-restrained and restrained American women (N=157) chose a portion of a fat-free or regular-fat hot fudge, to be eaten on a portion of fat-free or regular-fat (depending on the experimental condition) ice cream. The subjects had tasted and rated samples of both fudge and ice cream earlier in the same session and, prior to the choice, they were informed of their own hedonic ratings of both fudges and of the respective fat contents ("fat-free" vs. "regular-fat"). The higher the hedonic difference (fat-free minus regular-fat) between hot fudge samples and the higher the individual restraint score, the more likely was the choice of the fat-free option. Also, the less hungry the subjects were prior to testing, the more likely they were to choose the fat-free version. On average, the hedonic difference between the hot fudge samples was roughly -0.5 for those choosing the fat-free option, while the corresponding value for subjects choosing the regular-fat version was -3 (9-point scale). The type of ice cream did not affect the choice. The data demonstrate the effects of a food (its hedonic quality), person (restrained status), and context (perceived hunger) on food choice. Copyright 2000 Academic Press.

Impact of restraint and disinhibition on PYY plasma levels and subjective feelings of appetite.

PubMed

Martins, C; Robertson, M D; Morgan, L M

2010-10-01

The impact of eating behaviours on circulating levels of appetite-regulating hormones remains largely unknown. The aims of this study were to assess the role of restraint and disinhibition on fasting/postprandial peptide YY (PYY) plasma levels and subjective feelings of appetite in normal-weight individuals and to determine whether the effect was energy load dependent. 33 participants (12 men) were classified as restrained/unrestrained and low/high in disinhibition based on Three Factor Eating Questionnaire-18R and Dutch Eating Behaviour Questionnaire. The impact of restraint/disinhibition on PYY plasma levels and feelings of appetite was measured, after a 500kcal and 1000kcal breakfast, using a randomised crossover design. Restraint did not impact on either fasting or postprandial PYY plasma levels, but participants with high disinhibition had a tendency towards a blunted postprandial PYY response. Moreover, restrained eaters reported lower ratings of prospective food consumption postprandially, and a tendency towards higher fullness/lower hunger. In conclusion, circulating PYY is unaffected by restrained eating behaviour, despite being associated with increased fullness and reduced hunger in the fed state. High levels of disinhibition tend to be associated with a blunted PYY response and this may contribute towards the susceptibility to overconsumption and increased risk of weight gain characteristic of this trait.

A nonlinear theory for spinning anisotropic beams using restrained warping functions

NASA Technical Reports Server (NTRS)

Ie, C. A.; Kosmatka, J. B.

1993-01-01

A geometrically nonlinear theory is developed for spinning anisotropic beams having arbitrary cross sections. An assumed displacement field is developed using the standard 3D kinematics relations to describe the global beam behavior supplemented with an additional field that represents the local deformation within the cross section and warping out of the cross section plane. It is assumed that the magnitude of this additional field is directly proportional to the local stress resultants. In order to take into account the effects of boundary conditions, a restraining function is introduced. This function plays the role of reducing the amount of free warping deformation throughout the field due to the restraint of the cross section(s) at the end(s) of the beam, e.g., in the case of a cantilever beam. Using a developed ordering scheme, the nonlinear strains are calculated to the third order. The FEM is developed using the weak form variational formulation. Preliminary interesting numerical results have been obtained that indicate the role of the restraining function in the case of a cantilever beam with circular cross section. These results are for the cases of a tip displacement (static) and free vibration studies for both isotropic and anisotropic materials with varied fiber orientations.

Influence of stress restraint on the expansive behaviour of concrete affected by alkali-silica reaction

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

Berra, M., E-mail: mario.berra@erse-web.i; Faggiani, G.; Mangialardi, T.

2010-09-15

The primary objective of this study was to ascertain whether the Threshold Alkali Level (TAL) of the concrete aggregates may be taken as a suitable reactivity parameter for the selection of aggregates susceptible of alkali-silica reaction (ASR), even when ASR expansion in concrete develops under restrained conditions. Concrete mixes made with different alkali contents and two natural siliceous aggregates with very different TALs were tested for their expansivity at 38 {sup o}C and 100% RH under unrestrained and restrained conditions. Four compressive stress levels over the range from 0.17 to 3.50 N/mm{sup 2} were applied by using a new appositelymore » designed experimental equipment. The lowest stress (0.17 N/mm{sup 2}) was selected in order to estimate the expansive pressure developed by the ASR gel under 'free' expansion conditions. It was found that, even under restrained conditions, the threshold alkali level proves to be a suitable reactivity parameter for designing concrete mixes that are not susceptible of deleterious ASR expansion. An empirical relationship between expansive pressure, concrete alkali content and aggregate TAL was developed in view of its possible use for ASR diagnosis and/or safety evaluation of concrete structures.« less

Drinking without thinking: an implicit measure of alcohol motivation predicts failure to control alcohol use.

PubMed

Ostafin, Brian D; Marlatt, G Alan; Greenwald, Anthony G

2008-11-01

Addiction is characterized by dyscontrol - substance use despite intentions to restrain. Using a sample of at-risk drinkers, the present study examined whether an implicit measure of alcohol motivation (the Implicit Association Test [IAT]; Greenwald, A.G., McGhee, D.E., & Schwartz, J.L.K. (1998). Measuring individual differences in implicit cognition: the Implicit Association Test. Journal of Personality and Social Psychology, 74, 1464-1480) would predict dyscontrol of alcohol use. Participants completed an IAT and, to elicit motivation to restrain alcohol use, were instructed that greater consumption in a taste test would impair performance on a later task for which they could win a prize. All participants viewed aversive slides and then completed a thought-listing task. Participants either exerted self-control by suppressing negative affect and thoughts regarding the slides or did not exert self-control. Post-manipulation, the groups did not differ in mood, urge to drink or motivation to restrain consumption. During the subsequent taste test, participants whose self-control resources were depleted consumed more alcohol than did those in the control group. Additionally, the IAT, but not an explicit measure of alcohol motivation, more strongly predicted alcohol use when self-control resources were depleted. The results indicate that the IAT may have utility in predicting dyscontrolled alcohol use.

Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation.

PubMed

Mishra, Vikas; Shuai, Bing; Kodali, Maheedhar; Shetty, Geetha A; Hattiangady, Bharathi; Rao, Xiaolan; Shetty, Ashok K

2015-12-07

Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

Thermal Behavior of Cylindrical Buckling Restrained Braces at Elevated Temperatures

PubMed Central

Talebi, Elnaz; Tahir, Mahmood Md.; Yasreen, Airil

2014-01-01

The primary focus of this investigation was to analyze sequentially coupled nonlinear thermal stress, using a three-dimensional model. It was meant to shed light on the behavior of Buckling Restraint Brace (BRB) elements with circular cross section, at elevated temperature. Such bracing systems were comprised of a cylindrical steel core encased in a strong concrete-filled steel hollow casing. A debonding agent was rubbed on the core's surface to avoid shear stress transition to the restraining system. The numerical model was verified by the analytical solutions developed by the other researchers. Performance of BRB system under seismic loading at ambient temperature has been well documented. However, its performance in case of fire has yet to be explored. This study showed that the failure of brace may be attributed to material strength reduction and high compressive forces, both due to temperature rise. Furthermore, limiting temperatures in the linear behavior of steel casing and concrete in BRB element for both numerical and analytical simulations were about 196°C and 225°C, respectively. Finally it is concluded that the performance of BRB at elevated temperatures was the same as that seen at room temperature; that is, the steel core yields prior to the restraining system. PMID:24526915

Maternal mental health symptoms are positively related to emotional and restrained eating attitudes in a statewide sample of mothers participating in a supplemental nutrition program for women, infants and young children.

PubMed

Emerson, Jillian A; Hurley, Kristen M; Caulfield, Laura E; Black, Maureen M

2017-01-01

Postpartum, low-income mothers are at risk for mental health symptoms and obesity, and disordered eating attitudes may be associated with both mental health and obesity in this vulnerable population. The study objective is to determine whether higher levels of mental health symptoms are associated with increased odds of emotional and restrained eating attitudes in this sample of Special Supplemental Nutrition Program for Women, Infants and Children (WIC) participants. Data on 711 mothers of infants <13 months from a statewide sample of Maryland WIC participants were collected via telephone survey. Maternal mental health symptoms were measured on continuous scales for depression (PRIME-MD), stress (Perceived Stress Scale) and anxiety (Spielberger State-Trait Anxiety Inventory). Emotional and restrained eating attitudes were measured with questions adapted from the Dutch Eating Behavior Questionnaire. Multivariate logistic regression analysis was used. Obesity [body mass index (BMI) ≥ 30] was explored as a moderating variable. Mothers reporting higher levels of depression symptoms [odds ratio (OR) = 3.93, 95%CI: 2.71-5.69], anxiety symptoms (OR = 1.96, 95%CI: 1.47-2.65), stress symptoms (OR = 2.09, 95%CI: 1.67-2.61) and high overall mental health symptomatology (OR = 3.51, 95%CI: 2.43-5.3) had increased odds of emotional eating attitudes. There were significant associations between symptoms of depression (OR = 1.59, 95% CI: 1.12-2.25) and increased odds of restrained eating attitudes. Obesity did not moderate the association. Mothers with mental health symptoms are at risk for disordered eating attitudes, which may increase risk of poor diet. These findings underscore the need for greater focus on addressing maternal mental health status and eating attitudes in the postpartum period. © 2016 John Wiley & Sons Ltd.

Susceptibility of the squirrel monkey to different motion conditions

NASA Technical Reports Server (NTRS)

Fox, Robert A.; Daunton, Nancy G.; Coleman, J.

1991-01-01

The exact stimulus eliciting vomiting in animal studies of motion sickness is difficult to specify because the vestibular stimulation produced by many motion conditions is confounded by voluntary movements with animals. This is an important problem because experiments with animal models of motion sickness can provide useful information about antimotion sickness drugs or the role of neural mechanisms, only when animals are exposed to the same motion stimuli in each experimental session. A series of tests were conducted to determine the susceptibility of 15 adult squirrel monkeys to motion sickness in freely moving and restrained test conditions. Canal stimulation was varied by exposing the monkey in freely moving conditions to varying degrees of angular velocity (60, 90, 120, 150 deg/sec), and in restrained conditions to one angular velocity (150 deg/sec) and to cross-coupling effects of whole-body roll movements during rotation. Otolith stimulation was investigated by using sinusoidal vertical linear acceleration during free movement conditions, and off-vertical rotation and earth-horizontal (BBQ) rotation while restrained. The percentage of freely moving animal vomiting during vertical axis rotation was 27, 93, 86, and 92 for the angular velocities of 60, 90, 120, and 150 deg/sec respectively. None of the monkeys vomited during vertical axis rotation or cross-coupled rotation when restrained. Otolith stimulation appears to be a less provocative stimulus for the squirrel monkey as the percentage of animals vomiting were 13, 0, and 7 for the conditions of free movement during oscillation, restraint during off-vertical, and BBQ rotation respectively. Motion sickness to the point of vomiting occurred regularly only in conditions where self-motion was possible. Such effects could occur because voluntary movement during motion augments vestibular effects by producing self-inflicted cross-coupling, but the failure to elicit vomiting with experimenter-coupling cross-coupling argues against this interpretation. Alternatively, these results might imply that feedback from movement control mechanisms may play an important role in sensory conflict as suggested by Oman's sensory-motor conflict theory.

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

Membrane Disruption Mechanism of a Prion Peptide (106-126) Investigated by Atomic Force Microscopy, Raman and Electron Paramagnetic Resonance Spectroscopy.

PubMed

Pan, Jianjun; Sahoo, Prasana K; Dalzini, Annalisa; Hayati, Zahra; Aryal, Chinta M; Teng, Peng; Cai, Jianfeng; Rodriguez Gutierrez, Humberto; Song, Likai

2017-05-18

A fragment of the human prion protein spanning residues 106-126 (PrP106-126) recapitulates many essential properties of the disease-causing protein such as amyloidogenicity and cytotoxicity. PrP106-126 has an amphipathic characteristic that resembles many antimicrobial peptides (AMPs). Therefore, the toxic effect of PrP106-126 could arise from a direct association of monomeric peptides with the membrane matrix. Several experimental approaches are employed to scrutinize the impacts of monomeric PrP106-126 on model lipid membranes. Porous defects in planar bilayers are observed by using solution atomic force microscopy. Adding cholesterol does not impede defect formation. A force spectroscopy experiment shows that PrP106-126 reduces Young's modulus of planar lipid bilayers. We use Raman microspectroscopy to study the effect of PrP106-126 on lipid atomic vibrational dynamics. For phosphatidylcholine lipids, PrP106-126 disorders the intrachain conformation, while the interchain interaction is not altered; for phosphatidylethanolamine lipids, PrP106-126 increases the interchain interaction, while the intrachain conformational order remains similar. We explain the observed differences by considering different modes of peptide insertion. Finally, electron paramagnetic resonance spectroscopy shows that PrP106-126 progressively decreases the orientational order of lipid acyl chains in magnetically aligned bicelles. Together, our experimental data support the proposition that monomeric PrP106-126 can disrupt lipid membranes by using similar mechanisms found in AMPs.

Membrane Disruption Mechanism of a Prion Peptide (106-126) Investigated by Atomic Force Microscopy, Raman and Electron Paramagnetic Resonance Spectroscopy

PubMed Central

Pan, Jianjun; Sahoo, Prasana K.; Dalzini, Annalisa; Hayati, Zahra; Aryal, Chinta M.; Teng, Peng; Cai, Jianfeng; Gutierrez, Humberto Rodriguez; Song, Likai

2018-01-01

A fragment of the human prion protein spanning residues 106-126 (PrP106-126) recapitulates many essential properties of the disease-causing protein such as amyloidogenicity and cytotoxicity. PrP106-126 has an amphipathic characteristic that resembles many antimicrobial peptides (AMPs). Therefore, the toxic effect of PrP106-126 could arise from a direct association of monomeric peptides with membrane matrix. Several experimental approaches are employed to scrutinize the impacts of monomeric PrP106-126 on model lipid membranes. Porous defects in planar bilayers are observed by using solution atomic force microscopy. Adding cholesterol does not impede defect formation. Force spectroscopy experiment shows that PrP106-126 reduces Young’s modulus of planar lipid bilayers. We use Raman microspectroscopy to study the effect of PrP106-126 on lipid vibrational dynamics. For phosphatidylcholine lipids, PrP106-126 disorders the intra-chain conformation, while the inter-chain interaction is not altered; for phosphatidylethanolamine lipids, PrP106-126 increases the inter-chain interaction, while the intra-chain conformational order remains similar. We explain the observed differences by considering different modes of peptide insertion. Finally, electron paramagnetic resonance spectroscopy shows that PrP106-126 progressively decreases the orientational order of lipid acyl chains in magnetically aligned bicelles. Together, our experimental data support the proposition that monomeric PrP106-126 can disrupt lipid membranes by using similar mechanisms found in AMPs. PMID:28459565

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.

Exploring the conformational changes of the ATP binding site of gyrase B from Escherichia coli complexed with different established inhibitors by using molecular dynamics simulation: protein-ligand interactions in the light of the alanine scanning and free energy decomposition methods.

PubMed

Saíz-Urra, Liane; Cabrera, Miguel Angel; Froeyen, Matheus

2011-02-01

Currently, bacterial diseases cause a death toll around 2 million people a year encouraging the search for new antimicrobial agents. DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A(2)B(2). GyrA is involved in DNA breakage and reunion and GyrB catalyzes the hydrolysis of ATP. The GyrB subunit from Escherichia coli has been investigated, namely the ATP binding pocket both considering the protein without ligands and bound with the inhibitors clorobiocin, novobiocin and 5'-adenylyl-β-γ-imidodiphosphate. The stability of the systems was studied by molecular dynamics simulation with the further analysis of the time dependent root-mean-square coordinate deviation (RMSD) from the initial structure, and temperature factors. Moreover, exploration of the conformational space of the systems during the MD simulation was carried out by a clustering data mining technique using the average-linkage algorithm. Recognizing the key residues in the binding site of the enzyme that are involved in the binding mode with the aforementioned inhibitors was investigated by using two techniques: free energy decomposition and computational alanine scanning. The results from these simulations highlight the important residues in the ATP binding site and can be useful in the design process of potential new inhibitors. Copyright © 2010 Elsevier Inc. All rights reserved.

Conformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides.

PubMed

Vermeer, Louic S; Lan, Yun; Abbate, Vincenzo; Ruh, Emrah; Bui, Tam T; Wilkinson, Louise J; Kanno, Tokuwa; Jumagulova, Elmira; Kozlowska, Justyna; Patel, Jayneil; McIntyre, Caitlin A; Yam, W C; Siu, Gilman; Atkinson, R Andrew; Lam, Jenny K W; Bansal, Sukhvinder S; Drake, Alex F; Mitchell, Graham H; Mason, A James

2012-10-05

We used a combination of fluorescence, circular dichroism (CD), and NMR spectroscopies in conjunction with size exclusion chromatography to help rationalize the relative antibacterial, antiplasmodial, and cytotoxic activities of a series of proline-free and proline-containing model antimicrobial peptides (AMPs) in terms of their structural properties. When compared with proline-free analogs, proline-containing peptides had greater activity against Gram-negative bacteria, two mammalian cancer cell lines, and intraerythrocytic Plasmodium falciparum, which they were capable of killing without causing hemolysis. In contrast, incorporation of proline did not have a consistent effect on peptide activity against Mycobacterium tuberculosis. In membrane-mimicking environments, structures with high α-helix content were adopted by both proline-free and proline-containing peptides. In solution, AMPs generally adopted disordered structures unless their sequences comprised more hydrophobic amino acids or until coordinating phosphate ions were added. Proline-containing peptides resisted ordering induced by either method. The roles of the angle subtended by positively charged amino acids and the positioning of the proline residues were also investigated. Careful positioning of proline residues in AMP sequences is required to enable the peptide to resist ordering and maintain optimal antibacterial activity, whereas varying the angle subtended by positively charged amino acids can attenuate hemolytic potential albeit with a modest reduction in potency. Maintaining conformational flexibility improves AMP potency and selectivity toward bacterial, plasmodial, and cancerous cells while enabling the targeting of intracellular pathogens.

7 CFR 550.46 - Competition.

Code of Federal Regulations, 2010 CFR

2010-01-01

... performance, financial and technical resources or accessibility to other necessary resources. In certain... eliminate competition or otherwise restrain trade. In order to ensure objective contractor performance and...

Working harder to obtain more snack foods when wanting to eat less.

PubMed

Giesen, Janneke C A H; Havermans, Remco C; Nederkoorn, Chantal; Strafaci, Silvana; Jansen, Anita

2009-01-01

This study investigates individual differences in the reinforcing value of snack food. More specifically, it was investigated whether differences in restraint status are associated with differences in working for high-caloric snack food. Thirty-six unrestrained non-dieters, twenty restrained non-dieters and fifteen current dieters performed a concurrent schedules task in which they had the option to work for points for either snack food or fruit and vegetables. By progressively increasing the "price" of the snack foods (i.e., the amount of work required to obtain extra snack points) the relative reinforcing value of snack food was determined. As hypothesized, restrained non-dieters worked harder and current dieters worked less hard to obtain snack food as compared to unrestrained non-dieters.

A method for determining the column curve from tests of columns with equal restraints against rotation on the ends

NASA Technical Reports Server (NTRS)

Lundquist, Eugene E; Rossman, Carl A; Houbolt, John C

1943-01-01

The results are presented of a theoretical study for the determination of the column curve from tests of column specimens having ends equally restrained against rotation. The theory of this problem is studied and a curve is shown relating the fixity coefficient c to the critical load, the length of the column, and the magnitude of the elastic restraint. A method of using this curve for the determination of the column curve for columns with pin ends from tests of columns with elastically restrained ends is presented. The results of the method as applied to a series of tests on thin-strip columns of stainless steel are also given.

Susceptibility for thin ideal media and eating styles.

PubMed

Anschutz, Doeschka J; Engels, Rutger C M E; Van Strien, Tatjana

2008-03-01

This study examined the relations between susceptibility for thin ideal media and restrained, emotional and external eating, directly and indirectly through body dissatisfaction. Thin ideal media susceptibility, body dissatisfaction and eating styles were measured in a sample of 163 female students. Structural equation modelling was used for analyses, controlling for BMI. Higher susceptibility for thin ideal media was directly related to higher scores on all eating styles, and indirectly related to higher restrained and emotional eating through elevated levels of body dissatisfaction. So, thin ideal media susceptibility was not only related to restraint through body dissatisfaction, but also directly. Emotional eaters might be more vulnerable for negative affect, whereas external eaters might be more sensitive to external cues in general.

Single-pass incremental force updates for adaptively restrained molecular dynamics.

PubMed

Singh, Krishna Kant; Redon, Stephane

2018-03-30

Adaptively restrained molecular dynamics (ARMD) allows users to perform more integration steps in wall-clock time by switching on and off positional degrees of freedoms. This article presents new, single-pass incremental force updates algorithms to efficiently simulate a system using ARMD. We assessed different algorithms for speedup measurements and implemented them in the LAMMPS MD package. We validated the single-pass incremental force update algorithm on four different benchmarks using diverse pair potentials. The proposed algorithm allows us to perform simulation of a system faster than traditional MD in both NVE and NVT ensembles. Moreover, ARMD using the new single-pass algorithm speeds up the convergence of observables in wall-clock time. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Prudent Use of Antimicrobials in Exotic Animal Medicine.

PubMed

Broens, Els M; van Geijlswijk, Ingeborg M

2018-05-01

Reduction of antimicrobial use can result in reduction of resistance in commensal bacteria. In exotic animals, information on use of antimicrobials and resistance in commensals and pathogens is scarce. However, use of antimicrobials listed as critically important antimicrobials for human medicine seems high in exotic animals. Ideally, the selection of a therapy should be based on an accurate diagnosis and antimicrobial susceptibility testing. When prescribing antimicrobials based on empiricism, knowledge of the most common pathogens causing specific infections and the antimicrobial spectrum of antimicrobial agents is indispensable. Implementing antimicrobial stewardship promotes the prudent use of antimicrobials in exotic animals. Copyright © 2018 Elsevier Inc. All rights reserved.

The prevalence and impact of antimicrobial allergies and adverse drug reactions at an Australian tertiary centre.

PubMed

Trubiano, Jason A; Cairns, Kelly A; Evans, Jacqui A; Ding, Amally; Nguyen, Tuan; Dooley, Michael J; Cheng, Allen C

2015-12-16

The prevalence and impact of antimicrobial "allergy" labels and Adverse Drug Reactions (ADRs) on antibiotic usage and antimicrobial stewardship initiatives is ill defined. We sought to examine the rate of antimicrobial "allergy labels" at our tertiary referral centre and impacts on antimicrobial usage and appropriateness. Two inpatient antimicrobial prevalence surveys were conducted over a 1-week period in November 2013 and 2014 as part of the prospective National Antimicrobial Prescribing Survey (NAPS). Post survey, patients recorded in the NAPS database were assigned to two groups based upon recorded antimicrobial "allergy label" and ADR: (i) Antimicrobial Allergy/ADR (AA) or (ii) No Antimicrobial Allergy/ADR (NAA). Antimicrobial usage and antimicrobial appropriateness were compared between AA and NAA groups. From 509 identified patients the prevalence of an antimicrobial allergy or ADR was 25 %. The prevalence of "allergy labels"/ADR was 10 % (51/509) for penicillin V/G, 5 % (24/509) cephalosporins, 4 % (22/509) trimethroprim-sulfamethoxazole and 3 % (17/509) aminopenicillins. One thousand and seventy antimicrobials were prescribed during the study periods, the median antimicrobial duration was longer in the AA versus NAA group (6 days vs. 4 days; p = 0.018), and proportion of inappropriate antimicrobial prescribing higher in the AA group compared with NAA (29 %; 35/120 vs. 23 %; 86/367, p = 0.22). Oral antimicrobial administration was higher in the NAA than AA group (60 %; 177/297 vs. 46 %; 356/793, p = 0.0001). The proportion of patients that received a β-lactam was lower in the AA versus NAA group (60 % vs. 79 %, p = 0.0001). In an Australian tertiary referral centre an antimicrobial "allergy" or ADR label was found to significantly impacted on rate of oral antimicrobial administration, beta-lactam usage, antimicrobial duration and antimicrobial appropriateness.

36 CFR 1210.43 - Competition.

Code of Federal Regulations, 2011 CFR

2011-07-01

... practical, open and free competition. The recipient shall be alert to organizational conflicts of interest... otherwise restrain trade. In order to ensure objective contractor performance and eliminate unfair...

Antimicrobial use in the veterinary cancer patient.

PubMed

Boudreaux, Bonnie

2014-09-01

This article discusses the clinically relevant uses of antimicrobials in small animal cancer patients. The article focuses on general considerations of antimicrobial use, antimicrobials in the neutropenic patient, prophylactic antimicrobial usage, antimicrobials in radiation therapy, and antimicrobials in metronomic chemotherapy protocols. Copyright © 2014 Elsevier Inc. All rights reserved.

Post-translational amino acid racemization in the frog skin peptide deltorphin I in the secretion granules of cutaneous serous glands.

PubMed

Auvynet, Constance; Seddiki, Nabila; Dunia, Irene; Nicolas, Pierre; Amiche, Mohamed; Lacombe, Claire

2006-01-01

The dermal glands of the South American hylid frog Phyllomedusa bicolor synthesize and expel huge amounts of cationic, alpha-helical, 24- to 33-residue antimicrobial peptides, the dermaseptins B. These glands also produce a wide array of peptides that are similar to mammalian hormones and neuropeptides, including a heptapeptide opioid containing a D-amino acid, deltorphin I (Tyr-DAla-Phe-Asp-Val-Val-Gly NH2). Its biological activity is due to the racemization of L-Ala2 to D-Ala. The dermaseptins B and deltorphins are all derived from a single family of precursor polypeptides that have an N-terminal preprosequence that is remarkably well conserved, although the progenitor sequences giving rise to mature opioid or antimicrobial peptides are markedly different. Monoclonal and polyclonal antibodies were used to examine the cellular and ultrastructural distributions of deltorphin I and dermaseptin B in the serous glands by immunofluoresence confocal microscopy and immunogold-electron microscopy. Preprodeltorphin I and preprodermaseptins B are sorted into the regulated pathway of secretion, where they are processed to give the mature products. Deltorphin I, [l-Ala2]-deltorphin I and dermaseptin B are all stored together in secretion granules which accumulate in the cytoplasm of all serous glands. We conclude that the L- to D-amino acid isomerization of the deltorphin I occurs in the secretory granules as a post-translational event. Thus the specificity of isomerization depends on the presence of structural and/or conformational determinants in the peptide N-terminus surrounding the isomerization site.

Coordination behavior of new bis Schiff base ligand derived from 2-furan carboxaldehyde and propane-1,3-diamine. Spectroscopic, thermal, anticancer and antibacterial activity studies

NASA Astrophysics Data System (ADS)

Mohamed, Gehad G.; Zayed, Ehab M.; Hindy, Ahmed M. M.

2015-06-01

Novel bis Schiff base ligand, [N1,N3-bis(furan-2-ylmethylene)propane-1,3-diamine], was prepared by the condensation of furan-2-carboxaldehyde with propane-1,3-diamine. Its conformational changes on complexation with transition metal ions [Co(II), Ni(II), Cu(II), Mn(II), Cd(II), Zn(II) and Fe(III)] have been studied on the basis of elemental analysis, conductivity measurements, spectral (infrared, 1H NMR, electronic), magnetic and thermogravimetric studies. The conductance data of the complexes revealed their electrolytic nature suggesting them as 1:2 (for bivalent metal ions) and 1:3 (for Fe(III) ion) electrolytes. The complexes were found to have octahedral geometry based on magnetic moment and solid reflectance measurements. Thermal analysis data revealed the decomposition of the complexes in successive steps with the removal of anions, coordinated water and bis Schiff base ligand. The thermodynamic parameters were calculated using Coats-Redfern equation. The Anticancer screening studies were performed on human colorectal cancer (HCT), hepatic cancer (HepG2) and breast cancer (MCF-7) cell lines. The antimicrobial activity of all the compounds was studied against Gram negative (Escherichia coli and Proteus vulgaris) and Gram positive (Bacillus vulgaris and Staphylococcus pyogones) bacteria. It was observed that the coordination of metal ion has a pronounced effect on the microbial activities of the bis Schiff base ligand. All the metal complexes have shown higher antimicrobial effect than the free bis Schiff base ligand.

Inhibition of pneumococcal choline-binding proteins and cell growth by esters of bicyclic amines.

PubMed

Maestro, Beatriz; González, Ana; García, Pedro; Sanz, Jesús M

2007-01-01

Streptococcus pneumoniae is one of the major pathogens worldwide. The use of currently available antibiotics to treat pneumococcal diseases is hampered by increasing resistance levels; also, capsular polysaccharide-based vaccination is of limited efficacy. Therefore, it is desirable to find targets for the development of new antimicrobial drugs specifically designed to fight pneumococcal infections. Choline-binding proteins are a family of polypeptides, found in all S. pneumoniae strains, that take part in important physiologic processes of this bacterium. Among them are several murein hydrolases whose enzymatic activity is usually inhibited by an excess of choline. Using a simple chromatographic procedure, we have identified several choline analogs able to strongly interact with the choline-binding module (C-LytA) of the major autolysin of S. pneumoniae. Two of these compounds (atropine and ipratropium) display a higher binding affinity to C-LytA than choline, and also increase the stability of the protein. CD and fluorescence spectroscopy analyses revealed that the conformational changes of C-LytA upon binding of these alkaloids are different to those induced by choline, suggesting a different mode of binding. In vitro inhibition assays of three pneumococcal, choline-dependent cell wall lytic enzymes also demonstrated a greater inhibitory efficiency of those molecules. Moreover, atropine and ipratropium strongly inhibited in vitro pneumococcal growth, altering cell morphology and reducing cell viability, a very different response than that observed upon addition of an excess of choline. These results may open up the possibility of the development of bicyclic amines as new antimicrobials for use against pneumococcal pathologies.

P38/TRHr-Dependent Regulation of TPO in Thyroid Cells Contributes to the Hypothyroidism of Triclosan-Treated Rats.

PubMed

Zhang, Pei; Yang, Min; Zeng, Li; Liu, Changjiang

2018-01-01

Triclosan, as an antimicrobial agent and a potential endocrine disruptor, has been used extensively in diverse products, resulting in widespread human exposure. In recent years, studies suggest that triclosan could disturb thyroid functions and decline thyroid hormones (THs). To verify our hypothesis that the MAPK pathway may function significantly in triclosan-induced hypothyroidism, Sprague-Dawley rats were gavaged with triclosan for 31 consecutive days; Nthy-ori 3-1 cells were treated with triclosan in the presence/absence of NAC, inhibitors (SB203580 and SB202474), or TRHr siRNA. Tissues and/or cells were analyzed by several techniques including transmission electron microscopy, confocal laser scanning microscopy, gene silencing, western blot, and real-time PCR. Triclosan led to histopathologic changes in the thyroid and decreases in triiodothyronine (T3) and thyroxine (T4). Triclosan stimulated ROS production and oxidative stress occurrence, thereby activating the p38 pathway in vivo and in vitro. Thyrotropin releasing hormone receptor (TRHr) was induced when the p38 pathway was activated, and was suppressed when that pathway was inhibited. Moreover, thyroid peroxidase (TPO) was restrained and modulated by the p38/TRHr pathway after triclosan treatment. Furthermore, deiodinase 3 (D3) and hepatic enzymes (Ugt2b1, CYP1a1, CYP1a2, CYP2b1, CYP3a1, and Sult1e1) were also induced by triclosan. Taken together, p38/TRHr-dependent regulation of TPO in thyroid cells contributes to the hypothyroidism of triclosan-treated rats. © 2018 The Author(s). Published by S. Karger AG, Basel.

Human tRNA(Lys3)(UUU) is pre-structured by natural modifications for cognate and wobble codon binding through keto-enol tautomerism.

PubMed

Vendeix, Franck A P; Murphy, Frank V; Cantara, William A; Leszczyńska, Grażyna; Gustilo, Estella M; Sproat, Brian; Malkiewicz, Andrzej; Agris, Paul F

2012-03-02

Human tRNA(Lys3)(UUU) (htRNA(Lys3)(UUU)) decodes the lysine codons AAA and AAG during translation and also plays a crucial role as the primer for HIV-1 (human immunodeficiency virus type 1) reverse transcription. The posttranscriptional modifications 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U(34)), 2-methylthio-N(6)-threonylcarbamoyladenosine (ms(2)t(6)A(37)), and pseudouridine (Ψ(39)) in the tRNA's anticodon domain are critical for ribosomal binding and HIV-1 reverse transcription. To understand the importance of modified nucleoside contributions, we determined the structure and function of this tRNA's anticodon stem and loop (ASL) domain with these modifications at positions 34, 37, and 39, respectively (hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);Ψ(39)). Ribosome binding assays in vitro revealed that the hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);Ψ(39) bound AAA and AAG codons, whereas binding of the unmodified ASL(Lys3)(UUU) was barely detectable. The UV hyperchromicity, the circular dichroism, and the structural analyses indicated that Ψ(39) enhanced the thermodynamic stability of the ASL through base stacking while ms(2)t(6)A(37) restrained the anticodon to adopt an open loop conformation that is required for ribosomal binding. The NMR-restrained molecular-dynamics-derived solution structure revealed that the modifications provided an open, ordered loop for codon binding. The crystal structures of the hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);Ψ(39) bound to the 30S ribosomal subunit with each codon in the A site showed that the modified nucleotides mcm(5)s(2)U(34) and ms(2)t(6)A(37) participate in the stability of the anticodon-codon interaction. Importantly, the mcm(5)s(2)U(34)·G(3) wobble base pair is in the Watson-Crick geometry, requiring unusual hydrogen bonding to G in which mcm(5)s(2)U(34) must shift from the keto to the enol form. The results unambiguously demonstrate that modifications pre-structure the anticodon as a key prerequisite for efficient and accurate recognition of cognate and wobble codons. Copyright © 2011 Elsevier Ltd. All rights reserved.

22 CFR 518.43 - Competition.

Code of Federal Regulations, 2011 CFR

2011-04-01

... organizational conflicts of interest as well as noncompetitive practices among contractors that may restrict or eliminate competition or otherwise restrain trade. In order to ensure objective contractor performance and...

Antimicrobial use and antimicrobial resistance in food animals.

PubMed

Xiong, Wenguang; Sun, Yongxue; Zeng, Zhenling

2018-05-25

Antimicrobials have been widely used in food animals for growth promotion since the 1950s. Antimicrobial resistance emerges in animal production settings and frequently spreads to humans through the food chain and direct contact. There have been international efforts to restrict or ban antimicrobials used for both humans and animals. Denmark has taken positive strides in the development of a comprehensive database DANMAP to track antimicrobial usage and resistance. Although food animals are sources of antimicrobial resistance, there is little evidence that antimicrobial resistance originates from food animals. This review comprehensively introduces the history and trends of antimicrobial use, the emergence and spread of antimicrobial resistance in food animals provides suggestions to tackle the problems of the spread of antimicrobial resistance.

Night Eating is Associated with Emotional and External Eating in College Students

PubMed Central

Nolan, Laurence J.; Geliebter, Allan

2012-01-01

The night eating syndrome (NES) consists of evening hyperphagia and/or nocturnal eating and has been associated with depressed mood, that worsens in the evening. However, it is not consistently related to elevated BMI. The present study was conducted to examine whether a relationship exists between NES and emotional, external, and restrained eating. BMI and sleep quality were also obtained. A sample of 246 students completed the Night Eating Diagnostic Questionnaire (NEDQ), Night Eating Syndrome History and Inventory (NESHI), Sleep Quality Index (SQI), and Dutch Eating Behavior Questionnaire (DEBQ), containing subscales for emotional, external, and restrained eating. They also provided demographic information, including height and weight. Participants were grouped by severity of NES features using the NEDQ and NESHI: normal, mild night eater, moderate night eater, and full night eater syndrome. MANOVA was used to compare DEBQ subscores for the groups; those in the full syndrome category had significantly higher emotional eating scores and external eating scores than those in the normal and mild categories. There was no difference in restrained eating between the normal and full syndrome groups. Those with moderate and full syndrome NES symptoms also reported significantly lower sleep quality. No significant relationship was found between NES and BMI. The results show that NES is associated with more eating in response to negative mood and in response to food cues. PMID:22664397

Rats fed only during the light period are resistant to stress-induced weight loss.

PubMed

Harris, Ruth B S; Zhou, Jun; Mitchell, Tiffany; Hebert, Sadie; Ryan, Donna H

2002-08-01

Repeated restraint stress (3 h/day for 3 days) causes a chronic down-regulation of body weight in rats. This study determined whether weight loss was influenced by the time of day that rats had access to food or that stress was applied. Groups of male Sprague-Dawley rats were fed a 40% kcal fat diet with food given ad libitum, only during the light phase or only during the dark phase. After 2 weeks of adaptation, rats within each feeding treatment were divided into four groups. One was exposed to repeated restraint at the start of the light phase, another was restrained at the start of the dark phase and the remaining groups were nonstressed controls for restrained rats. Body weight was significantly reduced in ad libitum- and dark-fed restrained rats, compared with nonstressed controls, from Day 2 of restraint, regardless of the time of day that they were stressed. There was no significant effect of restraint on weight change of light-fed rats. Food intake was inhibited by stress in ad libitum- and dark-fed rats, but it was not changed in light-fed rats. Serum corticosterone was increased by restraint in all rats irrespective of feeding schedule. This study demonstrates that stress-induced weight loss only occurs when rats have food available during their normal feeding period (dark phase) and is not determined by increased corticosterone release.

Risks and Targeted Interventions: Firearms in Intimate Partner Violence.

PubMed

Zeoli, April M; Malinski, Rebecca; Turchan, Brandon

2016-01-01

The use of firearms in intimate partner violence (IPV) is widely recognized as an important public health threat. However, what we know about the risks of firearm access on IPV outcomes is limited. Therefore, we conducted a systematic review to determine the state of knowledge on 1) the risks of firearm access and use in IPV and 2) the effectiveness of interventions designed specifically to reduce firearm violence in intimate relationships. Only studies published in English in peer-reviewed journals from 1990 through 2014 were included. Results of the review suggest that, when violent intimates have access to firearms, IPV increases in severity and deadliness; however, increases in severity may not be due to firearm use. Additionally, statutes prohibiting persons under domestic violence restraining orders from accessing firearms are associated with reductions in intimate partner homicide, but certain provisions of these laws and their enforcement may impact their effectiveness. Future research should focus on elucidating the link between firearm access and increased IPV severity and on investigating whether and which specific provisions of domestic violence restraining order laws impact the laws' effectiveness. Additionally, more evaluations of initiatives designed to improve the enforcement of domestic violence restraining order firearm prohibitions are needed. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Weight stigma and eating behaviours in elementary school children: A prospective population-based study.

PubMed

Jendrzyca, Anna; Warschburger, Petra

2016-07-01

The relevance of weight stigma as an important factor in disordered eating has been supported by research. However, because most of the studies were cross-sectional and focussed on older children, the causal relationships could not be fully determined in childhood. The current study explores the role of weight stigma in body dissatisfaction and eating behaviours. The sample consisted of 773 girls and 713 boys, aged 6-11 years, who completed surveys assessing weight stigma experiences, body dissatisfaction and eating behaviours at two points of measurement, approximately one year apart. The children's external and disordered eating was rated via parental questionnaires. As expected, the pattern of the associations between weight status, weight stigma, body dissatisfaction and eating behaviours differed by gender. Experience of weight stigma in girls led to external and restrained eating one year later, whereas in boys no such association was observed. Body dissatisfaction mediated the association between weight stigma and restrained eating behaviours in girls, whereas in boys, body dissatisfaction directly influenced restrained eating behaviours. However, in both girls and boys weight status predicted body dissatisfaction and disordered eating, while weight stigma did not have a direct effect on disordered eating. Results suggest that interventions involving weight stigma should be a part of eating disorder prevention programmes, and gender-specific pathways should be considered. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural and kinematic evolution of a Miocene to Recent sinistral restraining bend: the Montejunto massif, Portugal

NASA Astrophysics Data System (ADS)

Curtis, Michael L.

1999-01-01

The Montejunto massif lies in the apex of a large-scale restraining bend at the southern termination of a sinistral transpressive fault system, in the Lusitanian basin of Portugal. Cenozoic deformation within the Montejunto massif initiated with southerly directed thrusting along the southern boundary of the massif, in association with the development of the E-W oriented Montejunto anticline, probably during the Langhian. Deformation switched to the northern boundary of the massif, in association with a change to NW-directed thrusting and continued development of the Montejunto anticline. The youngest set of structures within the massif is related to the sinistral reactivation of the Arieiro fault system, and steeply inclined bedding. This late phase of deformation represents the accommodation of a component of sinistral displacement across the restraining bend along mechanical anisotropies formed during this progressive Cenozoic deformation event. Variation in the kinematic style of the Main Arieiro fault is related to the angle ( α) between the fault plane and the displacement vector. Where α≈20°, abrupt pene-contemporaneous switches in displacement direction are recorded along the fault, whereas strike-slip kinematics predominate where α<20°. The timing of deformation events in the Montejunto massif is uncertain. However, correlation with the established Cenozoic Africa/Europe plate convergence directions may provide potential temporal constraints.

Gravitropism in Higher Plant Shoots 1

PubMed Central

Sliwinski, Julianne E.; Salisbury, Frank B.

1984-01-01

Cross and longitudinal sections were prepared for light microscopy from vertical control plants (Xanthium strumarium L. Chicago strain), free-bending horizontal stems, plants restrained 48 hours in a horizontal position, and plants restrained 48 hours and then released, bending immediately about 130°. Top cells of free-bending stems shrink or elongate little; bottom cells continue to elongate. In restrained stems, bottom cells elongate some and increase in diameter; top cells elongate about as much but decrease in diameter. Upon release, bottom cells elongate more and decrease in diameter, while top cells shorten and increase in diameter, accounting for the bend. During restraint, bottom cells take up water while tissue pressures increase; top cells fail to take up water although tissue pressures are decreasing. Settling of amyloplasts was observed in cells of the starch sheath. Removal of different amounts of stem (Xanthium; Lycopersicon esculentum Miller, cv Bonny Best; Ricinus communis L. cv Yolo Wonder) showed that perception of gravity occurs in the bending (elongation) zone, although bending of fourth and fifth internodes from the top was less than in uncut controls. Uniform application of 1% indoleacetic acid in lanolin to cut stem surfaces partially restored bending. Reversing the gradient in tension/compression in horizontal stems (top under compression, bottom under tension) did not affect gravitropic bending. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 PMID:16663939

Changes in Physiologic Parameters and Effects of Hooding in Red-tailed Hawks ( Buteo jamaicensis ) During Manual Restraint.

PubMed

Doss, Grayson A; Mans, Christoph

2016-06-01

Manual restraint in birds of prey is required for many veterinary and research procedures. To investigate the effects of handling stress on physiologic parameters in raptorial birds, 8 red-tailed hawks ( Buteo jamaicensis ) were manually restrained over a 15-minute period. Respiratory rate (RR), heart rate (HR), and cloacal temperature were monitored over time and recorded at defined intervals during the experiment. The effect of hooding on physiologic variables was also evaluated in a complete crossover design. Both RR and HR decreased significantly during the 15-minute restraint period (HR, -80 ± 101.4 beats/min [bpm], [P < .01]; RR, -17.5 ± 22.6 breaths/min, [P < .05]). Hooded birds had significantly lower HRs and RRs at 15 minutes of restraint (HR: 232.5 ± 26 bpm, [P < .037]; RR: 33.1 ± 6.7 breaths/min, [P < .05]) compared to birds restrained without a hood (HR: 280 ± 74.1 bpm; RR: 51.5 ± 28.8 breaths/min). Cloacal temperature increased significantly in all manually restrained birds (+2.2 ± 0.7°C, [P < .01]), with a comparable increase in hooded and nonhooded birds. In this study of the effects of manual restraint on red-tailed hawks, hooding versus nonhooding amplified the decrease in HR and RR but had no effect on stress-induced hyperthermia.

Prediction of BMI at age 11 in a longitudinal sample of the Ulm Birth Cohort Study

PubMed Central

Walter, Viola; Wabitsch, Martin; Rothenbacher, Dietrich; Brenner, Hermann; Schimmelmann, Benno G.

2017-01-01

Obesity is one of the greatest public health challenges in the world with childhood prevalence rates between 20–26% and numerous associated health risks. The aim of the current study was to analyze the 11-year follow-up data of the Ulm Birth Cohort Study (UBCS), to identify whether abnormal eating behavior patterns, especially restrained eating, predict body mass index (BMI) at 11 years of age and to explore other factors known to be longitudinally associated with it. Of the original UBCS, n = 422 children (~ 40% of the original sample) and their parents participated in the 11-year follow-up. BMI at age 8 and 11 as well as information on restrained eating, psychological problems, depressive symptoms, lifestyle, and IQ at age 8 were assessed. Partial Least Squares Structural Equation Modeling (PLS-SEM) was used to predict children’s BMI scores at age 11. PLS-SEM explained 68% of the variance of BMI at age 11, with BMI at age 8 being the most important predictor. Restrained eating, via BMI at age 8 as well as parental BMI, had further weak associations with BMI at age 11; no other predictor was statistically significant. Since established overweight at age 8 already predicts BMI scores at age 11 longitudinally, obesity interventions should be implemented in early childhood. PMID:28832593

Mathematical modeling and full-scale shaking table tests for multi-curve buckling restrained braces

NASA Astrophysics Data System (ADS)

Tsai, C. S.; Lin, Yungchang; Chen, Wenshin; Su, H. C.

2009-09-01

Buckling restrained braces (BRBs) have been widely applied in seismic mitigation since they were introduced in the 1970s. However, traditional BRBs have several disadvantages caused by using a steel tube to envelope the mortar to prevent the core plate from buckling, such as: complex interfaces between the materials used, uncertain precision, and time consumption during the manufacturing processes. In this study, a new device called the multi-curve buckling restrained brace (MC-BRB) is proposed to overcome these disadvantages. The new device consists of a core plate with multiple neck portions assembled to form multiple energy dissipation segments, and the enlarged segment, lateral support elements and constraining elements to prevent the BRB from buckling. The enlarged segment located in the middle of the core plate can be welded to the lateral support and constraining elements to increase buckling resistance and to prevent them from sliding during earthquakes. Component tests and a series of shaking table tests on a full-scale steel structure equipped with MC-BRBs were carried out to investigate the behavior and capability of this new BRB design for seismic mitigation. The experimental results illustrate that the MC-BRB possesses a stable mechanical behavior under cyclic loadings and provides good protection to structures during earthquakes. Also, a mathematical model has been developed to simulate the mechanical characteristics of BRBs.

The chemistry and applications of antimicrobial polymers: a state-of-the-art review.

PubMed

Kenawy, El-Refaie; Worley, S D; Broughton, Roy

2007-05-01

Microbial infection remains one of the most serious complications in several areas, particularly in medical devices, drugs, health care and hygienic applications, water purification systems, hospital and dental surgery equipment, textiles, food packaging, and food storage. Antimicrobials gain interest from both academic research and industry due to their potential to provide quality and safety benefits to many materials. However, low molecular weight antimicrobial agents suffer from many disadvantages, such as toxicity to the environment and short-term antimicrobial ability. To overcome problems associated with the low molecular weight antimicrobial agents, antimicrobial functional groups can be introduced into polymer molecules. The use of antimicrobial polymers offers promise for enhancing the efficacy of some existing antimicrobial agents and minimizing the environmental problems accompanying conventional antimicrobial agents by reducing the residual toxicity of the agents, increasing their efficiency and selectivity, and prolonging the lifetime of the antimicrobial agents. Research concerning the development of antimicrobial polymers represents a great a challenge for both the academic world and industry. This article reviews the state of the art of antimicrobial polymers primarily since the last comprehensive review by one of the authors in 1996. In particular, it discusses the requirements of antimicrobial polymers, factors affecting the antimicrobial activities, methods of synthesizing antimicrobial polymers, major fields of applications, and future and perspectives in the field of antimicrobial polymers.

An evaluation of the association between an antimicrobial stewardship score and antimicrobial usage

PubMed Central

Pakyz, Amy L.; Moczygemba, Leticia R.; Wang, Hui; Stevens, Michael P.; Edmond, Michael B.

2015-01-01

Objectives To determine whether an antimicrobial stewardship ‘intensity’ score predicts hospital antimicrobial usage. Methods An antimicrobial stewardship score for 44 academic medical centres was developed that comprised two main categories: resources (antimicrobial stewardship programme personnel and automated surveillance software) and strategies (preauthorization, audit with intervention and feedback, education, guidelines and clinical pathways, parenteral to oral therapy programmes, de-escalation of therapy, antimicrobial order forms and dose optimization). Multiple regression analyses were used to assess whether the composite score and also the categories were associated with either total or antimicrobial stewardship programme-target antimicrobial use as measured in days of therapy. Results The mean antimicrobial stewardship programme score was 55 (SD 21); the total composite score was not significantly associated with total or target antimicrobial use [estimate –0.49 (95% CI –2.30 to 0.89)], while the category strategies was significantly and negatively associated with target antimicrobial use [–5.91 (95% CI –9.51 to –2.31)]. Conclusions The strategy component of a score developed to measure the intensity of antimicrobial stewardship was associated with the amount of antimicrobials used. Thus, the number and types of strategies employed by antimicrobial stewardship programmes may be of particular importance in programme effectiveness. PMID:25614043

Traditional Sex and Gender Stereotypes in the Relationships of Non-Disclosing Behaviorally Bisexual Men.

PubMed

Siegel, Karolynn; Meunier, Étienne

2018-06-04

Traditional stereotypes about sex and gender present men as assertive, aggressive, sexually adventurous, and emotionally restrained, and women as docile, passive, sexually modest, and emotionally sensitive. Past research has shown that such stereotypes impose constraints on heterosexual relationships that decrease sexual satisfaction for men and women. This study examined the impact of traditional sex and gender stereotypes on a sample of 203 behaviorally bisexual men who were in a heterosexual relationship with a woman to whom they did not disclose their same-sex behaviors. Participants' descriptions of their partners reified several traditional stereotypes regarding men's and women's sexual dispositions (e.g., men are more sexually adventurous than women), role during sex (e.g., men should be dominant and women submissive), relationship desires (i.e., women prefer long-term intimate relationships and men prefer unattached sexual gratification), and emotional involvement (e.g., women are emotionally sensitive and men emotionally detached). These stereotypes shaped participants' sexual relations with women and men, which were widely conceived as acts of domination-submission. Perceiving women as more skilled for emotional intimacy and affection, most participants would only develop intimate relationships with them; however, some participants also perceived women as too emotionally sensitive and described men as better companions. Many participants were dissatisfied with these gender norms although they conformed to them, further supporting that traditional sex and gender stereotypes impose constraints on relationships that can limit authentic sexual expression and intimate satisfaction.

Binding Specificity Determines the Cytochrome P450 3A4 Mediated Enantioselective Metabolism of Metconazole.

PubMed

Zhuang, Shulin; Zhang, Leili; Zhan, Tingjie; Lu, Liping; Zhao, Lu; Wang, Haifei; Morrone, Joseph A; Liu, Weiping; Zhou, Ruhong

2018-01-25

Cytochrome P450 3A4 (CYP3A4) is a promiscuous enzyme, mediating the biotransformations of ∼50% of clinically used drugs, many of which are chiral molecules. Probing the interactions between CYP3A4 and chiral chemicals is thus essential for the elucidation of molecular mechanisms of enantioselective metabolism. We developed a stepwise-restrained-molecular-dynamics (MD) method to model human CYP3A4 in a complex with cis-metconazole (MEZ) isomers and performed conventional MD simulations with a total simulation time of 2.2 μs to probe the molecular interactions. Our current study, which employs a combined experimental and theoretical approach, reports for the first time on the distinct conformational changes of CYP3A4 that are induced by the enantioselective binding of cis-MEZ enantiomers. CYP3A4 preferably metabolizes cis-RS MEZ over the cis-SR isomer, with the resultant enantiomer fraction for cis-MEZ increasing rapidly from 0.5 to 0.82. cis-RS MEZ adopts a more extended structure in the active pocket with its Cl atom exposed to the solvent, whereas cis-SR MEZ sits within the hydrophobic core of the active pocket. Free-energy-perturbation calculations indicate that unfavorable van der Waals interactions between the cis-MEZ isomers and the CYP3A4 binding pocket predominantly contribute to their binding-affinity differences. These results demonstrate that binding specificity determines the cytochrome P450 3A4 mediated enantioselective metabolism of cis-MEZ.

30 CFR 77.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... black powder, dynamite, nitroglycerin, fulminate, ammonium nitrate when mixed with a hydrocarbon, and...; (d) Berm means a pile or mound of material capable of restraining a vehicle; (e) Blasting agent means...

Static Gas-Charging Plug

NASA Technical Reports Server (NTRS)

Indoe, William

2012-01-01

A gas-charging plug can be easily analyzed for random vibration. The design features two steeped O-rings in a radial configuration at two different diameters, with a 0.050-in. (.1.3-mm) diameter through-hole between the two O-rings. In the charging state, the top O-ring is engaged and sealing. The bottom O-ring outer diameter is not squeezed, and allows air to flow by it into the tank. The inner diameter is stretched to plug the gland diameter, and is restrained by the O-ring groove. The charging port bushing provides mechanical stop to restrain the plug during gas charge removal. It also prevents the plug from becoming a projectile when removing gas charge from the accumulator. The plug can easily be verified after installation to ensure leakage requirements are met.

[Decomposition model of energy-related carbon emissions in tertiary industry for China].

PubMed

Lu, Yuan-Qing; Shi, Jun

2012-07-01

Tertiary industry has been developed in recent years. And it is very important to find the factors influenced the energy-related carbon emissions in tertiary industry. A decomposition model of energy-related carbon emissions for China is set up by adopting logarithmic mean weight Divisia method based on the identity of carbon emissions. The model is adopted to analyze the influence of energy structure, energy efficiency, tertiary industry structure and economic output to energy-related carbon emissions in China from 2000 to 2009. Results show that the contribution rate of economic output and energy structure to energy-related carbon emissions increases year by year. Either is the contribution rate of energy efficiency or the tertiary industry restraining to energy-related carbon emissions. However, the restrain effect is weakening.

Emotional arousal and overeating in restrained eaters.

PubMed

Cools, J; Schotte, D E; McNally, R J

1992-05-01

We tested the effects of 3 mood inductions (neutral, positive, and negative) on food intake in 91 women of varying degrees of dietary restraint. Mood induction was accomplished by exposure to 1 of 3 film segments: a travelogue (neutral affect), a comedy film (positive affect), and a horror film (negative affect). In subjects exposed to the neutral film, food intake decreased with increasing levels of dietary restraint. Among subjects who viewed either the comedy film or the horror film, however, food intake increased with increasing restraint. Although the horror film appeared to be more disinhibiting than the comedy film, this effect may have resulted from a difference in the intensity of the emotions induced rather than from their valence. These results suggest that emotional arousal, regardless of valence, may trigger overeating among restrained eaters.

Relationship between body mass index and women's body image, self-esteem and eating behaviours in pregnancy: a cross-cultural study.

PubMed

Shloim, Netalie; Hetherington, Marion M; Rudolf, Mary; Feltbower, Richard G

2015-04-01

This study examined the relationship between self-esteem, restrained eating, body image and body mass index during pregnancy. A total of 110 pregnant Israeli and UK women completed the Rosenberg Self-Esteem Questionnaire, the Dutch Eating Behaviour Questionnaire, scales to assess body image and demographics. Body mass index was calculated from antenatal records. Regression modelling determined the relationship between variables, countries and body mass index categories. High correlations were found between body image and body mass index with significantly higher body dissatisfaction for Israeli women. Self-esteem scores for pregnant women were similar to those reported for non-pregnant women. Poorer body image and higher prevalence of restrained eating were found in healthy weight Israeli women. © The Author(s) 2013.

Robust consensus algorithm for multi-agent systems with exogenous disturbances under convergence conditions

NASA Astrophysics Data System (ADS)

Jiang, Yulian; Liu, Jianchang; Tan, Shubin; Ming, Pingsong

2014-09-01

In this paper, a robust consensus algorithm is developed and sufficient conditions for convergence to consensus are proposed for a multi-agent system (MAS) with exogenous disturbances subject to partial information. By utilizing H∞ robust control, differential game theory and a design-based approach, the consensus problem of the MAS with exogenous bounded interference is resolved and the disturbances are restrained, simultaneously. Attention is focused on designing an H∞ robust controller (the robust consensus algorithm) based on minimisation of our proposed rational and individual cost functions according to goals of the MAS. Furthermore, sufficient conditions for convergence of the robust consensus algorithm are given. An example is employed to demonstrate that our results are effective and more capable to restrain exogenous disturbances than the existing literature.

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