Design of High Performance Si/SiGe Heterojunction Tunneling FETs with a T-Shaped Gate

NASA Astrophysics Data System (ADS)

Li, Wei; Liu, Hongxia; Wang, Shulong; Chen, Shupeng; Yang, Zhaonian

2017-03-01

In this paper, a new Si/SiGe heterojunction tunneling field-effect transistor with a T-shaped gate (HTG-TFET) is proposed and investigated by Silvaco-Atlas simulation. The two source regions of the HTG-TFET are placed on both sides of the gate to increase the tunneling area. The T-shaped gate is designed to overlap with N+ pockets in both the lateral and vertical directions, which increases the electric field and tunneling rate at the top of tunneling junctions. Moreover, using SiGe in the pocket regions leads to the smaller tunneling distance. Therefore, the proposed HTG-TFET can obtain the higher on-state current. The simulation results show that on-state current of HTG-TFET is increased by one order of magnitude compared with that of the silicon-based counterparts. The average subthreshold swing (SS) of HTG-TFET is 44.64 mV/dec when V g is varied from 0.1 to 0.4 V, and the point SS is 36.59 mV/dec at V g = 0.2 V. Besides, this design cannot bring the sever Miller capacitance for the TFET circuit design. By using the T-shaped gate and SiGe pocket regions, the overall performance of the TFET is optimized.

The Crystal Structure of the Ring-Hydroxylating Dioxygenase from Sphingomonas CHY-1

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

Jakoncic,J.; Jouanneau, Y.; Meyer, C.

The ring-hydroxylating dioxygenase (RHD) from Sphingomonas CHY-1 is remarkable due to its ability to initiate the oxidation of a wide range of polycyclic aromatic hydrocarbons (PAHs), including PAHs containing four- and five-fused rings, known pollutants for their toxic nature. Although the terminal oxygenase from CHY-1 exhibits limited sequence similarity with well characterized RHDs from the naphthalene dioxygenase family, the crystal structure determined to 1.85 {angstrom} by molecular replacement revealed the enzyme to share the same global {alpha}{sub 3}{beta}{sub 3} structural pattern. The catalytic domain distinguishes itself from other bacterial non-heme Rieske iron oxygenases by a substantially larger hydrophobic substrate bindingmore » pocket, the largest ever reported for this type of enzyme. While residues in the proximal region close to the mononuclear iron atom are conserved, the central region of the catalytic pocket is shaped mainly by the side chains of three amino acids, Phe350, Phe404 and Leu356, which contribute to the rather uniform trapezoidal shape of the pocket. Two flexible loops, LI and LII, exposed to the solvent seem to control the substrate access to the catalytic pocket and control the pocket length. Compared with other naphthalene dioxygenases residues Leu223 and Leu226, on loop LI, are moved towards the solvent, thus elongating the catalytic pocket by at least 2 {angstrom}. An 11 {angstrom} long water channel extends from the interface between the {alpha} and {beta} subunits to the catalytic site. The comparison of these structures with other known oxygenases suggests that the broad substrate specificity presented by the CHY-1 oxygenase is primarily due to the large size and particular topology of its catalytic pocket and provided the basis for the study of its reaction mechanism.« less

Investigating the Importance of the Pocket-estimation Method in Pocket-based Approaches: An Illustration Using Pocket-ligand Classification.

PubMed

Caumes, Géraldine; Borrel, Alexandre; Abi Hussein, Hiba; Camproux, Anne-Claude; Regad, Leslie

2017-09-01

Small molecules interact with their protein target on surface cavities known as binding pockets. Pocket-based approaches are very useful in all of the phases of drug design. Their first step is estimating the binding pocket based on protein structure. The available pocket-estimation methods produce different pockets for the same target. The aim of this work is to investigate the effects of different pocket-estimation methods on the results of pocket-based approaches. We focused on the effect of three pocket-estimation methods on a pocket-ligand (PL) classification. This pocket-based approach is useful for understanding the correspondence between the pocket and ligand spaces and to develop pharmacological profiling models. We found pocket-estimation methods yield different binding pockets in terms of boundaries and properties. These differences are responsible for the variation in the PL classification results that can have an impact on the detected correspondence between pocket and ligand profiles. Thus, we highlighted the importance of the pocket-estimation method choice in pocket-based approaches. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Interactions between Hofmeister anions and the binding pocket of a protein.

PubMed

Fox, Jerome M; Kang, Kyungtae; Sherman, Woody; Héroux, Annie; Sastry, G Madhavi; Baghbanzadeh, Mostafa; Lockett, Matthew R; Whitesides, George M

2015-03-25

This paper uses the binding pocket of human carbonic anhydrase II (HCAII, EC 4.2.1.1) as a tool to examine the properties of Hofmeister anions that determine (i) where, and how strongly, they associate with concavities on the surfaces of proteins and (ii) how, upon binding, they alter the structure of water within those concavities. Results from X-ray crystallography and isothermal titration calorimetry show that most anions associate with the binding pocket of HCAII by forming inner-sphere ion pairs with the Zn(2+) cofactor. In these ion pairs, the free energy of anion-Zn(2+) association is inversely proportional to the free energetic cost of anion dehydration; this relationship is consistent with the mechanism of ion pair formation suggested by the "law of matching water affinities". Iodide and bromide anions also associate with a hydrophobic declivity in the wall of the binding pocket. Molecular dynamics simulations suggest that anions, upon associating with Zn(2+), trigger rearrangements of water that extend up to 8 Å away from their surfaces. These findings expand the range of interactions previously thought to occur between ions and proteins by suggesting that (i) weakly hydrated anions can bind complementarily shaped hydrophobic declivities, and that (ii) ion-induced rearrangements of water within protein concavities can (in contrast with similar rearrangements in bulk water) extend well beyond the first hydration shells of the ions that trigger them. This study paints a picture of Hofmeister anions as a set of structurally varied ligands that differ in size, shape, and affinity for water and, thus, in their ability to bind to—and to alter the charge and hydration structure of—polar, nonpolar, and topographically complex concavities on the surfaces of proteins.

Tunability of the topological nodal-line semimetal phase in ZrSi X -type materials ( X = S ,   Se ,   Te )

DOE PAGES

Hosen, M. Mofazzel; Dimitri, Klauss; Belopolski, Ilya; ...

2017-04-03

The discovery of a topological nodal-line (TNL) semimetal phase in ZrSiS has invigorated the study of other members of this family. In this paper, we present a comparative electronic structure study ofmore » $$\\mathrm{ZrSi}X$$ (where $$X=\\text{S}$$, Se, Te) using angle-resolved photoemission spectroscopy (ARPES) and first-principles calculations. Our ARPES studies show that the overall electronic structure of $$\\mathrm{ZrSi}X$$ materials comprises the diamond-shaped Fermi pocket, the nearly elliptical-shaped Fermi pocket, and a small electron pocket encircling the zone center ($$\\mathrm{{\\Gamma}}$$) point, the $M$ point, and the $X$ point of the Brillouin zone, respectively. We also observe a small Fermi surface pocket along the $$M{-}\\mathrm{{\\Gamma}}{-}M$$ direction in ZrSiTe, which is absent in both ZrSiS and ZrSiSe. Furthermore, our theoretical studies show a transition from nodal-line to nodeless gapped phase by tuning the chalcogenide from S to Te in these material systems. Finally, our findings provide direct evidence for the tunability of the TNL phase in $$\\mathrm{ZrSi}X$$ material systems by adjusting the spin-orbit coupling strength via the $X$ anion.« less

The CD1 family: serving lipid antigens to T cells since the Mesozoic era.

PubMed

Zajonc, Dirk M

2016-08-01

Class I-like CD1 molecules are in a family of antigen-presenting molecules that bind lipids and lipopeptides, rather than peptides for immune surveillance by T cells. Since CD1 lacks the high degree of polymorphism found in their major histocompatibility complex (MHC) class I molecules, different species express different numbers of CD1 isotypes, likely to be able to present structurally diverse classes of lipid antigens. In this review, we will present a historical overview of the structures of the different human CD1 isotypes and also discuss species-specific adaptations of the lipid-binding groove. We will discuss how single amino acid changes alter the shape and volume of the CD1 binding groove, how these minor changes can give rise to different numbers of binding pockets, and how these pockets affect the lipid repertoire that can be presented by any given CD1 protein. We will compare the structures of various lipid antigens and finally, we will discuss recognition of CD1-presented lipid antigens by antigen receptors on T cells (TCRs).

The CD1 family: serving lipid antigens to T cells since the Mesozoic era

PubMed Central

Zajonc, Dirk M.

2016-01-01

Class I-like CD1 molecules are in a family of antigen-presenting molecules that bind lipids and lipopeptides, rather than peptides for immune surveillance by T cells. Since CD1 lacks the high degree of polymorphism found in their major histocompatibility complex (MHC) class I molecules, different species express different numbers of CD1 isotypes, likely to be able to present structurally diverse classes of lipid antigens. In this review, we will present a historical overview of the structures of the different human CD1 isotypes and also discuss species-specific adaptations of the lipid-binding groove. We will discuss how single amino acid changes alter the shape and volume of the CD1 binding groove, how these minor changes can give rise to different numbers of binding pockets, and how these pockets affect the lipid repertoire that can be presented by any given CD1 protein. We will compare the structures of various lipid antigens and finally, we will discuss recognition of CD1-presented lipid antigens by antigen receptors on T cells (TCRs). PMID:27368414

Dynamic water behaviour due to one trapped air pocket in a laboratory pipeline apparatus

NASA Astrophysics Data System (ADS)

Bergant, A.; Karadžić, U.; Tijsseling, A.

2016-11-01

Trapped air pockets may cause severe operational problems in hydropower and water supply systems. A locally isolated air pocket creates distinct amplitude, shape and timing of pressure pulses. This paper investigates dynamic behaviour of a single trapped air pocket. The air pocket is incorporated as a boundary condition into the discrete gas cavity model (DGCM). DGCM allows small gas cavities to form at computational sections in the method of characteristics (MOC). The growth of the pocket and gas cavities is described by the water hammer compatibility equation(s), the continuity equation for the cavity volume, and the equation of state of an ideal gas. Isentropic behaviour is assumed for the trapped gas pocket and an isothermal bath for small gas cavities. Experimental investigations have been performed in a laboratory pipeline apparatus. The apparatus consists of an upstream end high-pressure tank, a horizontal steel pipeline (total length 55.37 m, inner diameter 18 mm), four valve units positioned along the pipeline including the end points, and a downstream end tank. A trapped air pocket is captured between two ball valves at the downstream end of the pipeline. The transient event is initiated by rapid opening of the upstream end valve; the downstream end valve stays closed during the event. Predicted and measured results for a few typical cases are compared and discussed.

Differentiating defects in red oak lumber by discriminant analysis using color, shape, and density

Treesearch

B. H. Bond; D. Earl Kline; Philip A. Araman

2002-01-01

Defect color, shape, and density measures aid in the differentiation of knots, bark pockets, stain/mineral streak, and clearwood in red oak, (Quercus rubra). Various color, shape, and density measures were extracted for defects present in color and X-ray images captured using a color line scan camera and an X-ray line scan detector. Analysis of variance was used to...

Formation of Micro-Scale Gas Pockets From Underwater Wall Orifices

NASA Astrophysics Data System (ADS)

Pereira, Francisco A.; Gharib, Morteza

2012-11-01

Our experiments examine the formation of micro-scale gas pockets from orifices on walls with hydrophilic and hydrophobic wetting properties. Bubble injection is operated in a liquid at rest at constant flow rate and in a quasi-static regime, and the mechanism of bubble growth is investigated through high speed recordings. The growth dynamics is studied in terms of orifice size, surface wetting properties and buoyancy sign. The bubble formation is characterized by an explosive growth, with a pressure wave that causes the bubble to take highly transient shapes in its very initial stages, before stabilizing as a sphere and growing at a relatively slow rate. In case of positive buoyancy, the bubble elongates with the formation of a neck before detaching from the wall. When buoyancy acts towards the wall, the bubble attaches to the wall and expands laterally with a moving contact line. In presence of hydrophobic surfaces, the bubble attaches immediately to the wall irrespective of buoyancy direction and takes a hemispherical shape, expanding radially along the surface. A force balance is outlined to explain the different figures. The work was performed by FAP while on leave from CNR-INSEAN, and is supported by the Office of Naval Research (ONR).

Large scale analysis of protein-binding cavities using self-organizing maps and wavelet-based surface patches to describe functional properties, selectivity discrimination, and putative cross-reactivity.

PubMed

Kupas, Katrin; Ultsch, Alfred; Klebe, Gerhard

2008-05-15

A new method to discover similar substructures in protein binding pockets, independently of sequence and folding patterns or secondary structure elements, is introduced. The solvent-accessible surface of a binding pocket, automatically detected as a depression on the protein surface, is divided into a set of surface patches. Each surface patch is characterized by its shape as well as by its physicochemical characteristics. Wavelets defined on surfaces are used for the description of the shape, as they have the great advantage of allowing a comparison at different resolutions. The number of coefficients to describe the wavelets can be chosen with respect to the size of the considered data set. The physicochemical characteristics of the patches are described by the assignment of the exposed amino acid residues to one or more of five different properties determinant for molecular recognition. A self-organizing neural network is used to project the high-dimensional feature vectors onto a two-dimensional layer of neurons, called a map. To find similarities between the binding pockets, in both geometrical and physicochemical features, a clustering of the projected feature vector is performed using an automatic distance- and density-based clustering algorithm. The method was validated with a small training data set of 109 binding cavities originating from a set of enzymes covering 12 different EC numbers. A second test data set of 1378 binding cavities, extracted from enzymes of 13 different EC numbers, was then used to prove the discriminating power of the algorithm and to demonstrate its applicability to large scale analyses. In all cases, members of the data set with the same EC number were placed into coherent regions on the map, with small distances between them. Different EC numbers are separated by large distances between the feature vectors. A third data set comprising three subfamilies of endopeptidases is used to demonstrate the ability of the algorithm to detect similar substructures between functionally related active sites. The algorithm can also be used to predict the function of novel proteins not considered in training data set. 2007 Wiley-Liss, Inc.

PockDrug-Server: a new web server for predicting pocket druggability on holo and apo proteins

PubMed Central

Hussein, Hiba Abi; Borrel, Alexandre; Geneix, Colette; Petitjean, Michel; Regad, Leslie; Camproux, Anne-Claude

2015-01-01

Predicting protein pocket's ability to bind drug-like molecules with high affinity, i.e. druggability, is of major interest in the target identification phase of drug discovery. Therefore, pocket druggability investigations represent a key step of compound clinical progression projects. Currently computational druggability prediction models are attached to one unique pocket estimation method despite pocket estimation uncertainties. In this paper, we propose ‘PockDrug-Server’ to predict pocket druggability, efficient on both (i) estimated pockets guided by the ligand proximity (extracted by proximity to a ligand from a holo protein structure) and (ii) estimated pockets based solely on protein structure information (based on amino atoms that form the surface of potential binding cavities). PockDrug-Server provides consistent druggability results using different pocket estimation methods. It is robust with respect to pocket boundary and estimation uncertainties, thus efficient using apo pockets that are challenging to estimate. It clearly distinguishes druggable from less druggable pockets using different estimation methods and outperformed recent druggability models for apo pockets. It can be carried out from one or a set of apo/holo proteins using different pocket estimation methods proposed by our web server or from any pocket previously estimated by the user. PockDrug-Server is publicly available at: http://pockdrug.rpbs.univ-paris-diderot.fr. PMID:25956651

PockDrug-Server: a new web server for predicting pocket druggability on holo and apo proteins.

PubMed

Hussein, Hiba Abi; Borrel, Alexandre; Geneix, Colette; Petitjean, Michel; Regad, Leslie; Camproux, Anne-Claude

2015-07-01

Predicting protein pocket's ability to bind drug-like molecules with high affinity, i.e. druggability, is of major interest in the target identification phase of drug discovery. Therefore, pocket druggability investigations represent a key step of compound clinical progression projects. Currently computational druggability prediction models are attached to one unique pocket estimation method despite pocket estimation uncertainties. In this paper, we propose 'PockDrug-Server' to predict pocket druggability, efficient on both (i) estimated pockets guided by the ligand proximity (extracted by proximity to a ligand from a holo protein structure) and (ii) estimated pockets based solely on protein structure information (based on amino atoms that form the surface of potential binding cavities). PockDrug-Server provides consistent druggability results using different pocket estimation methods. It is robust with respect to pocket boundary and estimation uncertainties, thus efficient using apo pockets that are challenging to estimate. It clearly distinguishes druggable from less druggable pockets using different estimation methods and outperformed recent druggability models for apo pockets. It can be carried out from one or a set of apo/holo proteins using different pocket estimation methods proposed by our web server or from any pocket previously estimated by the user. PockDrug-Server is publicly available at: http://pockdrug.rpbs.univ-paris-diderot.fr. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Retinoid X Receptors and Their Ligands

PubMed Central

Dawson, Marcia I.; Xia, Zebin

2014-01-01

This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. PMID:22020178

Pocket ECG electrode

NASA Technical Reports Server (NTRS)

Lund, Gordon F. (Inventor)

1982-01-01

A low-noise electrode suited for sensing electrocardiograms when chronically and subcutaneously implanted in a free-ranging subject. The electrode comprises a pocket-shaped electrically conductive member with a single entrance adapted to receive body fluids. The exterior of the member and the entrance region is coated with electrical insulation so that the only electrolyte/electrode interface is within the member remote from artifact-generating tissue. Cloth straps are bonded to the member to permit the electrode to be sutured to tissue and to provide electrical lead flexure relief.

Pocket ECG electrode

NASA Technical Reports Server (NTRS)

Lund, G. F. (Inventor)

1980-01-01

A low noise electrode suited for sensing electrocardiograms when chronically and subcutaneously implanted in a free ranging subject is described. The electrode comprises a pocket shaped electrically conductive member with a single entrance adapted to receive body fluids. The exterior of the member and the entrance region is coated with electrical insulation so that the only electrolyte/electrode interface is within the member, remote from artifact-generating tissue. Cloth straps are bonded to the member to permit the electrode to be sutured to tissue and to provide electrical lead flexure relief.

Cofactor-binding sites in proteins of deviating sequence: comparative analysis and clustering in torsion angle, cavity, and fold space.

PubMed

Stegemann, Björn; Klebe, Gerhard

2012-02-01

Small molecules are recognized in protein-binding pockets through surface-exposed physicochemical properties. To optimize binding, they have to adopt a conformation corresponding to a local energy minimum within the formed protein-ligand complex. However, their conformational flexibility makes them competent to bind not only to homologous proteins of the same family but also to proteins of remote similarity with respect to the shape of the binding pockets and folding pattern. Considering drug action, such observations can give rise to unexpected and undesired cross reactivity. In this study, datasets of six different cofactors (ADP, ATP, NAD(P)(H), FAD, and acetyl CoA, sharing an adenosine diphosphate moiety as common substructure), observed in multiple crystal structures of protein-cofactor complexes exhibiting sequence identity below 25%, have been analyzed for the conformational properties of the bound ligands, the distribution of physicochemical properties in the accommodating protein-binding pockets, and the local folding patterns next to the cofactor-binding site. State-of-the-art clustering techniques have been applied to group the different protein-cofactor complexes in the different spaces. Interestingly, clustering in cavity (Cavbase) and fold space (DALI) reveals virtually the same data structuring. Remarkable relationships can be found among the different spaces. They provide information on how conformations are conserved across the host proteins and which distinct local cavity and fold motifs recognize the different portions of the cofactors. In those cases, where different cofactors are found to be accommodated in a similar fashion to the same fold motifs, only a commonly shared substructure of the cofactors is used for the recognition process. Copyright © 2011 Wiley Periodicals, Inc.

PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties.

PubMed

Borrel, Alexandre; Regad, Leslie; Xhaard, Henri; Petitjean, Michel; Camproux, Anne-Claude

2015-04-27

Predicting protein druggability is a key interest in the target identification phase of drug discovery. Here, we assess the pocket estimation methods' influence on druggability predictions by comparing statistical models constructed from pockets estimated using different pocket estimation methods: a proximity of either 4 or 5.5 Å to a cocrystallized ligand or DoGSite and fpocket estimation methods. We developed PockDrug, a robust pocket druggability model that copes with uncertainties in pocket boundaries. It is based on a linear discriminant analysis from a pool of 52 descriptors combined with a selection of the most stable and efficient models using different pocket estimation methods. PockDrug retains the best combinations of three pocket properties which impact druggability: geometry, hydrophobicity, and aromaticity. It results in an average accuracy of 87.9% ± 4.7% using a test set and exhibits higher accuracy (∼5-10%) than previous studies that used an identical apo set. In conclusion, this study confirms the influence of pocket estimation on pocket druggability prediction and proposes PockDrug as a new model that overcomes pocket estimation variability.

Sutureless Corneal Transplantation Apparatus And Method

DOEpatents

Rowsey, J. James

1996-12-17

An eye with a cornea repaired without sutures comprising a donor material in the shape of a partial sphere having a generally central extent, the central extent being of the size and shape of the central portion of a cornea of an eye, the central extent having a periphery of a fixed diameter with an exterior surface in a convex configuration and an interior surface in a concave configuration and with an essentially common thickness throughout, the central extent having a plurality of corneal flaps extending radially from the periphery of the central extent, the flaps having exterior surfaces as a continuation of the exterior surface of the central extent; and a recipient eye in the shape of a partial sphere having a circular aperture in the cornea at its central portion, the central aperture being of a size and shape essentially that of the periphery of the central extent of the donor material, the aperture being of a common thickness at the periphery of the aperture, the central portion having pockets and with the central extent of the donor material located within the aperture of the recipient eye and with the flaps of the central extent being imbricated into the pockets of the recipient eye.

Profiling charge complementarity and selectivity for binding at the protein surface.

PubMed

Sulea, Traian; Purisima, Enrico O

2003-05-01

A novel analysis and representation of the protein surface in terms of electrostatic binding complementarity and selectivity is presented. The charge optimization methodology is applied in a probe-based approach that simulates the binding process to the target protein. The molecular surface is color coded according to calculated optimal charge or according to charge selectivity, i.e., the binding cost of deviating from the optimal charge. The optimal charge profile depends on both the protein shape and charge distribution whereas the charge selectivity profile depends only on protein shape. High selectivity is concentrated in well-shaped concave pockets, whereas solvent-exposed convex regions are not charge selective. This suggests the synergy of charge and shape selectivity hot spots toward molecular selection and recognition, as well as the asymmetry of charge selectivity at the binding interface of biomolecular systems. The charge complementarity and selectivity profiles map relevant electrostatic properties in a readily interpretable way and encode information that is quite different from that visualized in the standard electrostatic potential map of unbound proteins.

Validity of a Smartphone-Based Fall Detection Application on Different Phones Worn on a Belt or in a Trouser Pocket.

PubMed

Vermeulen, Joan; Willard, Sarah; Aguiar, Bruno; De Witte, Luc P

2015-01-01

The objective of this study was to evaluate the sensitivity and specificity of a smartphone-based fall detection application when different smartphone models are worn on a belt or in a trouser pocket. Eight healthy adults aged between 18 and 24 years old simulated 10 different types of true falls, 5 different types of falls with recovery, and 11 daily activities, five consecutive times. Participants wore one smartphone in a pocket that was attached to their belt and another one in their trouser pocket. All smartphones were equipped with a built-in accelerometer and the fall detection application. Four participants tested the application on a Samsung S3 and four tested the application on a Samsung S3 mini. Sensitivity scores were .75 (Samsung S3 belt), .88 (Samsung S3 mini trouser pocket), and .90 (Samsung S3 mini belt/Samsung S3 trouser pocket). Specificity scores were .87 (Samsung S3 trouser pocket), .91 (Samsung S3 mini trouser pocket), .97 (Samsung S3 belt), and .99 (Samsung S3 mini belt). These results suggest that an application on a smartphone can generate valid fall alarms when worn on a belt or in a trouser pocket. However, sensitivity should be improved before implementation of the application in practice.

Is it the shape of the cavity, or the shape of the water in the cavity?

NASA Astrophysics Data System (ADS)

Snyder, Phillip W.; Lockett, Matthew R.; Moustakas, Demetri T.; Whitesides, George M.

2014-04-01

Historical interpretations of the thermodynamics characterizing biomolecular recognition have marginalized the role of water. An important (even, perhaps, dominant) contribution to molecular recognition in water comes from the "hydrophobic effect," in which non-polar portions of a ligand interact preferentially with non-polar regions of a protein. Water surrounds the ligand, and water fills the binding pocket of the protein: when the protein-ligand complex forms, and hydrophobic surfaces of the binding pocket and the ligand approach one another, the molecules (and hydrogen-bonded networks of molecules) of water associated with both surfaces rearrange and, in part, entirely escape into the bulk solution. It is now clear that neither of the two most commonly cited rationalizations for the hydrophobic effect-an entropy-dominated hydrophobic effect, in which ordered waters at the surface of the ligand, and water at the surface of the protein, are released to the bulk upon binding, and a "lock-and-key" model, in which the surface of a ligand interacts directly with a surface of a protein having a complementary shape-can account for water-mediated interactions between the ligand and the protein, and neither is sufficient to account for the experimental observation of both entropy- andenthalpy-dominated hydrophobic effects. What is now clear is that there is no single hydrophobic effect, with a universally applicable, common, thermodynamic description: different processes (i.e., partitioning between phases of different hydrophobicity, aggregation in water, and binding) with different thermodynamics, depend on the molecular-level details of the structures of the molecules involved, and of the aggregates that form. A "water-centric" description of the hydrophobic effect in biomolecular recognition focuses on the structures of water surrounding the ligand, and of water filling the binding pocket of the protein, both before and after binding. This view attributes the hydrophobic effect to changes in the free energy of the networks of hydrogen bonds that are formed, broken, or re-arranged when two hydrophobic surfaces approach (but do not necessarily contact) one another. The details of the molecular topography (and the polar character) of the mole- cular surfaces play an important role in determining the structure of these networks of hydrogen-bonded waters, and in the thermodynamic description of the hydrophobic effect(s). Theorists have led the formulation of this "water-centric view", although experiments are now supplying support for it. It poses complex problems for would-be "designers" of protein-ligand interactions, and for so-called "rational drug design".

Data transmission element for downhole drilling components

DOEpatents

Hall, David R.; Hall, Jr., H. Tracy; Pixton, David S.; Dahlgren, Scott; Fox, Joe; Sneddon, Cameron; Briscoe, Michael

2006-01-31

A robust data transmission element for transmitting information between downhole components, such as sections of drill pipe, in the presence of hostile environmental conditions, such as heat, dirt, rocks, mud, fluids, lubricants, and the like. The data transmission element components include a generally U-shaped annular housing, a generally U-shaped magnetically conductive, electrically insulating element such as ferrite, and an insulated conductor. Features on the magnetically conducting, electrically insulating element and the annular housing create a pocket when assembled. The data transmission element is filled with a polymer to retain the components within the annular housing by filling the pocket with the polymer. The polymer can bond with the annular housing and the insulated conductor but preferably not the magnetically conductive, electrically insulating element. A data transmission element is mounted within a recess proximate a mating surface of a downhole drilling component, such as a section of drill pipe.

SVM prediction of ligand-binding sites in bacterial lipoproteins employing shape and physio-chemical descriptors.

PubMed

Kadam, Kiran; Prabhakar, Prashant; Jayaraman, V K

2012-11-01

Bacterial lipoproteins play critical roles in various physiological processes including the maintenance of pathogenicity and numbers of them are being considered as potential candidates for generating novel vaccines. In this work, we put forth an algorithm to identify and predict ligand-binding sites in bacterial lipoproteins. The method uses three types of pocket descriptors, namely fpocket descriptors, 3D Zernike descriptors and shell descriptors, and combines them with Support Vector Machine (SVM) method for the classification. The three types of descriptors represent shape-based properties of the pocket as well as its local physio-chemical features. All three types of descriptors, along with their hybrid combinations are evaluated with SVM and to improve classification performance, WEKA-InfoGain feature selection is applied. Results obtained in the study show that the classifier successfully differentiates between ligand-binding and non-binding pockets. For the combination of three types of descriptors, 10 fold cross-validation accuracy of 86.83% is obtained for training while the selected model achieved test Matthews Correlation Coefficient (MCC) of 0.534. Individually or in combination with new and existing methods, our model can be a very useful tool for the prediction of potential ligand-binding sites in bacterial lipoproteins.

SELF-CENTERING POSITIVE LOCKING GRAPNEL

DOEpatents

Hopper, C.G.

1961-07-01

A grapnel used for remotely securing a load to be hoisted is described. The grapnel of the invention is generally conical in shape with a plurality of semi-open bores laterally disposed about the device. The bores meet at the apex of the grapnel and there provde a securing pocket for a spherical member. A load provided with a rigid support rod having a spherical member at its end can be secured by directing the spherical member down one of the bores and into the securing pocket. The major advantsges of the invention reside in the self- centering and positive locking features.

Profiling Charge Complementarity and Selectivity for Binding at the Protein Surface

PubMed Central

Sulea, Traian; Purisima, Enrico O.

2003-01-01

A novel analysis and representation of the protein surface in terms of electrostatic binding complementarity and selectivity is presented. The charge optimization methodology is applied in a probe-based approach that simulates the binding process to the target protein. The molecular surface is color coded according to calculated optimal charge or according to charge selectivity, i.e., the binding cost of deviating from the optimal charge. The optimal charge profile depends on both the protein shape and charge distribution whereas the charge selectivity profile depends only on protein shape. High selectivity is concentrated in well-shaped concave pockets, whereas solvent-exposed convex regions are not charge selective. This suggests the synergy of charge and shape selectivity hot spots toward molecular selection and recognition, as well as the asymmetry of charge selectivity at the binding interface of biomolecular systems. The charge complementarity and selectivity profiles map relevant electrostatic properties in a readily interpretable way and encode information that is quite different from that visualized in the standard electrostatic potential map of unbound proteins. PMID:12719221

Correction of hyperopia by intrastromal cutting and biocompatible filler injection (Conference Presentation)

NASA Astrophysics Data System (ADS)

Freidank, Sebastian; Vogel, Alfred; Anderson, Richard R.; Birngruber, Reginald; Linz, Norbert

2017-02-01

For ametropic eyes, LASIK is a common surgical procedure to correct the refractive error. However, the correction of hyperopia is more difficult than that of myopia because the increase of the central corneal curvature by excimer ablation is only possible by intrastromal tissue removal within a ring-like zone in the corneal periphery. For high hyperopia, the ring-shaped indentation leads to problems with the stability and reproducibility of the correction due to epithelial regrowth. Recently, it was shown that the correction of hyperopia can be achieved by implanting intracorneal inlays into a laser-dissected intrastromal pocket. In this paper we demonstrate the feasibility of a new approach in which a transparent, and biocompatible liquid filler material is injected into a laser-dissected corneal pocket, and the refractive change is monitored via OCT. This technique allows for a precise and adjustable change of the corneal curvature. Precise cutting of the intrastromal pocket was achieved by focusing UV laser picosecond pulses from a microchip laser system into the cornea. After laser dissection, the transparent filler material was injected into the pocket. The increase of the refractive power by filler injection was evaluated by taking OCT images from the cornea. With this novel technique, it is possible to precisely correct hyperopia of up to 10 diopters. An astigmatism correction is also possible by using ellipsoidal intrastromal pockets.

Observation of topological nodal fermion semimetal phase in ZrSiS

DOE PAGES

Neupane, Madhab; Belopolski, Ilya; Hosen, M. Mofazzel; ...

2016-05-11

We present that unveiling new topological phases of matter is one of the current objectives in condensed matter physics. Recent experimental discoveries of Dirac and Weyl semimetals prompt the search for other exotic phases of matter. Here we present a systematic angle-resolved photoemission spectroscopy study of ZrSiS, a prime topological nodal semimetal candidate. Our wider Brillouin zone (BZ) mapping shows multiple Fermi surface pockets such as the diamond-shaped Fermi surface, elliptical-shaped Fermi surface, and a small electron pocket encircling at the zone center (Γ) point, the M point, and the X point of the BZ, respectively. We experimentally establish themore » spinless nodal fermion semimetal phase in ZrSiS, which is supported by our first-principles calculations. Our findings evidence that the ZrSiS-type of material family is a new platform on which to explore exotic states of quantum matter; these materials are expected to provide an avenue for engineering two-dimensional topological insulator systems.« less

Large-scale binding ligand prediction by improved patch-based method Patch-Surfer2.0

PubMed Central

Zhu, Xiaolei; Xiong, Yi; Kihara, Daisuke

2015-01-01

Motivation: Ligand binding is a key aspect of the function of many proteins. Thus, binding ligand prediction provides important insight in understanding the biological function of proteins. Binding ligand prediction is also useful for drug design and examining potential drug side effects. Results: We present a computational method named Patch-Surfer2.0, which predicts binding ligands for a protein pocket. By representing and comparing pockets at the level of small local surface patches that characterize physicochemical properties of the local regions, the method can identify binding pockets of the same ligand even if they do not share globally similar shapes. Properties of local patches are represented by an efficient mathematical representation, 3D Zernike Descriptor. Patch-Surfer2.0 has significant technical improvements over our previous prototype, which includes a new feature that captures approximate patch position with a geodesic distance histogram. Moreover, we constructed a large comprehensive database of ligand binding pockets that will be searched against by a query. The benchmark shows better performance of Patch-Surfer2.0 over existing methods. Availability and implementation: http://kiharalab.org/patchsurfer2.0/ Contact: dkihara@purdue.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25359888

Form and deformity: the trouble with Victorian pockets.

PubMed

Matthews, Christopher Todd

2010-01-01

This essay explores the Victorian debate about the place of pockets in men's and women's clothing. By studying the representation of men as naturally pocketed creatures and the general denial of useful pockets to middle-class women, the essay demonstrates the tenacious cultural logic by which men's and women's pockets were imagined to correspond to sexual differences and to index access, or lack thereof, to public mobility and financial agency. Interconnected readings of visual art, essays, and novels show how the common sense about gendered pockets was utilized and promulgated in Victorian narratives. The question of who gets pockets is thus positioned as part of the history of gendered bodies in public space.

Monte Carlo modeling of the MammoSite(Reg) treatments: Dose effects of air pockets

NASA Astrophysics Data System (ADS)

Huang, Yu-Huei Jessica

In the treatment of early-stage breast cancer, MammoSiteRTM has been used as one of the partial breast irradiation techniques after breast-conserving surgery. The MammoSiteRTM applicator is a single catheter with an inflatable balloon at its distal end that can be placed in the resected cavity (tumor bed). The treatment is performed by delivering the Ir-192 high-dose-rate source through the center lumen of the catheter by a remote afterloader while the balloon is inflated in the tumor bed cavity. In the MammoSiteRTM treatment, it has been found that air pockets occasionally exist and can be seen and measured in CT images. Experiences have shown that about 90% of the patients have air pockets when imaged two days after the balloon placement. The criterion for the air pocket volume is less than or equal to 10% of the planning target volume in volume. The purpose of this study is to quantify dose errors occurring at the interface of the air pocket in MammoSiteRTM treatments with Monte Carlo calculations, so that the dosimetric effects from the air pocket can be fully understood. Modern brachytherapy treatment planning systems typically consider patient anatomy as a homogeneous water medium, and incorrectly model lateral and backscatter radiation during treatment delivery. Heterogeneities complicate the problem and may result in overdosage to the tissue located near the medium interface. This becomes a problem in MammoSiteRTM brachytherapy when air pocket appears during the treatment. The resulting percentage dose difference near the air-tissue interface is hypothesized to be greater than 10% when comparing Monte Carlo N-Particle (version 5) with current treatment planning systems. The specific aims for this study are: (1) Validate Monte Carlo N-Particle (Version 5) source modeling. (2) Develop phantom. (3) Calculate phantom doses with Monte Carlo N-Particle (Version 5) and investigate doses difference between thermoluminescent dosimeter measurement, treatment planning system, and Monte Carlo results. (4) Calculate dose differences for various treatment parameters. The results from thermoliminescent dosimeter phantom measurements proves that with correct geometric and source models, Monte Carlo method can be used to estimate homogeneity and heterogeneity doses in MammoSiteRTM treatment. The resulting dose differences at various points of interests in Monte Carlo calculations were presented and compared between different calculation methods. The air pocket doses were found to be underestimated by the treatment planning system. It was concluded that after correcting for inverse square law, the underestimation error from the treatment planning system will be less than +/- 2.0%, and +/- 3.5%, at the air pocket surface and air pocket planning target volume, respectively, when comparing Monte Carlo N-Particle (version 5) results. If the skin surface is located close to the air pocket, the underestimation effect at the air pocket surface and air pocket planning target volume doses becomes less because the air outside of the skin surface reduces the air pocket inhomogeneity effect. In order to maintain appropriate skin dose within tolerance, the skin surface criterion should be considered as the smallest thickness of the breast tissue located between the air pocket and the skin surface. The thickness should be at least 5 mm. In conclusion, the air pocket outside the balloon had less than 10% inhomogeneity effect based on the situations studied. It is recommended that at least an inverse square correction should be taken into consideration in order to relate clinical outcomes to actual delivered doses to the air pocket and surrounding tissues.

Structural, Functional, and Genetic Analysis of Sorangicin Inhibition of Bacterial RNA Polymerase

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

Campbell,E.; Pavlova, O.; Zenkin, N.

2005-01-01

A combined structural, functional, and genetic approach was used to investigate inhibition of bacterial RNA polymerase (RNAP) by sorangicin (Sor), a macrolide polyether antibiotic. Sor lacks chemical and structural similarity to the ansamycin rifampicin (Rif), an RNAP inhibitor widely used to treat tuberculosis. Nevertheless, structural analysis revealed Sor binds in the same RNAP {beta} subunit pocket as Rif, with almost complete overlap of RNAP binding determinants, and functional analysis revealed that both antibiotics inhibit transcription by directly blocking the path of the elongating transcript at a length of 2-3 nucleotides. Genetic analysis indicates that Rif binding is extremely sensitive tomore » mutations expected to change the shape of the antibiotic binding pocket, while Sor is not. We suggest that conformational flexibility of Sor, in contrast to the rigid conformation of Rif, allows Sor to adapt to changes in the binding pocket. This has important implications for drug design against rapidly mutating targets.« less

Electronic band structure study of colossal magnetoresistance in Tl 2Mn 2O 7

NASA Astrophysics Data System (ADS)

Seo, D.-K.; Whangbo, M.-H.; Subramanian, M. A.

1997-02-01

The electronic structure of Tl 2Mn 2O 7 was examined by performing tight binding band calculations. The overlap between the Mn t 2g- and Tl 6 s-block bands results in a partial filling of the Tl 6 s-block bands. The associated Fermi surface consists of 12 cigar-shape electron pockets with each electron pocket about {1}/{1000} of the first Brillouin zone in size. The Tl 6 s-block bands have orbital contributions from the Mn atoms, and the carrier density is very low. These are important for the occurrence of a colossal magnetoresistance in Tl 2Mn 2O 7.

PatchSurfers: Two methods for local molecular property-based binding ligand prediction.

PubMed

Shin, Woong-Hee; Bures, Mark Gregory; Kihara, Daisuke

2016-01-15

Protein function prediction is an active area of research in computational biology. Function prediction can help biologists make hypotheses for characterization of genes and help interpret biological assays, and thus is a productive area for collaboration between experimental and computational biologists. Among various function prediction methods, predicting binding ligand molecules for a target protein is an important class because ligand binding events for a protein are usually closely intertwined with the proteins' biological function, and also because predicted binding ligands can often be directly tested by biochemical assays. Binding ligand prediction methods can be classified into two types: those which are based on protein-protein (or pocket-pocket) comparison, and those that compare a target pocket directly to ligands. Recently, our group proposed two computational binding ligand prediction methods, Patch-Surfer, which is a pocket-pocket comparison method, and PL-PatchSurfer, which compares a pocket to ligand molecules. The two programs apply surface patch-based descriptions to calculate similarity or complementarity between molecules. A surface patch is characterized by physicochemical properties such as shape, hydrophobicity, and electrostatic potentials. These properties on the surface are represented using three-dimensional Zernike descriptors (3DZD), which are based on a series expansion of a 3 dimensional function. Utilizing 3DZD for describing the physicochemical properties has two main advantages: (1) rotational invariance and (2) fast comparison. Here, we introduce Patch-Surfer and PL-PatchSurfer with an emphasis on PL-PatchSurfer, which is more recently developed. Illustrative examples of PL-PatchSurfer performance on binding ligand prediction as well as virtual drug screening are also provided. Copyright © 2015 Elsevier Inc. All rights reserved.

Exploring the reversal of enantioselectivity on a zinc-dependent alcohol dehydrogenase† †Electronic supplementary information (ESI) available. See DOI: 10.1039/C7OB00482F Click here for additional data file.

PubMed Central

Maria-Solano, Miguel A.; Romero-Rivera, Adrian

2017-01-01

Alcohol Dehydrogenase (ADH) enzymes catalyse the reversible reduction of prochiral ketones to the corresponding alcohols. These enzymes present two differently shaped active site pockets, which dictate their substrate scope and selectivity. In this study, we computationally evaluate the effect of two commonly reported active site mutations (I86A, and W110T) on a secondary alcohol dehydrogenase from Thermoanaerobacter brockii (TbSADH) through Molecular Dynamics simulations. Our results indicate that the introduced mutations induce dramatic changes in the shape of the active site, but most importantly they impact the substrate–enzyme interactions. We demonstrate that the combination of Molecular Dynamics simulations with the tools POVME and NCIplot corresponds to a powerful strategy for rationalising and engineering the stereoselectivity of ADH variants. PMID:28436515

Ultra-High-Throughput Structure-Based Virtual Screening for Small-Molecule Inhibitors of Protein-Protein Interactions

PubMed Central

Johnson, David K.; Karanicolas, John

2016-01-01

Protein-protein interactions play important roles in virtually all cellular processes, making them enticing targets for modulation by small-molecule therapeutics: specific examples have been well validated in diseases ranging from cancer and autoimmune disorders, to bacterial and viral infections. Despite several notable successes, however, overall these remain a very challenging target class. Protein interaction sites are especially challenging for computational approaches, because the target protein surface often undergoes a conformational change to enable ligand binding: this confounds traditional approaches for virtual screening. Through previous studies, we demonstrated that biased “pocket optimization” simulations could be used to build collections of low-energy pocket-containing conformations, starting from an unbound protein structure. Here, we demonstrate that these pockets can further be used to identify ligands that complement the protein surface. To do so, we first build from a given pocket its “exemplar”: a perfect, but non-physical, pseudo-ligand that would optimally match the shape and chemical features of the pocket. In our previous studies, we used these exemplars to quantitatively compare protein surface pockets to one another. Here, we now introduce this exemplar as a template for pharmacophore-based screening of chemical libraries. Through a series of benchmark experiments, we demonstrate that this approach exhibits comparable performance as traditional docking methods for identifying known inhibitors acting at protein interaction sites. However, because this approach is predicated on ligand/exemplar overlays, and thus does not require explicit calculation of protein-ligand interactions, exemplar screening provides a tremendous speed advantage over docking: 6 million compounds can be screened in about 15 minutes on a single 16-core, dual-GPU computer. The extreme speed at which large compound libraries can be traversed easily enables screening against a “pocket-optimized” ensemble of protein conformations, which in turn facilitates identification of more diverse classes of active compounds for a given protein target. PMID:26726827

The Role of the Acid Pocket in Gastroesophageal Reflux Disease.

PubMed

Mitchell, David R; Derakhshan, Mohammad H; Robertson, Elaine V; McColl, Kenneth E L

2016-02-01

Gastroesophageal reflux disease is one of the commonest chronic conditions in the western world and its prevalence is increasing worldwide. The discovery of the acid pocket explained the paradox of acid reflux occurring more frequently in the postprandial period despite intragastric acidity being low due to the buffering effect of the meal. The acid pocket was first described in 2001 when it was detected as an area of low pH immediately distal to the cardia using dual pH electrode pull-through studies 15 minutes after a meal. It was hypothesized that there was a local pocket of acid close to the gastroesophageal junction that escapes the buffering effect of the meal, and that this is the source of postprandial acidic reflux. The presence of the acid pocket has been confirmed in other studies using different techniques including high-resolution pHmetry, Bravo capsule, magnetic resonance imaging, and scintigraphy. This review aims to describe what we know about the acid pocket including its length, volume, fluid constituents, and its relationship to the lower esophageal sphincter and squamocolumnar junction. We will discuss the possible mechanisms that lead to the formation of the acid pocket and examine what differences exist in patients who suffer from acid reflux. Treatments for reflux disease that affect the acid pocket will also be discussed.

Interplay between Magnetism, Superconductivity, and Orbital Order in 5-Pocket Model for Iron-Based Superconductors: Parquet Renormalization Group Study.

PubMed

Classen, Laura; Xing, Rui-Qi; Khodas, Maxim; Chubukov, Andrey V

2017-01-20

We report the results of the parquet renormalization group (RG) analysis of the phase diagram of the most general 5-pocket model for Fe-based superconductors. We use as an input the orbital structure of excitations near the five pockets made out of d_{xz}, d_{yz}, and d_{xy} orbitals and argue that there are 40 different interactions between low-energy fermions in the orbital basis. All interactions flow under the RG, as one progressively integrates out fermions with higher energies. We find that the low-energy behavior is amazingly simple, despite the large number of interactions. Namely, at low energies the full 5-pocket model effectively reduces either to a 3-pocket model made of one d_{xy} hole pocket and two electron pockets or a 4-pocket model made of two d_{xz}/d_{yz} hole pockets and two electron pockets. The leading instability in the effective 4-pocket model is a spontaneous orbital (nematic) order, followed by s^{+-} superconductivity. In the effective 3-pocket model, orbital fluctuations are weaker, and the system develops either s^{+-} superconductivity or a stripe spin-density wave. In the latter case, nematicity is induced by composite spin fluctuations.

Free enthalpies of replacing water molecules in protein binding pockets.

PubMed

Riniker, Sereina; Barandun, Luzi J; Diederich, François; Krämer, Oliver; Steffen, Andreas; van Gunsteren, Wilfred F

2012-12-01

Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate the displacement of water molecules by an apolar probe in the binding pocket of two proteins, cyclin-dependent kinase 2 and tRNA-guanine transglycosylase, using the method of enveloping distribution sampling (EDS) to obtain free enthalpy differences. In both cases, a ligand core is placed inside the respective pocket and the remaining water molecules are converted to apolar probes, both individually and in pairs. The free enthalpy difference between a water molecule and a CH(3) group at the same location in the pocket in comparison to their presence in bulk solution calculated from EDS molecular dynamics simulations corresponds to the binding free enthalpy of CH(3) at this location. From the free enthalpy difference and the enthalpy difference, the entropic contribution of the displacement can be obtained too. The overlay of the resulting occupancy volumes of the water molecules with crystal structures of analogous ligands shows qualitative correlation between experimentally measured inhibition constants and the calculated free enthalpy differences. Thus, such an EDS analysis of the water molecules in the binding pocket may give valuable insight for potency optimization in drug design.

Free enthalpies of replacing water molecules in protein binding pockets

NASA Astrophysics Data System (ADS)

Riniker, Sereina; Barandun, Luzi J.; Diederich, François; Krämer, Oliver; Steffen, Andreas; van Gunsteren, Wilfred F.

2012-12-01

Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate the displacement of water molecules by an apolar probe in the binding pocket of two proteins, cyclin-dependent kinase 2 and tRNA-guanine transglycosylase, using the method of enveloping distribution sampling (EDS) to obtain free enthalpy differences. In both cases, a ligand core is placed inside the respective pocket and the remaining water molecules are converted to apolar probes, both individually and in pairs. The free enthalpy difference between a water molecule and a CH3 group at the same location in the pocket in comparison to their presence in bulk solution calculated from EDS molecular dynamics simulations corresponds to the binding free enthalpy of CH3 at this location. From the free enthalpy difference and the enthalpy difference, the entropic contribution of the displacement can be obtained too. The overlay of the resulting occupancy volumes of the water molecules with crystal structures of analogous ligands shows qualitative correlation between experimentally measured inhibition constants and the calculated free enthalpy differences. Thus, such an EDS analysis of the water molecules in the binding pocket may give valuable insight for potency optimization in drug design.

Carbon monoxide recombination dynamics in truncated hemoglobins studied with visible-pump midIR-probe spectroscopy.

PubMed

Lapini, Andrea; Di Donato, Mariangela; Patrizi, Barbara; Marcelli, Agnese; Lima, Manuela; Righini, Roberto; Foggi, Paolo; Sciamanna, Natascia; Boffi, Alberto

2012-08-02

Carbon monoxide recombination dynamics upon photodissociation with visible light has been characterized by means of ultrafast visible-pump/MidIR probe spectroscopy for the truncated hemoglobins from Thermobifida fusca and Bacillus subtilis. Photodissociation has been induced by exciting the sample at two different wavelengths: 400 nm, corresponding to the heme absorption in the B-band, and 550 nm, in the Q-bands. The bleached iron-CO coordination band located at 1850-1950 cm(-1) and the free CO absorption band in the region 2050-2200 cm(-1) have been observed by probe pulses tuned in the appropriate infrared region. The kinetic traces measured at 1850-1950 cm(-1) reveal multiexponential subnanosecond dynamics that have been interpreted as arising from fast geminate recombination of the photolyzed CO. A compared analysis of the crystal structure of the two proteins reveals a similar structure of their distal heme pocket, which contains conserved polar and aromatic amino acid residues closely interacting with the iron ligand. Although fast geminate recombination is observed in both proteins, several kinetic differences can be evidenced, which can be interpreted in terms of a different structural flexibility of the corresponding heme distal pockets. The analysis of the free CO band-shape and of its dynamic evolution brings out novel features about the nature of the docking site inside the protein cavity.

Defending against parasites: fungus-growing ants combine specialized behaviours and microbial symbionts to protect their fungus gardens

PubMed Central

Little, Ainslie E.F; Murakami, Takahiro; Mueller, Ulrich G; Currie, Cameron R

2005-01-01

Parasites influence host biology and population structure, and thus shape the evolution of their hosts. Parasites often accelerate the evolution of host defences, including direct defences such as evasion and sanitation and indirect defences such as the management of beneficial microbes that aid in the suppression or removal of pathogens. Fungus-growing ants are doubly burdened by parasites, needing to protect their crops as well as themselves from infection. We show that parasite removal from fungus gardens is more complex than previously realized. In response to infection of their fungal gardens by a specialized virulent parasite, ants gather and compress parasitic spores and hyphae in their infrabuccal pockets, then deposit the resulting pellet in piles near their gardens. We reveal that the ants' infrabuccal pocket functions as a specialized sterilization device, killing spores of the garden parasite Escovopsis. This is apparently achieved through a symbiotic association with actinomycetous bacteria in the infrabuccal pocket that produce antibiotics which inhibit Escovopsis. The use of the infrabuccal pocket as a receptacle to sequester Escovopsis, and as a location for antibiotic administration by the ants' bacterial mutualist, illustrates how the combination of behaviour and microbial symbionts can be a successful defence strategy for hosts. PMID:17148313

Defending against parasites: fungus-growing ants combine specialized behaviours and microbial symbionts to protect their fungus gardens.

PubMed

Little, Ainslie E F; Murakami, Takahiro; Mueller, Ulrich G; Currie, Cameron R

2006-03-22

Parasites influence host biology and population structure, and thus shape the evolution of their hosts. Parasites often accelerate the evolution of host defences, including direct defences such as evasion and sanitation and indirect defences such as the management of beneficial microbes that aid in the suppression or removal of pathogens. Fungus-growing ants are doubly burdened by parasites, needing to protect their crops as well as themselves from infection. We show that parasite removal from fungus gardens is more complex than previously realized. In response to infection of their fungal gardens by a specialized virulent parasite, ants gather and compress parasitic spores and hyphae in their infrabuccal pockets, then deposit the resulting pellet in piles near their gardens. We reveal that the ants' infrabuccal pocket functions as a specialized sterilization device, killing spores of the garden parasite Escovopsis. This is apparently achieved through a symbiotic association with actinomycetous bacteria in the infrabuccal pocket that produce antibiotics which inhibit Escovopsis. The use of the infrabuccal pocket as a receptacle to sequester Escovopsis, and as a location for antibiotic administration by the ants' bacterial mutualist, illustrates how the combination of behaviour and microbial symbionts can be a successful defence strategy for hosts.

Large-scale binding ligand prediction by improved patch-based method Patch-Surfer2.0.

PubMed

Zhu, Xiaolei; Xiong, Yi; Kihara, Daisuke

2015-03-01

Ligand binding is a key aspect of the function of many proteins. Thus, binding ligand prediction provides important insight in understanding the biological function of proteins. Binding ligand prediction is also useful for drug design and examining potential drug side effects. We present a computational method named Patch-Surfer2.0, which predicts binding ligands for a protein pocket. By representing and comparing pockets at the level of small local surface patches that characterize physicochemical properties of the local regions, the method can identify binding pockets of the same ligand even if they do not share globally similar shapes. Properties of local patches are represented by an efficient mathematical representation, 3D Zernike Descriptor. Patch-Surfer2.0 has significant technical improvements over our previous prototype, which includes a new feature that captures approximate patch position with a geodesic distance histogram. Moreover, we constructed a large comprehensive database of ligand binding pockets that will be searched against by a query. The benchmark shows better performance of Patch-Surfer2.0 over existing methods. http://kiharalab.org/patchsurfer2.0/ CONTACT: dkihara@purdue.edu Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Haptics using a smart material for eyes-free interaction in personal devices

NASA Astrophysics Data System (ADS)

Wang, Huihui; Lane, William Brian; Pappas, Devin; Duque, Bryam; Leong, John

2014-03-01

In this paper we present a prototype using a dry ionic polymer metal composite (IPMC) in interactive personal devices such as bracelet, necklace, pocket key chain or mobile devices for haptic interaction when audio or visual feedback is not possible or practical. This prototype interface is an electro-mechanical system that realizes a shape-changing haptic display for information communication. A dry IPMC will change its dimensions due to the electrostatic effect when an electrical potential is provided to them. The IPMC can operate at a lower voltage (less than 2.5V) which is compatible with requirements for personal electrical devices or mobile devices. The prototype consists of the addressable arrays of the IPMCs with different dimensions which are deformable to different shapes with proper handling or customization. 3D printing technology will be used to form supporting parts. Microcontrollers (about 3cm square) from DigiKey will be imbedded into this personal device. An Android based mobile APP will be developed to talk with microcontrollers to control IPMCs. When personal devices receive information signals, the original shape of the prototype will change to another shape related to the specific sender or types of information sources. This interactive prototype can simultaneously realize multiple methods for conveying haptic information such as dimension, force, and texture due to the flexible array design. We conduct several studies of user experience to explore how users' respond to shape change information.

A new mechanism of failure on polymers

NASA Technical Reports Server (NTRS)

Fedors, R. F.

1974-01-01

Transparent laminates containing imbedded crystals of various ionic and nonionic substances were prepared and their swelling in distilled water was observed. It was found that under certain conditions, disk-shaped cracks formed around the swollen pockets containing a dissolving crystal. Such cracks can form before equilibrium swelling is reached and may severely damage the elastomer.

Structure of spin excitations in heavily electron-doped Li 0.8Fe 0.2ODFeSe superconductors

DOE PAGES

Pan, Bingying; Shen, Yao; Hu, Die; ...

2017-07-25

Heavily electron-doped iron-selenide high-transition-temperature (high-T c) superconductors, which have no hole Fermi pockets, but have a notably high T c, have challenged the prevailing s± pairing scenario originally proposed for iron pnictides containing both electron and hole pockets. The microscopic mechanism underlying the enhanced superconductivity in heavily electron-doped iron-selenide remains unclear. Here, we used neutron scattering to study the spin excitations of the heavily electron-doped iron-selenide material Li 0.8Fe 0.2ODFeSe (T c = 41 K). Our data revealed nearly ring-shaped magnetic resonant excitations surrounding (π, π) at ~21 meV. As the energy increased, the spin excitations assumed a diamond shape,more » and they dispersed outward until the energy reached ~60 meV and then inward at higher energies. The observed energy-dependent momentum structure and twisted dispersion of spin excitations near (π, π) are analogous to those of hole-doped cuprates in several aspects, thus implying that such spin excitations are essential for the remarkably high T c in these materials.« less

Mental health care and out-of-pocket expenditures in Europe: results from the ESEMeD project.

PubMed

Sevilla-Dedieu, Christine; Kovess-Masfety, Viviane; Gilbert, Fabien; Vilagut, Gemma; Koenig, Hans-Helmut; Bruffaerts, Ronny; Haro, Josep Maria; Alonso, Jordi

2011-06-01

Most published data on out-of-pocket spending on mental health originate from the United States, where insurance payments for mental health have traditionally been much less generous than benefits for other health care services. Given the difference in the structure of health care funding in Europe, it is clearly important to obtain similar information on out-of-pocket expenditure in different European countries. To estimate out-of-pocket costs paid by people who receive mental health care in six European countries (Belgium, France, Germany, Italy, the Netherlands, and Spain). Of the 8,796 participants in a cross-sectional survey conducted in these six European countries, 1,128 reported having consulted a professional for a mental health problem in the year preceding the interview and provided information on how many times in the past year they consulted each type of provider, and the money they and their family members had paid out-of-pocket for their mental health care. In addition to sociodemographic characteristics, information on mental health status was collected using the CIDI 3.0. Descriptive statistics on out-of-pocket expenditure and share of income across countries were generated. Two-part models were employed to identify the relationship between the different covariates, notably the types of providers consulted, and out-of-pocket expenditure. Overall, 41.0% of those who used services for a mental health problem paid something for the care they received. This represented a minority of respondents in all countries except Belgium (87.9%) and Italy (61.7%). The financial burden of these costs relative to income was found to be low (1.2%), ranging from 0.4% in Germany to 2.3% in France. Out-of-pocket expenditure differed according to the type of providers consulted, with non-physician health professionals and medical specialists being more often associated with significant expenditure. Although the study is limited principally by data collection from self-report, it is the first of its kind, to our knowledge, and suggests that out-of-pocket costs for mental health care in Europe are relatively low compared to the United States. However, differences between countries exist, which may be partially due to differences in coverage for specialized care. Consultations with non-physician mental health professionals such as psychologists are expensive for patients, since they are reimbursed to a lesser extent than consultations with physicians, or not reimbursed at all. This limits their role and increases the burden on psychiatrists. Monitoring out-of-pocket spending on mental health, preferably on the basis of administrative data when available, is essential in the current context of cost containment policy, where out-of-pocket spending may be expected to increase.

A salt bridge turns off the foot-pocket in class-II HDACs.

PubMed

Zhou, Jingwei; Yang, Zuolong; Zhang, Fan; Luo, Hai-Bin; Li, Min; Wu, Ruibo

2016-08-21

Histone Deacetylases (HDACs) are promising anticancer targets and several selective inhibitors have been created based on the architectural differences of foot-pockets among HDACs. However, the "gate-keeper" of foot-pockets is still controversial. Herein, it is for the first time revealed that a conserved R-E salt bridge plays a critical role in keeping foot-pockets closed in class-II HDACs by computational simulations. This finding is further substantiated by our mutagenesis experiments.

Geometric measures of large biomolecules: surface, volume, and pockets.

PubMed

Mach, Paul; Koehl, Patrice

2011-11-15

Geometry plays a major role in our attempts to understand the activity of large molecules. For example, surface area and volume are used to quantify the interactions between these molecules and the water surrounding them in implicit solvent models. In addition, the detection of pockets serves as a starting point for predictive studies of biomolecule-ligand interactions. The alpha shape theory provides an exact and robust method for computing these geometric measures. Several implementations of this theory are currently available. We show however that these implementations fail on very large macromolecular systems. We show that these difficulties are not theoretical; rather, they are related to the architecture of current computers that rely on the use of cache memory to speed up calculation. By rewriting the algorithms that implement the different steps of the alpha shape theory such that we enforce locality, we show that we can remediate these cache problems; the corresponding code, UnionBall has an apparent O(n) behavior over a large range of values of n (up to tens of millions), where n is the number of atoms. As an example, it takes 136 sec with UnionBall to compute the contribution of each atom to the surface area and volume of a viral capsid with more than five million atoms on a commodity PC. UnionBall includes functions for computing analytically the surface area and volume of the intersection of two, three and four spheres that are fully detailed in an appendix. UnionBall is available as an OpenSource software. Copyright © 2011 Wiley Periodicals, Inc.

Geometric Measures of Large Biomolecules: Surface, Volume and Pockets

PubMed Central

Mach, Paul; Koehl, Patrice

2011-01-01

Geometry plays a major role in our attempt to understand the activity of large molecules. For example, surface area and volume are used to quantify the interactions between these molecules and the water surrounding them in implicit solvent models. In addition, the detection of pockets serves as a starting point for predictive studies of biomolecule-ligand interactions. The alpha shape theory provides an exact and robust method for computing these geometric measures. Several implementations of this theory are currently available. We show however that these implementations fail on very large macromolecular systems. We show that these difficulties are not theoretical; rather, they are related to the architecture of current computers that rely on the use of cache memory to speed up calculation. By rewriting the algorithms that implement the different steps of the alpha shape theory such that we enforce locality, we show that we can remediate these cache problems; the corresponding code, UnionBall has an apparent (n) behavior over a large range of values of n (up to tens of millions), where n is the number of atoms. As an example, it takes 136 seconds with UnionBall to compute the contribution of each atom to the surface area and volume of a viral capsid with more than five million atoms on a commodity PC. UnionBall includes functions for computing the surface area and volume of the intersection of two, three and four spheres that are fully detailed in an appendix. UnionBall is available as an OpenSource software. PMID:21823134

Work of Breathing into Snow in the Presence versus Absence of an Artificial Air Pocket Affects Hypoxia and Hypercapnia of a Victim Covered with Avalanche Snow: A Randomized Double Blind Crossover Study.

PubMed

Roubík, Karel; Sieger, Ladislav; Sykora, Karel

2015-01-01

Presence of an air pocket and its size play an important role in survival of victims buried in the avalanche snow. Even small air pockets facilitate breathing. We hypothesize that the size of the air pocket significantly affects the airflow resistance and work of breathing. The aims of the study are (1) to investigate the effect of the presence of an air pocket on gas exchange and work of breathing in subjects breathing into the simulated avalanche snow and (2) to test whether it is possible to breathe with no air pocket. The prospective interventional double-blinded study involved 12 male volunteers, from which 10 completed the whole protocol. Each volunteer underwent two phases of the experiment in a random order: phase "AP"--breathing into the snow with a one-liter air pocket, and phase "NP"--breathing into the snow with no air pocket. Physiological parameters, fractions of oxygen and carbon dioxide in the airways and work of breathing expressed as pressure-time product were recorded continuously. The main finding of the study is that it is possible to breath in the avalanche snow even with no air pocket (0 L volume), but breathing under this condition is associated with significantly increased work of breathing. The significant differences were initially observed for end-tidal values of the respiratory gases (EtO2 and EtCO2) and peripheral oxygen saturation (SpO2) between AP and NP phases, whereas significant differences in inspiratory fractions occurred much later (for FIO2) or never (for FICO2). The limiting factor in no air pocket conditions is excessive increase in work of breathing that induces increase in metabolism accompanied by higher oxygen consumption and carbon dioxide production. The presence of even a small air pocket reduces significantly the work of breathing.

Human Anti-V3 HIV-1 Monoclonal Antibodies Encoded by the VH5-51/VL Lambda Genes Define a Conserved Antigenic Structure

PubMed Central

Gorny, Miroslaw K.; Sampson, Jared; Li, Huiguang; Jiang, Xunqing; Totrov, Maxim; Wang, Xiao-Hong; Williams, Constance; O'Neal, Timothy; Volsky, Barbara; Li, Liuzhe; Cardozo, Timothy; Nyambi, Phillipe; Zolla-Pazner, Susan; Kong, Xiang-Peng

2011-01-01

Preferential usage of immunoglobulin (Ig) genes that encode antibodies (Abs) against various pathogens is rarely observed and the nature of their dominance is unclear in the context of stochastic recombination of Ig genes. The hypothesis that restricted usage of Ig genes predetermines the antibody specificity was tested in this study of 18 human anti-V3 monoclonal Abs (mAbs) generated from unrelated individuals infected with various subtypes of HIV-1, all of which preferentially used pairing of the VH5-51 and VL lambda genes. Crystallographic analysis of five VH5-51/VL lambda-encoded Fabs complexed with various V3 peptides revealed a common three dimensional (3D) shape of the antigen-binding sites primarily determined by the four complementarity determining regions (CDR) for the heavy (H) and light (L) chains: specifically, the H1, H2, L1 and L2 domains. The CDR H3 domain did not contribute to the shape of the binding pocket, as it had different lengths, sequences and conformations for each mAb. The same shape of the binding site was further confirmed by the identical backbone conformation exhibited by V3 peptides in complex with Fabs which fully adapted to the binding pocket and the same key contact residues, mainly germline-encoded in the heavy and light chains of five Fabs. Finally, the VH5-51 anti-V3 mAbs recognized an epitope with an identical 3D structure which is mimicked by a single mimotope recognized by the majority of VH5-51-derived mAbs but not by other V3 mAbs. These data suggest that the identification of preferentially used Ig genes by neutralizing mAbs may define conserved epitopes in the diverse virus envelopes. This will be useful information for designing vaccine immunogen inducing cross-neutralizing Abs. PMID:22164215

Influence of edging practices on cutting yields of Alaska birch lumber

Treesearch

David L. Nicholls; J.W. Funck; C.C. Brunner; J.E. Reeb

2009-01-01

Birch lumber is often characterized by a high degree of knots, bark pockets, heartwood, and other features which force sawmill owners to decide whether to edge and trim boards to produce standard grade lumber vs. proprietary grade character-marked lumber. In addition, the edging strategies used with irregularly shaped flitches can greatly influence cut-stock recovery....

Probing the interaction of archaeal DNA polymerases with deaminated bases using X-ray crystallography and non-hydrogen bonding isosteric base analogues.

PubMed

Killelea, Tom; Ghosh, Samantak; Tan, Samuel S; Heslop, Pauline; Firbank, Susan J; Kool, Eric T; Connolly, Bernard A

2010-07-13

Archaeal family-B DNA polymerases stall replication on encountering the pro-mutagenic bases uracil and hypoxanthine. This publication describes an X-ray crystal structure of Thermococcus gorgonarius polymerase in complex with a DNA containing hypoxanthine in the single-stranded region of the template, two bases ahead of the primer-template junction. Full details of the specific recognition of hypoxanthine are revealed, allowing a comparison with published data that describe uracil binding. The two bases are recognized by the same pocket, in the N-terminal domain, and make very similar protein-DNA interactions. Specificity for hypoxanthine (and uracil) arises from a combination of polymerase-base hydrogen bonds and shape fit between the deaminated bases and the pocket. The structure with hypoxanthine at position 2 explains the stimulation of the polymerase 3'-5' proofreading exonuclease, observed with deaminated bases at this location. A beta-hairpin element, involved in partitioning the primer strand between the polymerase and exonuclease active sites, inserts between the two template bases at the extreme end of the double-stranded DNA. This denatures the two complementary primer bases and directs the resulting 3' single-stranded extension toward the exonuclease active site. Finally, the relative importance of hydrogen bonding and shape fit in determining selectivity for deaminated bases has been examined using nonpolar isosteres. Affinity for both 2,4-difluorobenzene and fluorobenzimidazole, non-hydrogen bonding shape mimics of uracil and hypoxanthine, respectively, is strongly diminished, suggesting polar protein-base contacts are important. However, residual interaction with 2,4-difluorobenzene is seen, confirming a role for shape recognition.

What induces pocket openings on protein surface patches involved in protein-protein interactions?

PubMed

Eyrisch, Susanne; Helms, Volkhard

2009-02-01

We previously showed for the proteins BCL-X(L), IL-2, and MDM2 that transient pockets at their protein-protein binding interfaces can be identified by applying the PASS algorithm to molecular dynamics (MD) snapshots. We now investigated which aspects of the natural conformational dynamics of proteins induce the formation of such pockets. The pocket detection protocol was applied to three different conformational ensembles for the same proteins that were extracted from MD simulations of the inhibitor bound crystal conformation in water and the free crystal/NMR structure in water and in methanol. Additional MD simulations studied the impact of backbone mobility. The more efficient CONCOORD or normal mode analysis (NMA) techniques gave significantly smaller pockets than MD simulations, whereas tCONCOORD generated pockets comparable to those observed in MD simulations for two of the three systems. Our findings emphasize the influence of solvent polarity and backbone rearrangements on the formation of pockets on protein surfaces and should be helpful in future generation of transient pockets as putative ligand binding sites at protein-protein interfaces.

What induces pocket openings on protein surface patches involved in protein-protein interactions?

NASA Astrophysics Data System (ADS)

Eyrisch, Susanne; Helms, Volkhard

2009-02-01

We previously showed for the proteins BCL-XL, IL-2, and MDM2 that transient pockets at their protein-protein binding interfaces can be identified by applying the PASS algorithm to molecular dynamics (MD) snapshots. We now investigated which aspects of the natural conformational dynamics of proteins induce the formation of such pockets. The pocket detection protocol was applied to three different conformational ensembles for the same proteins that were extracted from MD simulations of the inhibitor bound crystal conformation in water and the free crystal/NMR structure in water and in methanol. Additional MD simulations studied the impact of backbone mobility. The more efficient CONCOORD or normal mode analysis (NMA) techniques gave significantly smaller pockets than MD simulations, whereas tCONCOORD generated pockets comparable to those observed in MD simulations for two of the three systems. Our findings emphasize the influence of solvent polarity and backbone rearrangements on the formation of pockets on protein surfaces and should be helpful in future generation of transient pockets as putative ligand binding sites at protein-protein interfaces.

Rupture of DNA aptamer: New insights from simulations

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

Mishra, Rakesh Kumar; Nath, Shesh; Kumar, Sanjay

2015-10-28

Base-pockets (non-complementary base-pairs) in a double-stranded DNA play a crucial role in biological processes. Because of thermal fluctuations, it can lower the stability of DNA, whereas, in case of DNA aptamer, small molecules, e.g., adenosinemonophosphate and adenosinetriphosphate, form additional hydrogen bonds with base-pockets termed as “binding-pockets,” which enhance the stability. Using the Langevin dynamics simulations of coarse grained model of DNA followed by atomistic simulations, we investigated the influence of base-pocket and binding-pocket on the stability of DNA aptamer. Striking differences have been reported here for the separation induced by temperature and force, which require further investigation by single moleculemore » experiments.« less

A medical bandage in an Italian Renaissance mummy (Naples, XVI century).

PubMed

Giuffra, Valentina; Marinozzi, Silvia; Vultaggio, Claudia; Fornaciari, Gino

2008-01-01

A dressing was observed on the left arm of the mummy of Mary of Aragon (1503-1568), under her precious Renaissance clothes. It consisted of a true medical bandage, covering a large syphilitic cutaneous ulcer, with a sulphur-embedded wad still in situ. The bandage has a very peculiar shape, rather different from the usual dressings described in the contemporary medical texts: a central rectangular pad, used as compressing appliance, is provided with a sort of pocket containing ivy leaves. The function of the dressing was not only to cover and protect the ulcer, but also to apply a plant drug. This is the first case of ancient medical bandage studied directly on a mummified body.

Circadian periodicity of resistance to ionizing radiation in the pocket mouse.

NASA Technical Reports Server (NTRS)

Lindberg, R. G.; Hayden, P.; Gambino, J. J.

1971-01-01

Investigation of the response of pocket mice to Co 60 irradiation delivered at two times of day - namely, the predicted high and low points of the metabolic rate. The validity of torpor as an assay of the circadian period of body temperature in pocket mice and as a basis for selecting irradiation times is examined. A study is made of the mitotic activity in the pocket mouse intestinal epithelium as an example of a physiological rhythm which might influence radiation sensitivity. The results of tests in which pocket mice were exposed to ionizing radiation at two different times of day are cited. It is found that under the investigated conditions pocket mice irradiated during their metabolically active period (2330 hr) live significantly longer than those irradiated while their metabolic rate is low (0900 hr).

Do Out-of-Pocket Health Expenditures Rise with Age Among Older Americans?

ERIC Educational Resources Information Center

Stewart, Susan T.

2004-01-01

Purpose: Relationships are examined between age and out-of-pocket costs for different health goods and services among the older population. Design and Methods: Age patterns in health service use and out-of-pocket costs are examined by use of the 1990 Elderly Health Supplement to the Panel Study of Income Dynamics (N = 1,031, age 66+). Multivariate…

Contributions of gopher mound and casting disturbances to plant community structure in a Cascade Range meadow complex

Treesearch

M. Case; C.B. Halpern; S.A. Levin

2013-01-01

Pocket gophers (Geomyidae) are major agents of disturbance in North American grasslands. Gopher mounds bury existing plants and influence community structure through various mechanisms. However, in mountain meadows that experience winter snowpack, gophers also create winter castings, smaller tube-shaped deposits, previously ignored in studies of plant–gopher...

Structural studies and molecular dynamics simulations suggest a processive mechanism of exolytic lytic transglycosylase from Campylobacter jejuni.

PubMed

Vijayaraghavan, Jagamya; Kumar, Vijay; Krishnan, Nikhil P; Kaufhold, Ross T; Zeng, Ximin; Lin, Jun; van den Akker, Focco

2018-01-01

The bacterial soluble lytic transglycosylase (LT) breaks down the peptidoglycan (PG) layer during processes such as cell division. We present here crystal structures of the soluble LT Cj0843 from Campylobacter jejuni with and without bulgecin A inhibitor in the active site. Cj0843 has a doughnut shape similar but not identical to that of E. coli SLT70. The C-terminal catalytic domain is preceded by an L-domain, a large helical U-domain, a flexible linker, and a small N-terminal NU-domain. The flexible linker allows the NU-domain to reach over and complete the circular shape, using residues conserved in the Epsilonproteobacteria LT family. The inner surface of the Cj0843 doughnut is mostly positively charged including a pocket that has 8 Arg/Lys residues. Molecular dynamics simulations with PG strands revealed a potential functional role for this pocket in anchoring the negatively charged terminal tetrapeptide of the PG during several steps in the reaction including homing and aligning the PG strand for exolytic cleavage, and subsequent ratcheting of the PG strand to enhance processivity in degrading PG strands.

Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation

PubMed Central

Rajasekaran, M.; Abirami, Santhanam; Chen, Chinpan

2011-01-01

Background Arylamine N-acetyltransferase 2 (NAT2) is an important catalytic enzyme that metabolizes the carcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E, are classified as slow acetylators, whereas the wild-type NAT2 is classified as a fast acetylator. The slow acetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutations have previously been characterized, but the structural basis behind the reduced catalytic activity and reduced protein level is not clear. Methodology/Principal Findings We performed multiple molecular dynamics simulations of these mutants as well as NAT2 to investigate the structural and dynamical effects throughout the protein structure, specifically the catalytic triad, cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confined to the inter-domain, domain 3 and 17-residue insert region, where the flexibility was significantly reduced relative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conformation, cofactor binding site, substrate binding pocket size/shape and electrostatic potential. Conclusions/Significance Our results showed that the dynamical properties of all the mutant structures, especially in inter-domain, domain 3 and 17-residue insert region were affected in the same manner. Similarly, the electrostatic potential of all the mutants were altered and also the functionally important regions such as catalytic triad, cofactor binding site, and substrate binding pocket adopted different orientation and/or conformation relative to the wild-type that may affect the functions of the mutants. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms. PMID:21980537

Adsorption and molecular siting of CO2, water, and other gases in the superhydrophobic, flexible pores of FMOF-1 from experiment and simulation† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00278e Click here for additional data file.

PubMed Central

Moghadam, Peyman Z.; Ivy, Joshua F.; Arvapally, Ravi K.; dos Santos, Antonio M.; Pearson, John C.; Zhang, Li; Tylianakis, Emmanouil; Ghosh, Pritha; Oswald, Iain W. H.; Kaipa, Ushasree

2017-01-01

FMOF-1 is a flexible, superhydrophobic metal–organic framework with a network of channels and side pockets decorated with –CF3 groups. CO2 adsorption isotherms measured between 278 and 313 K and up to 55 bar reveal a maximum uptake of ca. 6.16 mol kg–1 (11.0 mol L–1) and unusual isotherm shapes at the higher temperatures, suggesting framework expansion. We used neutron diffraction and molecular simulations to investigate the framework expansion behaviour and the accessibility of the small pockets to N2, O2, and CO2. Neutron diffraction in situ experiments on the crystalline powder show that CO2 molecules are favourably adsorbed at three distinct adsorption sites in the large channels of FMOF-1 and cannot access the small pockets in FMOF-1 at 290 K and oversaturated pressure at 61 bar. Stepped adsorption isotherms for N2 and O2 at 77 K can be explained by combining Monte Carlo simulations in several different crystal structures of FMOF-1 obtained from neutron and X-ray diffraction under different conditions. A similar analysis is successful for CO2 adsorption at 278 and 283 K up to ca. 30 bar; however, at 298 K and pressures above 30 bar, the results suggest even more substantial expansion of the FMOF-1 framework. The measured contact angle for water on an FMOF-1 pellet is 158°, demonstrating superhydrophobicity. Simulations and adsorption measurements also show that FMOF-1 is hydrophobic and water is not adsorbed in FMOF-1 at room temperature. Simulated mixture isotherms of CO2 in the presence of 80% relative humidity predict that water does not influence the CO2 adsorption in FMOF-1, suggesting that hydrophobic MOFs could hold promise for CO2 capture from humid gas streams. PMID:28553541

Adsorption and molecular siting of CO2, water, and other gases in the superhydrophobic, flexible pores of FMOF-1 from experiment and simulation.

PubMed

Moghadam, Peyman Z; Ivy, Joshua F; Arvapally, Ravi K; Dos Santos, Antonio M; Pearson, John C; Zhang, Li; Tylianakis, Emmanouil; Ghosh, Pritha; Oswald, Iain W H; Kaipa, Ushasree; Wang, Xiaoping; Wilson, Angela K; Snurr, Randall Q; Omary, Mohammad A

2017-05-01

FMOF-1 is a flexible, superhydrophobic metal-organic framework with a network of channels and side pockets decorated with -CF 3 groups. CO 2 adsorption isotherms measured between 278 and 313 K and up to 55 bar reveal a maximum uptake of ca. 6.16 mol kg -1 (11.0 mol L -1 ) and unusual isotherm shapes at the higher temperatures, suggesting framework expansion. We used neutron diffraction and molecular simulations to investigate the framework expansion behaviour and the accessibility of the small pockets to N 2 , O 2 , and CO 2 . Neutron diffraction in situ experiments on the crystalline powder show that CO 2 molecules are favourably adsorbed at three distinct adsorption sites in the large channels of FMOF-1 and cannot access the small pockets in FMOF-1 at 290 K and oversaturated pressure at 61 bar. Stepped adsorption isotherms for N 2 and O 2 at 77 K can be explained by combining Monte Carlo simulations in several different crystal structures of FMOF-1 obtained from neutron and X-ray diffraction under different conditions. A similar analysis is successful for CO 2 adsorption at 278 and 283 K up to ca. 30 bar; however, at 298 K and pressures above 30 bar, the results suggest even more substantial expansion of the FMOF-1 framework. The measured contact angle for water on an FMOF-1 pellet is 158°, demonstrating superhydrophobicity. Simulations and adsorption measurements also show that FMOF-1 is hydrophobic and water is not adsorbed in FMOF-1 at room temperature. Simulated mixture isotherms of CO 2 in the presence of 80% relative humidity predict that water does not influence the CO 2 adsorption in FMOF-1, suggesting that hydrophobic MOFs could hold promise for CO 2 capture from humid gas streams.

Differences in medical care expenditures for adults with depression compared to adults with major chronic conditions.

PubMed

Lurie, Ithai Z; Manheim, Larry M; Dunlop, Dorothy D

2009-06-01

Approximately 17.1 million adults report having a major depressive episode in 2004 which represents 8% of the adult population in the U.S. Of these, more than one-third did not seek treatment. In spite of the large and extensive literature on the cost of mental health, we know very little about the differences in out-of-pocket expenditures between adults with depression and adults with other major chronic disease and the sources of those expenditures. For persons under age 65, compare total and out-of-pocket expenditures of those with depression to non-depressed individuals who have another major chronic disease. This study uses two linked, nationally representative surveys, the 1999 National Health Interview Survey (NHIS) and the 2000 Medical Expenditure Panel Survey (MEPS), to identify the population of interest. Depression was systematically assessed using a short form of the World Health Organization's (WHO) Composite International Diagnostic Interview--Short Form (CIDI-SF). To control for differences from potentially confounding factors, we matched depressed cases to controls using propensity score matching. We estimate that persons with depression have about the same out-of-pocket expenditures while having 11.8% less total medical expenditures (not a statistically significant difference) compared to non-depressed individuals with at least one chronic disease. High out-of-pocket expenditures are a concern for individuals with chronic diseases. Our study shows that those with depression have comparable out-of-pocket expenses to those with other chronic diseases, but given their lower income levels, this may result in a more substantial financial burden. IMPLICATION FOR POLICY: High out-of-pocket expenditures are a concern for individuals with depression and other chronic diseases. For both depressed individuals and non-depressed individuals with other chronic diseases, prescription drug expenditures contribute most to out-of-pocket expenses. Given the important role medications play in treatment of depression, high copayment rates are a concern for limiting compliance with appropriate treatment.

Probing the interaction of archaeal DNA polymerases with deaminated bases using X-ray crystallography and non-hydrogen bonding isosteric base analogues†

PubMed Central

Killelea, Tom; Ghosh, Samantak; Tan, Samuel S.; Heslop, Pauline; Firbank, Susan; Kool, Eric T.; Connolly, Bernard A.

2010-01-01

Archaeal family-B DNA polymerases stall replication on encountering the pro-mutagenic bases uracil and hypoxanthine. This publication describes an X-ray crystal structure of Thermococcus gorgonarius polymerase in complex with a DNA containing hypoxanthine in the single-stranded region of the template, two bases ahead of the primer-template junction. Full details of the specific recognition of hypoxanthine are revealed, allowing a comparison with published data that describes uracil binding. The two bases are recognized by the same pocket, in the N-terminal domain, and make very similar protein-DNA interactions. Specificity for hypoxanthine (and uracil) arises from a combination of polymerase-base hydrogen bonds and shape fit between the deaminated bases and the pocket. The structure with hypoxanthine at the +2 position explains the stimulation of the polymerase 3′-5′ proof reading exonuclease, observed with deaminated bases at this location. A β hairpin element, involved in partitioning the primer strand between the polymerase and exonuclease active sites, inserts between the two template bases at the extreme end of the double stranded DNA. This denatures the two complementary primer bases and directs the resulting 3′ single-stranded extension towards the exonuclease active site. Finally the relative importance of hydrogen bonding and shape fit in determining selectivity for deaminated bases has been examined using non-polar isosteres. Affinity for both 2,4 difluorobenzene and fluorobenzimidazole, non-hydrogen bonding shape mimics of uracil and hypoxanthine respectively, is strongly diminished, suggesting polar protein-base contacts are important. However, residual interaction with 2,4 difluorobenzene is seen, confirming a role for shape recognition. PMID:20527806

Exploring Strategies for Labeling Viruses with Gold Nanoclusters through Non-equilibrium Molecular Dynamics Simulations.

PubMed

Pohjolainen, Emmi; Malola, Sami; Groenhof, Gerrit; Häkkinen, Hannu

2017-09-20

Biocompatible gold nanoclusters can be utilized as contrast agents in virus imaging. The labeling of viruses can be achieved noncovalently but site-specifically by linking the cluster to the hydrophobic pocket of a virus via a lipid-like pocket factor. We have estimated the binding affinities of three different pocket factors of echovirus 1 (EV1) in molecular dynamics simulations combined with non-equilibrium free-energy calculations. We have also studied the effects on binding affinities with a pocket factor linked to the Au 102 pMBA 44 nanocluster in different protonation states. Although the absolute binding affinities are over-estimated for all the systems, the trend is in agreement with recent experiments.3 Our results suggest that the natural pocket factor (palmitic acid) can be replaced by molecules pleconaril (drug) and its derivative Kirtan1 that have higher estimated binding affinities. Our results also suggest that including the gold nanocluster does not decrease the affinity of the pocket factor to the virus, but the affinity is sensitive to the protonation state of the nanocluster, i.e., to pH conditions. The methodology introduced in this work helps in the design of optimal strategies for gold-virus bioconjugation for virus detection and manipulation.

Evidence for Lipid Packaging in the Crystal Structure of the GM2-Activator Complex with Platelet Activating Factor

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

Wright, Christine S.; Mi, Li-Zhi; Rastinejad, Fraydoon

2010-11-16

GM2-activator protein (GM2-AP) is a lipid transfer protein that has the ability to stimulate the enzymatic processing of gangliosides as well as T-cell activation through lipid presentation. Our previous X-ray crystallographic studies of GM2-AP have revealed a large lipid binding pocket as the central overall feature of the structure with non-protein electron density within this pocket suggesting bound lipid. To extend these studies, we present here the 2 {angstrom} crystal structure of GM2-AP complexed with platelet activating factor (PAF). PAF is a potent phosphoacylglycerol whose toxic patho-physiological effects can be inhibited by GM2-AP. The structure shows an ordered arrangement ofmore » two bound lipids and a fatty acid molecule. One PAF molecule binds in an extended conformation within the hydrophobic channel that has an open and closed conformation, and was seen to contain bound phospholipid in the low pH apo structure. The second molecule is submerged inside the pocket in a U-shaped conformation with its head group near the single polar residue S141. It was refined as lyso-PAF as it lacks electron density for the sn-2 acetate group. The alkyl chains of PAF interact through van der Waals contacts, while the head groups bind in different environments with their phosphocholine moieties in contact with aromatic rings (Y137, F80). The structure has revealed further insights into the lipid binding properties of GM2-AP, suggesting an unexpected unique mode of lipid packaging that may explain the efficiency of GM2-AP in inhibiting the detrimental biological effects of PAF.« less

Sampling and energy evaluation challenges in ligand binding protein design.

PubMed

Dou, Jiayi; Doyle, Lindsey; Jr Greisen, Per; Schena, Alberto; Park, Hahnbeom; Johnsson, Kai; Stoddard, Barry L; Baker, David

2017-12-01

The steroid hormone 17α-hydroxylprogesterone (17-OHP) is a biomarker for congenital adrenal hyperplasia and hence there is considerable interest in development of sensors for this compound. We used computational protein design to generate protein models with binding sites for 17-OHP containing an extended, nonpolar, shape-complementary binding pocket for the four-ring core of the compound, and hydrogen bonding residues at the base of the pocket to interact with carbonyl and hydroxyl groups at the more polar end of the ligand. Eight of 16 designed proteins experimentally tested bind 17-OHP with micromolar affinity. A co-crystal structure of one of the designs revealed that 17-OHP is rotated 180° around a pseudo-two-fold axis in the compound and displays multiple binding modes within the pocket, while still interacting with all of the designed residues in the engineered site. Subsequent rounds of mutagenesis and binding selection improved the ligand affinity to nanomolar range, while appearing to constrain the ligand to a single bound conformation that maintains the same "flipped" orientation relative to the original design. We trace the discrepancy in the design calculations to two sources: first, a failure to model subtle backbone changes which alter the distribution of sidechain rotameric states and second, an underestimation of the energetic cost of desolvating the carbonyl and hydroxyl groups of the ligand. The difference between design model and crystal structure thus arises from both sampling limitations and energy function inaccuracies that are exacerbated by the near two-fold symmetry of the molecule. © 2017 The Authors Protein Science published by Wiley Periodicals, Inc. on behalf of The Protein Society.

Pocket guide to transportation, 1999

DOT National Transportation Integrated Search

1998-12-01

Statistics published in this Pocket Guide to Transportation come from many different sources. Some statistics are based on samples and are subject to sampling variability. Statistics may also be subject to omissions and errors in reporting, recording...

Pocket guide to transportation, 2009

DOT National Transportation Integrated Search

2009-01-01

Statistics published in this Pocket Guide to Transportation come from many different sources. Some statistics are based on samples and are subject to sampling variability. Statistics may also be subject to omissions and errors in reporting, recording...

Pocket guide to transportation, 2013.

DOT National Transportation Integrated Search

2013-01-01

Abstract Statistics published in this Pocket Guide to Transportation come from many different sources. Some statistics are based on samples and are subject to sampling variability. Statistics may also be subject to omissions and errors in reporting, ...

Pocket guide to transportation, 2010

DOT National Transportation Integrated Search

2010-01-01

Statistics published in this Pocket Guide to Transportation come from many different sources. Some statistics are based on samples and are subject to sampling variability. Statistics may also be subject to omissions and errors in reporting, recording...

Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

PubMed

Liu, Mao-Hua; Chen, Shi-Bing; Yu, Juan; Liu, Cheng-Jun; Zhang, Xiao-Jing

2017-08-01

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity. Copyright © 2017 Elsevier Inc. All rights reserved.

The Subgingival Microbiome of Periodontal Pockets With Different Probing Depths in Chronic and Aggressive Periodontitis: A Pilot Study.

PubMed

Shi, Meng; Wei, Yiping; Hu, Wenjie; Nie, Yong; Wu, Xiaolei; Lu, Ruifang

2018-01-01

Periodontitis is a kind of infectious disease initiated by colonization of subgingival periodontal pathogens, which cause destruction of tooth-supporting tissues, and is a predominant threat to oral health as the most common cause of loss of teeth. The aim of this pilot study was to characterize the subgingival bacterial biodiversity of periodontal pockets with different probing depths in patients with different forms of periodontitis. Twenty-one subgingival plaque samples were collected from three patients with chronic periodontitis (ChP), three patients with aggressive periodontitis (AgP) and three periodontally healthy subjects (PH). Each patient with periodontitis was sampled at three sites, at different probing depths (PDs, one each at 4 mm, 5-6 mm, and ≥ 7 mm). Using 16S rRNA gene high-throughput sequencing and bioinformatic analysis, we found that subgingival communities in health and periodontitis samples largely differed. Meanwhile, Acholeplasma, Fretibacterium, Porphyromonas, Peptococcus, Treponema_2, Defluviitaleaceae_UCG_011, Filifactor , and Mycoplasma increased with the deepening of the pockets in ChP, whilst only Corynebacterium was negatively associated with PD. In AgP, Corynebacterium and Klebsiella were positively associated with PD, while Serratia, Pseudoramibacter, Defluviitaleaceae_UCG_011 , and Desulfobulbus were negatively associated with PD. And among these two groups, Corynebacterium shifted differently. Moreover, in subgingival plaque, the unweighted UniFrac distances between samples from pockets with different PD in the same patients were significantly lower than those from pockets within the same PD category from different patients. This study demonstrated the shift of the subgingival microbiome in individual teeth sites during disease development. Within the limitation of the relative small sample size, this pilot study shed new light on the dynamic relationship between the extent of periodontal destruction and the subgingival microbiome.

Amphibole incongruent melting under Lithospheric Mantle conditions in spinel peridotites from Balaton area, Hungary

NASA Astrophysics Data System (ADS)

Ntaflos, Theodoros; Abart, Rainer; Bizimis, Michel

2017-04-01

Pliocene alkali basalts from the western Pannonian Basin carry mantle xenoliths comprising hydrous and anhydrous spinel peridotites. We studied coarse and fine grained fertile to depleted spinel lherzolites, spinel harzubrgites and dunites from Szentbékálla, Balaton, in detail, using XRF, EPMA and LA-ICP-MS and MC-ICP-MS techniques. Pliocene alkali basalts containing mantle xenoliths with three major types of textures are widespread in the studied area: fine-grained primary and secondary equigranular, coarse-grained protogranular and transitional between equigranular and protogranular textures. Melt pockets, are common in the studied xenoliths. The shape of several melt pockets resembles euhedral amphibole. Other samples have thin films of intergranular glass attributed to the host basalt infiltration. Calculations have shown that such xenoliths experienced an up to 2.4% host basalt infiltration. The bulk rock Al2O3 and CaO concentrations vary from 0.75 to 4.1 and from 0.9 to 3.6 wt% respectively, and represent residues after variable degrees of partial melting. Using bulk rock major element abundances, the estimated degree of partial melting ranges from 4 to 20%.. The Primitive Mantle normalized clinopyroxene trace element abundances reveal a complicated evolution of the Lithospheric mantle underneath Balaton, which range from partial melting to modal and cryptic metasomatism. Subduction-related melt/fluids and/or infiltration of percolating undersaturated melts could be account for the metasomatic processes. The radiogenic isotopes of Sr, Nd and Hf in clinopyroxene suggest that this metasomatism was a relatively recent event. Textural evidence suggests that the calcite filling up the vesicles in the melt pockets and in veinlets cross-cutting the constituent minerals is of epigenetic nature and not due to carbonatite metasomatism. Mass balance calculations have shown that the bulk composition of the melt pockets is identical to small amphibole relics found as inclusions in second generation clinopyroxene within the melt pockets. Evidently the melt pockets represent amphibole, which have been incongruently molten. The necessary heat for the amphibole breakdown was derived from the host basalt. The estimated time for diffusive Ca exchange between matrix olivine and olivine overgrowth in contact with the melt pockets is very short, ranging between 21 and 200 days, indicating that amphibole breakdown took place immediately before or during the xenolith entrainment in the alkali basalt.

Compensated electron and hole pockets in an underdoped high- Tc superconductor

NASA Astrophysics Data System (ADS)

Sebastian, Suchitra E.; Harrison, N.; Goddard, P. A.; Altarawneh, M. M.; Mielke, C. H.; Liang, Ruixing; Bonn, D. A.; Hardy, W. N.; Andersen, O. K.; Lonzarich, G. G.

2010-06-01

We report quantum oscillations in the underdoped high-temperature superconductor YBa2Cu3O6+x over a wide range in magnetic field 28≤μ0H≤85T corresponding to ≈12 oscillations, enabling the Fermi surface topology to be mapped to high resolution. As earlier reported by Sebastian [Nature (London) 454, 200 (2008)10.1038/nature07095], we find a Fermi surface comprising multiple pockets, as revealed by the additional distinct quantum oscillation frequencies and harmonics reported in this work. We find the originally reported broad low-frequency Fourier peak at ≈535T to be clearly resolved into three separate peaks at ≈460 , ≈532 , and ≈602T , in reasonable agreement with the reported frequencies of Audouard [Phys. Rev. Lett. 103, 157003 (2009)10.1103/PhysRevLett.103.157003]. However, our increased resolution and angle-resolved measurements identify these frequencies to originate from two similarly sized pockets with greatly contrasting degrees of interlayer corrugation. The spectrally dominant frequency originates from a pocket (denoted α ) that is almost ideally two-dimensional in form (exhibiting negligible interlayer corrugation). In contrast, the newly resolved weaker adjacent spectral features originate from a deeply corrugated pocket (denoted γ ). On comparison with band structure, the d -wave symmetry of the interlayer dispersion locates the minimally corrugated α pocket at the “nodal” point knodal=(π/2,π/2) , and the significantly corrugated γ pocket at the “antinodal” point kantinodal=(π,0) within the Brillouin zone. The differently corrugated pockets at different locations indicate creation by translational symmetry breaking—a spin-density wave has been suggested from the suppression of Zeeman splitting for the spectrally dominant pocket. In a broken-translational symmetry scenario, symmetry points to the nodal (α) pocket corresponding to holes, with the weaker antinodal (γ) pocket corresponding to electrons—likely responsible for the negative Hall coefficient reported by LeBoeuf [Nature (London) 450, 533 (2007)10.1038/nature06332]. Given the similarity in α and γ pocket volumes, their opposite carrier type and the previous report of a diverging effective mass in Sebastian [Proc. Nat. Am. Soc. 107, 6175 (2010)10.1073/pnas.0913711107], we discuss the possibility of a secondary Fermi surface instability at low dopings of the excitonic insulator type, associated with the metal-insulator quantum critical point. Its potential involvement in the enhancement of superconducting transition temperatures is also discussed.

Butterfly magnetoresistance, quasi-2D Dirac Fermi surface and topological phase transition in ZrSiS.

PubMed

Ali, Mazhar N; Schoop, Leslie M; Garg, Chirag; Lippmann, Judith M; Lara, Erik; Lotsch, Bettina; Parkin, Stuart S P

2016-12-01

Magnetoresistance (MR), the change of a material's electrical resistance in response to an applied magnetic field, is a technologically important property that has been the topic of intense study for more than a quarter century. We report the observation of an unusual "butterfly"-shaped titanic angular magnetoresistance (AMR) in the nonmagnetic Dirac material, ZrSiS, which we find to be the most conducting sulfide known, with a 2-K resistivity as low as 48(4) nΩ⋅cm. The MR in ZrSiS is large and positive, reaching nearly 1.8 × 10 5 percent at 9 T and 2 K at a 45° angle between the applied current ( I || a ) and the applied field (90° is H || c ). Approaching 90°, a "dip" is seen in the AMR, which, by analyzing Shubnikov de Haas oscillations at different angles, we find to coincide with a very sharp topological phase transition unlike any seen in other known Dirac/Weyl materials. We find that ZrSiS has a combination of two-dimensional (2D) and 3D Dirac pockets comprising its Fermi surface and that the combination of high-mobility carriers and multiple pockets in ZrSiS allows for large property changes to occur as a function of angle between applied fields. This makes it a promising platform to study the physics stemming from the coexistence of 2D and 3D Dirac electrons as well as opens the door to creating devices focused on switching between different parts of the Fermi surface and different topological states.

Out-of-pocket payments for health care in Serbia.

PubMed

Arsenijevic, Jelena; Pavlova, Milena; Groot, Wim

2015-10-01

This study focuses on out-of-pocket payments for health care in Serbia. In contrast to previous studies, we distinguish three types of out-of-pocket patient payments: official co-payments, informal (under-the-table) payments and payments for "bought and brought goods" (i.e. payments for health care goods brought by the patient to the health care facility). We analyse the probability and intensity of three different types of out-of-pocket patient payments in the public health care sector in Serbia and their distribution among different population groups. We use data from the Serbian Living Standard Measures Study carried out in 2007. Out-of-pocket patients payments for both outpatient and inpatient health care are included. The data are analysed using regression analysis. The majority of health care users report official co-payments (84.7%) and payments for "bought and brought goods" (61.1%), whereas only 5.7% health care users declare that they have paid informally. Regarding the regression results, users with an income below the poverty line, those from rural areas and who are not married are more likely to report payments for "bought and brought goods, while young and more educated users are more likely to report informal patient payments. Overall, the three types of out-of-pocket payments are not correlated. Payments for "bought and brought goods" take the highest share of the total annual household budget. Serbian policymakers need to consider different strategies to deal with informal payments and to eliminate the practice of "bought and brought goods". Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparative evaluation of effectiveness of intra-pocket anesthetic gel and injected local anesthesia during scaling and root planing - A split-mouth clinical trial.

PubMed

Chintala, Kalyan; Kumar, Sandhya Pavan; Murthy, K Raja V

2017-01-01

Pain control is an important outcome measure for successful periodontal therapy. Injected local anesthesia has been used to secure anesthesia for scaling and root planing (SRP) and continues to be the anesthetic of choice for pain control. Alternatively, intra-pocket anesthetic gel has been used as an anesthetic during SRP. Hence, this clinical trial was done to compare the effectiveness of intra-pocket anesthetic gel and injected local anesthesia during SRP and also to assess the influence of intra-pocket anesthetic gel on treatment outcomes in chronic periodontitis patients. Fifteen systemically healthy chronic periodontitis patients were recruited. The dental quadrants on right side received either intra-pocket 20% benzocaine gel (Gel group) or infiltration/block by 2% lidocaine with 1:80,000 adrenaline (injection group). Quadrants on the left side received the alternative. Pain perception and patients preference for the type of anesthesia was recorded. Clinical parameters: plaque index, modified gingival index, modified sulcular bleeding index, probing pocket depth, and clinical attachment level were recorded at baseline and 1 month after treatment. No difference was observed in visual analog scale (P > 0.05) and verbal rating scale (P > 0.05) pain perception between gel group and injection group. A slightly increased preference to gel as anesthesia (53% vs. 47%) was observed. The treatment outcome after SRP did not show a significant difference between gel and injection group (P > 0.05). Intra-pocket administration of 20% benzocaine gel may be effective for pain control during SRP and may offer an alternative to conventional injection anesthesia.

Pocket Money: Influence on Body Mass Index and Dental Caries among Urban Adolescents.

PubMed

Punitha, V C; Amudhan, A; Sivaprakasam, P; Rathnaprabhu, V

2014-12-01

To explore the influence of pocket money on Dental Caries and Body Mass Index. A cross-sectional study was conducted wherein urban adolescent schoolchildren of age 13-18(n=916) were selected by two stage random sampling technique. Dental caries was measured using the DMFT Index. The children's nutritional status was assessed by means of anthropometric measurements. Body Mass Index using weight and height of children was evaluated using the reference standard of the WHO 2007. RESULTS showed that 50% of children receive pocket money from parents. The average amount received was Rs. 360/month. There was a significant correlation between age and amount of money received (r=0.160, p=.001). The average amount received by male children was significantly higher (Rs. 400) when compared to female children (Rs. 303). It was observed that income of the family (>30,000 Rs./month) and socioeconomic status (Upper class) was significantly dependent on the amount of money received by children (p<0.05). There was no significant difference in the occurrence of caries among children receiving pocket money or not. When BMI categories and pocket money were considered, statistically significant difference was seen among overweight and obese and normal weight children (p<.05). Higher proportion (40.1%) of overweight and obese adolescent children frequented the fast food restaurants every week when compared to the underweight (31.7%) and normal weight children (29.9%). Adolescent children receiving pocket money from parents could influence their eating habits in turn affect general health. Parents and teachers should motivate children on healthy spending of their pocket money.

Asymmetric interactions in the adenosine-binding pockets of the MS2 coat protein dimer

PubMed Central

Powell, Amy J; Peabody, David S

2001-01-01

Background The X-ray structure of the MS2 coat protein-operator RNA complex reveals the existence of quasi-synmetric interactions of adenosines -4 and -10 in pockets formed on different subunits of the coat protein dimer. Both pockets utilize the same five amino acid residues, namely Val29, Thr45, Ser47, Thr59, and Lys61. We call these sites the adenosine-binding pockets. Results We present here a heterodimer complementation analysis of the contributions of individual A-pocket amino acids to the binding of A-4 and A-10 in different halves of the dimer. Various substitutions of A-pocket residues were introduced into one half of single-chain coat protein heterodimers where they were tested for their abilities to complement Y85H or T91I substitutions (defects in the A-4 and A-10 half-sites, respectively) present in the other dimer half. Conclusions These experiments provide functional tests of interactions predicted from structural analyses, demonstrating the importance of certain amino acid-nucleotide contacts observed in the crystal structure, and showing that others make little or no contribution to the stability of the complex. In summary, Val29 and Lys61 form important stabilizing interactions with both A-4 and A-10. Meanwhile, Ser47 and Thr59 interact primarily with A-10. The important interactions with Thr45 are restricted to A-4. PMID:11504563

Allelic variation in key peptide-binding pockets discriminates between closely related diabetes-protective and diabetes-susceptible HLA-DQB1*06 alleles.

PubMed

Ettinger, Ruth A; Papadopoulos, George K; Moustakas, Antonis K; Nepom, Gerald T; Kwok, William W

2006-02-01

HLA-DQA1*0102-DQB1*0602 is associated with protection against type 1 diabetes (T1D). A similar allele, HLA-DQA1*0102-DQB1*0604, contributes to T1D susceptibility in certain populations but differs only at seven amino acids from HLA-DQA1*0102-DQB1*0602. Five of these polymorphisms are found within the peptide-binding groove, suggesting that differences in peptide binding contribute to the mechanism of their association with T1D. In this study, we determine the peptide-binding motif for HLA-DQA1*0102-DQB1*0604 allelic protein (DQ0604) in comparison to the established HLA-DQA1*0102-DQB1*0602 (DQ0602) motif using binding assays with model peptides from T1D autoantigens and homology modeling using the coordinates of the DQ0602-hypocretin 1-13 crystal structure. The peptide binding preferences were deduced with a peptide from insulin that bound both with a 2- to 3-fold difference in avidity using the same amino acids in the peptide as anchors. Peptide binding differences directly influenced by the polymorphisms in or nearby pockets 1, 6, and 9 were observed. In pocket 1, DQ0604 was better able to accommodate aromatic residues due to the beta86 and beta87 polymorphisms. A negatively charged amino acid was preferred by DQ0604 in pocket 6 due to the positively charged beta30His. In pocket 9, DQ0604 preferred aromatic amino acids due to the beta9 and beta30 polymorphisms and had low tolerance of acidic residues. beta57Val in DQ0604 functions differently than beta57Ala, in that it pushes alpha76Arg outside of the pocket, preventing the formation of a salt bridge with an acidic amino acid in the peptide. This study furthers our understanding of the structure-function relationships of MHC class II polymorphisms.

A randomised crossover comparison of mouth-to-face-shield ventilation and mouth-to-pocket-mask ventilation by surf lifeguards in a manikin.

PubMed

Adelborg, K; Bjørnshave, K; Mortensen, M B; Espeseth, E; Wolff, A; Løfgren, B

2014-07-01

Thirty surf lifeguards (mean (SD) age: 25.1 (4.8) years; 21 male, 9 female) were randomly assigned to perform 2 × 3 min of cardiopulmonary resuscitation on a manikin using mouth-to-face-shield ventilation (AMBU LifeKey) and mouth-to-pocket-mask ventilation (Laerdal Pocket Mask). Interruptions in chest compressions, effective ventilation (visible chest rise) ratio, tidal volume and inspiratory time were recorded. Interruptions in chest compressions per cycle were increased with mouth-to-face-shield ventilation (mean (SD) 8.6 (1.7) s) compared with mouth-to-pocket-mask ventilation (6.9 (1.2) s, p < 0.0001). The proportion of effective ventilations was less using mouth-to-face-shield ventilation (199/242 (82%)) compared with mouth-to-pocket-mask ventilation (239/240 (100%), p = 0.0002). Tidal volume was lower using mouth-to-face-shield ventilation (mean (SD) 0.36 (0.20) l) compared with mouth-to-pocket-mask ventilation (0.45 (0.20) l, p = 0.006). No differences in inspiratory times were observed between mouth-to-face-shield ventilation and mouth-to-pocket-mask ventilation. In conclusion, mouth-to-face-shield ventilation increases interruptions in chest compressions, reduces the proportion of effective ventilations and decreases delivered tidal volumes compared with mouth-to-pocket-mask ventilation. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

Architecture of a Diels-Alderase ribozyme with a preformed catalytic pocket.

PubMed

Keiper, Sonja; Bebenroth, Dirk; Seelig, Burckhard; Westhof, Eric; Jäschke, Andres

2004-09-01

Artificial ribozymes catalyze a variety of chemical reactions. Their structures and reaction mechanisms are largely unknown. We have analyzed a ribozyme catalyzing Diels-Alder cycloaddition reactions by comprehensive mutation analysis and a variety of probing techniques. New tertiary interactions involving base pairs between nucleotides of the 5' terminus and a large internal loop forming a pseudoknot fold were identified. The probing data indicate a preformed tertiary structure that shows no major changes on substrate or product binding. Based on these observations, a molecular architecture featuring a Y-shaped arrangement is proposed. The tertiary structure is formed in a rather unusual way; that is, the opposite sides of the asymmetric internal loop are clamped by the four 5'-terminal nucleotides, forming two adjacent two base-pair helices. It is proposed that the catalytic pocket is formed by a wedge within one of these helices.

The I-Raum: A new shaped hohlraum for improved inner beam propagation in indirectly-driven ICF implosions on the National Ignition Facility

NASA Astrophysics Data System (ADS)

Robey, H. F.; Berzak Hopkins, L.; Milovich, J. L.; Meezan, N. B.

2018-01-01

Recent work in indirectly-driven inertial confinement fusion implosions on the National Ignition Facility has indicated that late-time propagation of the inner cones of laser beams (23° and 30°) is impeded by the growth of a "bubble" of hohlraum wall material (Au or depleted uranium), which is initiated by and is located at the location where the higher-intensity outer beams (44° and 50°) hit the hohlraum wall. The absorption of the inner cone beams by this "bubble" reduces the laser energy reaching the hohlraum equator at late time driving an oblate or pancaked implosion, which limits implosion performance. In this article, we present the design of a new shaped hohlraum designed specifically to reduce the impact of this bubble by adding a recessed pocket at the location where the outer cones hit the hohlraum wall. This recessed pocket displaces the bubble radially outward, reducing the inward penetration of the bubble at all times throughout the implosion and increasing the time for inner beam propagation by approximately 1 ns. This increased laser propagation time allows one to drive a larger capsule, which absorbs more energy and is predicted to improve implosion performance. The new design is based on a recent National Ignition Facility shot, N170601, which produced a record neutron yield. The expansion rate and absorption of laser energy by the bubble is quantified for both cylindrical and shaped hohlraums, and the predicted performance is compared.

Drug-like density: a method of quantifying the "bindability" of a protein target based on a very large set of pockets and drug-like ligands from the Protein Data Bank.

PubMed

Sheridan, Robert P; Maiorov, Vladimir N; Holloway, M Katharine; Cornell, Wendy D; Gao, Ying-Duo

2010-11-22

One approach to estimating the "chemical tractability" of a candidate protein target where we know the atomic resolution structure is to examine the physical properties of potential binding sites. A number of other workers have addressed this issue. We characterize ~290,000 "pockets" from ~42,000 protein crystal structures in terms of a three parameter "pocket space": volume, buriedness, and hydrophobicity. A metric DLID (drug-like density) measures how likely a pocket is to bind a drug-like molecule. This is calculated from the count of other pockets in its local neighborhood in pocket space that contain drug-like cocrystallized ligands and the count of total pockets in the neighborhood. Surprisingly, despite being defined locally, a global trend in DLID can be predicted by a simple linear regression on log(volume), buriedness, and hydrophobicity. Two levels of simplification are necessary to relate the DLID of individual pockets to "targets": taking the best DLID per Protein Data Bank (PDB) entry (because any given crystal structure can have many pockets), and taking the median DLID over all PDB entries for the same target (because different crystal structures of the same protein can vary because of artifacts and real conformational changes). We can show that median DLIDs for targets that are detectably homologous in sequence are reasonably similar and that median DLIDs correlate with the "druggability" estimate of Cheng et al. (Nature Biotechnology 2007, 25, 71-75).

Mechanistic differences between methanol and dimethyl ether carbonylation in side pockets and large channels of mordenite.

PubMed

Boronat, Mercedes; Martínez, Cristina; Corma, Avelino

2011-02-21

The activity and selectivity towards carbonylation presented by Brønsted acid sites located inside the 8MR pockets or in the main 12MR channels of mordenite is studied by means of quantum-chemical calculations, and the mechanistic differences between methanol and DME carbonylation are investigated. The selectivity towards carbonylation is higher inside the 8MR pockets, where the competitive formation of DME and hydrocarbons that finally leads to catalyst deactivation is sterically impeded. Moreover, inclusion of dispersion interactions in the calculations leads to agreement between the calculated activation barriers for the rate determining step and the experimentally observed higher reactivity of methoxy groups located inside the 8MR channels.

PoLi: A Virtual Screening Pipeline Based On Template Pocket And Ligand Similarity

PubMed Central

Roy, Ambrish; Srinivasan, Bharath; Skolnick, Jeffrey

2015-01-01

Often in pharmaceutical research, the goal is to identify small molecules that can interact with and appropriately modify the biological behavior of a new protein target. Unfortunately, most proteins lack both known structures and small molecule binders, prerequisites of many virtual screening, VS, approaches. For such proteins, ligand homology modeling, LHM, that copies ligands from homologous and perhaps evolutionarily distant template proteins, has been shown to be a powerful VS approach to identify possible binding ligands. However, if we want to target a specific pocket for which there is no homologous holo template protein structure, then LHM will not work. To address this issue, in a new pocket based approach, PoLi, we generalize LHM by exploiting the fact that the number of distinct small molecule ligand binding pockets in proteins is small. PoLi identifies similar ligand binding pockets in a holo-template protein library, selectively copies relevant parts of template ligands and uses them for VS. In practice, PoLi is a hybrid structure and ligand based VS algorithm that integrates 2D fingerprint-based and 3D shape-based similarity metrics for improved virtual screening performance. On standard DUD and DUD-E benchmark databases, using modeled receptor structures, PoLi achieves an average enrichment factor of 13.4 and 9.6 respectively, in the top 1% of the screened library. In contrast, traditional docking based VS using AutoDock Vina and homology-based VS using FINDSITEfilt have an average enrichment of 1.6 (3.0) and 9.0 (7.9) on the DUD (DUD-E) sets respectively. Experimental validation of PoLi predictions on dihydrofolate reductase, DHFR, using differential scanning fluorimetry, DSF, identifies multiple ligands with diverse molecular scaffolds, thus demonstrating the advantage of PoLi over current state-of-the-art VS methods. PMID:26225536

Tunnel optical radiation in In{sub x}Ga{sub 1−x}N

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

Alexandrov, Dimiter; Skerget, Shawn

2014-02-21

An investigation of tunnel optical radiation in epitaxial layers of n-type In{sub x}Ga{sub 1−x}N grown on p-type GaN by novel plasma based migration enhanced epitaxy is presented. Experimental results of electro-luminescence spectra for In{sub x}Ga{sub 1−x}N/p−GaN hetero-junctions were obtained and they show two well expressed optical bands - one in range 500-540 nm and other in range 550-610 nm. An interesting detail is that each band begins and ends by sharp drops of the radiation, which nearly approach zero. A theoretical investigation of the unusual behavior of these spectra was done using LCAO electron band structure calculations. The optical rangesmore » of these bands show that the radiation occurs in the In{sub x}Ga{sub 1−x}N region. In fact, substitutions of In atoms in Ga sites creates defects in the structure of In{sub x}Ga{sub 1−x}N and the corresponding LCAO matrix elements are found on this basis. The LCAO electron band structures are calculated considering the interactions between nearest-neighbor orbitals. Electron energy pockets are found in both the conduction and the valence bands at the Γ point of the electron band structures. Also it is found that these pockets are separated by distances, for which there is overlapping between the electron wave functions describing localized states belonging to the pockets, and as a result tunnel optical radiation can take place. This type of electron transition - between such a pocket in the conduction band and a pocket in the valence band - occurs in In{sub x}Ga{sub 1−x}N, causing the above described optical bands. This conclusion concurs with the fact that the shapes of these bands change with change of the applied voltage.« less

Pocket Money: Influence on Body Mass Index and Dental Caries among Urban Adolescents

PubMed Central

Amudhan, A.; Sivaprakasam, P.; Rathnaprabhu, V.

2014-01-01

Objective: To explore the influence of pocket money on Dental Caries and Body Mass Index. Materials and Methods: A cross-sectional study was conducted wherein urban adolescent schoolchildren of age 13-18(n=916) were selected by two stage random sampling technique. Dental caries was measured using the DMFT Index. The children’s nutritional status was assessed by means of anthropometric measurements. Body Mass Index using weight and height of children was evaluated using the reference standard of the WHO 2007. Results: Results showed that 50% of children receive pocket money from parents. The average amount received was Rs. 360/month. There was a significant correlation between age and amount of money received (r=0.160, p=.001). The average amount received by male children was significantly higher (Rs. 400) when compared to female children (Rs. 303). It was observed that income of the family (>30,000 Rs./month) and socioeconomic status (Upper class) was significantly dependent on the amount of money received by children (p<0.05). There was no significant difference in the occurrence of caries among children receiving pocket money or not. When BMI categories and pocket money were considered, statistically significant difference was seen among overweight and obese and normal weight children (p<.05). Higher proportion (40.1%) of overweight and obese adolescent children frequented the fast food restaurants every week when compared to the underweight (31.7%) and normal weight children (29.9%). Conclusion: Adolescent children receiving pocket money from parents could influence their eating habits in turn affect general health. Parents and teachers should motivate children on healthy spending of their pocket money. PMID:25653973

Analysis of drug binding pockets and repurposing opportunities for twelve essential enzymes of ESKAPE pathogens

PubMed Central

Naz, Sadia; Ngo, Tony; Farooq, Umar

2017-01-01

Background The rapid increase in antibiotic resistance by various bacterial pathogens underlies the significance of developing new therapies and exploring different drug targets. A fraction of bacterial pathogens abbreviated as ESKAPE by the European Center for Disease Prevention and Control have been considered a major threat due to the rise in nosocomial infections. Here, we compared putative drug binding pockets of twelve essential and mostly conserved metabolic enzymes in numerous bacterial pathogens including those of the ESKAPE group and Mycobacterium tuberculosis. The comparative analysis will provide guidelines for the likelihood of transferability of the inhibitors from one species to another. Methods Nine bacterial species including six ESKAPE pathogens, Mycobacterium tuberculosis along with Mycobacterium smegmatis and Eschershia coli, two non-pathogenic bacteria, have been selected for drug binding pocket analysis of twelve essential enzymes. The amino acid sequences were obtained from Uniprot, aligned using ICM v3.8-4a and matched against the Pocketome encyclopedia. We used known co-crystal structures of selected target enzyme orthologs to evaluate the location of their active sites and binding pockets and to calculate a matrix of pairwise sequence identities across each target enzyme across the different species. This was used to generate sequence maps. Results High sequence identity of enzyme binding pockets, derived from experimentally determined co-crystallized structures, was observed among various species. Comparison at both full sequence level and for drug binding pockets of key metabolic enzymes showed that binding pockets are highly conserved (sequence similarity up to 100%) among various ESKAPE pathogens as well as Mycobacterium tuberculosis. Enzymes orthologs having conserved binding sites may have potential to interact with inhibitors in similar way and might be helpful for design of similar class of inhibitors for a particular species. The derived pocket alignments and distance-based maps provide guidelines for drug discovery and repurposing. In addition they also provide recommendations for the relevant model bacteria that may be used for initial drug testing. Discussion Comparing ligand binding sites through sequence identity calculation could be an effective approach to identify conserved orthologs as drug binding pockets have shown higher level of conservation among various species. By using this approach we could avoid the problems associated with full sequence comparison. We identified essential metabolic enzymes among ESKAPE pathogens that share high sequence identity in their putative drug binding pockets (up to 100%), of which known inhibitors can potentially antagonize these identical pockets in the various species in a similar manner. PMID:28948099

Analysis of drug binding pockets and repurposing opportunities for twelve essential enzymes of ESKAPE pathogens.

PubMed

Naz, Sadia; Ngo, Tony; Farooq, Umar; Abagyan, Ruben

2017-01-01

The rapid increase in antibiotic resistance by various bacterial pathogens underlies the significance of developing new therapies and exploring different drug targets. A fraction of bacterial pathogens abbreviated as ESKAPE by the European Center for Disease Prevention and Control have been considered a major threat due to the rise in nosocomial infections. Here, we compared putative drug binding pockets of twelve essential and mostly conserved metabolic enzymes in numerous bacterial pathogens including those of the ESKAPE group and Mycobacterium tuberculosis . The comparative analysis will provide guidelines for the likelihood of transferability of the inhibitors from one species to another. Nine bacterial species including six ESKAPE pathogens, Mycobacterium tuberculosis along with Mycobacterium smegmatis and Eschershia coli , two non-pathogenic bacteria, have been selected for drug binding pocket analysis of twelve essential enzymes. The amino acid sequences were obtained from Uniprot, aligned using ICM v3.8-4a and matched against the Pocketome encyclopedia. We used known co-crystal structures of selected target enzyme orthologs to evaluate the location of their active sites and binding pockets and to calculate a matrix of pairwise sequence identities across each target enzyme across the different species. This was used to generate sequence maps. High sequence identity of enzyme binding pockets, derived from experimentally determined co-crystallized structures, was observed among various species. Comparison at both full sequence level and for drug binding pockets of key metabolic enzymes showed that binding pockets are highly conserved (sequence similarity up to 100%) among various ESKAPE pathogens as well as Mycobacterium tuberculosis . Enzymes orthologs having conserved binding sites may have potential to interact with inhibitors in similar way and might be helpful for design of similar class of inhibitors for a particular species. The derived pocket alignments and distance-based maps provide guidelines for drug discovery and repurposing. In addition they also provide recommendations for the relevant model bacteria that may be used for initial drug testing. Comparing ligand binding sites through sequence identity calculation could be an effective approach to identify conserved orthologs as drug binding pockets have shown higher level of conservation among various species. By using this approach we could avoid the problems associated with full sequence comparison. We identified essential metabolic enzymes among ESKAPE pathogens that share high sequence identity in their putative drug binding pockets (up to 100%), of which known inhibitors can potentially antagonize these identical pockets in the various species in a similar manner.

Analysis of ASTER data for mapping bauxite rich pockets within high altitude lateritic bauxite, Jharkhand, India

NASA Astrophysics Data System (ADS)

Guha, Arindam; Singh, Vivek Kr.; Parveen, Reshma; Kumar, K. Vinod; Jeyaseelan, A. T.; Dhanamjaya Rao, E. N.

2013-04-01

Bauxite deposits of Jharkhand in India are resulted from the lateritization process and therefore are often associated with the laterites. In the present study, ASTER (Advanced Space borne Thermal Emission and Reflection Radiometer) image is processed to delineate bauxite rich pockets within the laterites. In this regard, spectral signatures of lateritic bauxite samples are analyzed in the laboratory with reference to the spectral features of gibbsite (main mineral constituent of bauxite) and goethite (main mineral constituent of laterite) in VNIR-SWIR (visible-near infrared and short wave infrared) electromagnetic domain. The analysis of spectral signatures of lateritic bauxite samples helps in understanding the differences in the spectral features of bauxites and laterites. Based on these differences; ASTER data based relative band depth and simple ratio images are derived for spatial mapping of the bauxites developed within the lateritic province. In order to integrate the complementary information of different index image, an index based principal component (IPC) image is derived to incorporate the correlative information of these indices to delineate bauxite rich pockets. The occurrences of bauxite rich pockets derived from density sliced IPC image are further delimited by the topographic controls as it has been observed that the major bauxite occurrences of the area are controlled by slope and altitude. In addition to above, IPC image is draped over the digital elevation model (DEM) to illustrate how bauxite rich pockets are distributed with reference to the topographic variability of the terrain. Bauxite rich pockets delineated in the IPC image are also validated based on the known mine occurrences and existing geological map of the bauxite. It is also conceptually validated based on the spectral similarity of the bauxite pixels delineated in the IPC image with the ASTER convolved laboratory spectra of bauxite samples.

Root-like enamel pearl: a case report

PubMed Central

2014-01-01

Introduction In general, enamel pearls are found in maxillary molars as a small globule of enamel. However, this case report describes an enamel pearl with a prolate spheroid shape which is 1.8mm wide and 8mm long. The different type of enamel pearl found in my clinic has significantly improved our understanding of enamel pearl etiology and pathophysiology. Case presentation A 42-year-old Han Chinese woman with severe toothache received treatment in my Department of Endodontics. She had no significant past medical history. A dental examination revealed extensive distal decay in her left mandibular first molar, tenderness to percussion and palpation of the periradicular zone, and found a deep periodontal pocket on the buccal lateral. Vitality testing was negative. Periapical radiographic images revealed radiolucency around the mesial apex. Cone beam computed tomography detected an opaque enamel pearl in the furcation area with a prolate spheroid shape of 1.8mm wide and 8mm long. Conclusion The enamel pearl described in this case report is like a very long dental root. Cone beam computed tomography may be used for evaluating enamel pearls. PMID:25008098

Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/delta dual agonists for the treatment of metabolic syndrome.

PubMed

Kasuga, Jun-ichi; Yamasaki, Daisuke; Araya, Yoko; Nakagawa, Aya; Makishima, Makoto; Doi, Takefumi; Hashimoto, Yuichi; Miyachi, Hiroyuki

2006-12-15

A series of alpha-alkyl-substituted phenylpropanoic acids was prepared as dual agonists of peroxisome proliferator-activated receptors alpha and delta (PPARalpha/delta). Structure-activity relationship studies indicated that the shape of the linking group and the shape of the substituent at the distal benzene ring play key roles in determining the potency and the selectivity of PPAR subtype transactivation. Structure-activity relationships among the amide series (10) and the reversed amide series (13) are similar, but not identical, especially in the case of the compounds bearing a bulky hydrophobic substituent at the distal benzene ring, indicating that the hydrophobic tail part of the molecules in these two series binds at somewhat different positions in the large binding pocket of PPAR. alpha-Alkyl-substituted phenylpropanoic acids of (S)-configuration were identified as potent human PPARalpha/delta dual agonists. Representative compounds exhibited marked nuclear receptor selectivity for PPARalpha and PPARdelta. Subtype-selective PPAR activation was also examined by analysis of the mRNA expression of PPAR-regulated genes.

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

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

HP-65 PROGRAMMABLE POCKET CALCULATOR APPLIED TO AIR POLLUTION MEASUREMENT STUDIES: STATIONARY SOURCES

EPA Science Inventory

The handbook is intended for persons concerned with air pollution measurement studies of stationary industrial sources. It gives detailed descriptions of 22 different programs written specifically for the Hewlett Packard Model HP-65 card-programmable pocket calculator. For each p...

Complementary health insurance, out- of- pocket expenditures, and health services utilization: A population- based survey.

PubMed

Homaie Rad, Enayatollah; Kavosi, Zahra; Moghadamnia, Mohammad Taghi; Arefnezhad, Masoud; Arefnezhad, Masoumeh; Felezi Nasiri, Banfashe

2017-01-01

Background: Studies have shown that people using complementary health insurances have more access to health services than others. In the present study, we aimed at finding the differences between out- of- pocket payments and health service utilizations in complementary health insurances (CHIs) users and nonusers. Methods: Propensity score matching was used to compare the 2 groups. First, confounder variables were identified, and then propensity score matching was used to compare out- of- pocket expenditures with dental, general physician, hospital inpatient, emergency services, nursing, midwifery, laboratory services, specialists and rehabilitation services utilization. Results: Our results revealed no significant differences between the 2 groups in out- of- pocket health expenditures. Also, the specialist visits, inpatient services at the hospital, and dental services were higher in people who used CHIs compared to nonusers. Conclusion: People did not change their budget share for health care services after using CHIs. The payments were equal for people who were not CHIs users due to the increase in the quantity of the services.

Lock Culvert Valves; Hydraulic Design Considerations

DTIC Science & Technology

2011-06-01

gate.” Musical note shape seals are also not suitable as sill seals although they appear to be in use. Lewin (1995) also warns that particular...of the tailwater rather than the high water surface maintained with a reverse tainter valve. Air entrainment through the valve well, which would...the valve. The air vent is located such that the air drawn into the culvert is entrained in the form of very small bubbles, avoiding large air pockets

Assessment and management of retraction pockets.

PubMed

Alper, Cuneyt; Olszewska, Ewa

2017-02-28

This manuscript intends to review types, pathogenesis, associated risk factors, and potential methods of prevention and treatment of the retraction pockets in adults and children. The importance of retraction pockets (RP) lies in loss of original histological and anatomical structure which is associated with development of ossicular chain erosion, cho¬lesteatoma formation and potentially life threatening complications of cholesteatoma. The trans-mucosal exchange each gas in the middle ear (ME) is towards equalizing its partial pressures with the partial pressure in the environ¬ment. MEs that have abnormalities in the volume and ventilation pathways in the epitympanic may be more suscep¬tible to retraction pockets. Sustained pressure differences and/or inflammation leads to destruction of collagen fibers in the lamina propria. Inflammatory mediators and cytokines lead to release of collagenases result in viscoelastic properties of the lamina propria. The process of changes in the tympanic membrane structure may evolve to the cho¬lesteatoma formation. There are many different staging systems that clinicians prioritize in their decision making in the management of RP. The authors discuss the management possibilities in different clinical situations: RP without and with ongoing or intermittent evidence of Eustachian Tube Dysfunction (ETD), presence of adenoid hypertrophy or re-growth of adenoids, presence or absence of effusion, invisible depth of RP without effusion. invisible depth of RP with effusion, ongoing RP after VT insertion, and finally suspicion of cholesteatoma in a deep RP with ME effusion. A decision algorithm regarding the management of TM retraction and retraction pockets is provided.

Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs

PubMed Central

Farelli, Jeremiah D.; Galvin, Brendan D.; Li, Zhiru; Liu, Chunliang; Aono, Miyuki; Garland, Megan; Hallett, Olivia E.; Causey, Thomas B.; Ali-Reynolds, Alana; Saltzberg, Daniel J.; Carlow, Clotilde K. S.; Dunaway-Mariano, Debra; Allen, Karen N.

2014-01-01

Parasitic nematodes are responsible for devastating illnesses that plague many of the world's poorest populations indigenous to the tropical areas of developing nations. Among these diseases is lymphatic filariasis, a major cause of permanent and long-term disability. Proteins essential to nematodes that do not have mammalian counterparts represent targets for therapeutic inhibitor discovery. One promising target is trehalose-6-phosphate phosphatase (T6PP) from Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. We determined the X-ray crystal structure of T6PP from B. malayi. The protein structure revealed a stabilizing N-terminal MIT-like domain and a catalytic C-terminal C2B-type HAD phosphatase fold. Structure-guided mutagenesis, combined with kinetic analyses using a designed competitive inhibitor, trehalose 6-sulfate, identified five residues important for binding and catalysis. This structure-function analysis along with computational mapping provided the basis for the proposed model of the T6PP-trehalose 6-phosphate complex. The model indicates a substrate-binding mode wherein shape complementarity and van der Waals interactions drive recognition. The mode of binding is in sharp contrast to the homolog sucrose-6-phosphate phosphatase where extensive hydrogen-bond interactions are made to the substrate. Together these results suggest that high-affinity inhibitors will be bi-dentate, taking advantage of substrate-like binding to the phosphoryl-binding pocket while simultaneously utilizing non-native binding to the trehalose pocket. The conservation of the key residues that enforce the shape of the substrate pocket in T6PP enzymes suggest that development of broad-range anthelmintic and antibacterial therapeutics employing this platform may be possible. PMID:24992307

Butterfly magnetoresistance, quasi-2D Dirac Fermi surface and topological phase transition in ZrSiS

PubMed Central

Ali, Mazhar N.; Schoop, Leslie M.; Garg, Chirag; Lippmann, Judith M.; Lara, Erik; Lotsch, Bettina; Parkin, Stuart S. P.

2016-01-01

Magnetoresistance (MR), the change of a material’s electrical resistance in response to an applied magnetic field, is a technologically important property that has been the topic of intense study for more than a quarter century. We report the observation of an unusual “butterfly”-shaped titanic angular magnetoresistance (AMR) in the nonmagnetic Dirac material, ZrSiS, which we find to be the most conducting sulfide known, with a 2-K resistivity as low as 48(4) nΩ⋅cm. The MR in ZrSiS is large and positive, reaching nearly 1.8 × 105 percent at 9 T and 2 K at a 45° angle between the applied current (I || a) and the applied field (90° is H || c). Approaching 90°, a “dip” is seen in the AMR, which, by analyzing Shubnikov de Haas oscillations at different angles, we find to coincide with a very sharp topological phase transition unlike any seen in other known Dirac/Weyl materials. We find that ZrSiS has a combination of two-dimensional (2D) and 3D Dirac pockets comprising its Fermi surface and that the combination of high-mobility carriers and multiple pockets in ZrSiS allows for large property changes to occur as a function of angle between applied fields. This makes it a promising platform to study the physics stemming from the coexistence of 2D and 3D Dirac electrons as well as opens the door to creating devices focused on switching between different parts of the Fermi surface and different topological states. PMID:28028541

Periodontal Pocket Depth, Hyperglycemia, and Progression of Chronic Kidney Disease: A Population-Based Longitudinal Study.

PubMed

Chang, Jia-Feng; Yeh, Jih-Chen; Chiu, Ya-Lin; Liou, Jian-Chiun; Hsiung, Jing-Ru; Tung, Tao-Hsin

2017-01-01

No large epidemiological study has been conducted to investigate the interaction and joint effects of periodontal pocket depth and hyperglycemia on progression of chronic kidney disease in patients with periodontal diseases. Periodontal pocket depth was utilized for the grading severity of periodontal disease in 2831 patients from January 2002 to June 2013. Progression of chronic kidney disease was defined as progression of color intensity in glomerular filtration rate and albuminuria grid of updated Kidney Disease-Improving Global Outcomes guidelines. Multivariable-adjusted hazard ratios (aHR) in various models were presented across different levels of periodontal pocket depth and hemoglobin A1c (HbA1c) in forest plots and 3-dimensional histograms. During 7621 person-years of follow-up, periodontal pocket depth and HbA1C levels were robustly associated with incremental risks for progression of chronic kidney disease (aHR 3.1; 95% confidence interval [CI], 2.0-4.6 for periodontal pocket depth >4.5 mm, and 2.5; 95% CI, 1.1-5.4 for HbA1C >6.5%, respectively). The interaction between periodontal pocket depth and HbA1C on progression of chronic kidney disease was strong (P <.01). Patients with higher periodontal pocket depth (>4.5 mm) and higher HbA1C (>6.5%) had the greatest risk (aHR 4.2; 95% CI, 1.7-6.8) compared with the lowest aHR group (periodontal pocket depth ≤3.8 mm and HbA1C ≤6%). Our study identified combined periodontal pocket depth and HbA1C as a valuable predictor of progression of chronic kidney disease in patients with periodontal diseases. While considering the interaction between periodontal diseases and hyperglycemia, periodontal survey and optimizing glycemic control are warranted to minimize the risk of worsening renal function. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular dynamics simulations and docking studies on 3D models of the heterodimeric and homodimeric 5-HT(2A) receptor subtype.

PubMed

Bruno, Agostino; Beato, Claudia; Costantino, Gabriele

2011-04-01

G-protein coupled receptors may exist as functional homodimers, heterodimers and even as higher aggregates. In this work, we investigate the 5-HT(2A) receptor, which is a known target for antipsychotic drugs. Recently, 5-HT(2A) has been shown to form functional homodimers and heterodimers with the mGluR2 receptor. The objective of this study is to build up 3D models of the 5-HT(2A)/mGluR2 heterodimer and of the 5-HT(2A)-5-HT(2A) homodimer, and to evaluate the impact of the dimerization interface on the shape of the 5-HT(2A) binding pocket by using molecular dynamics simulations and docking studies. The heterodimer, homodimer and monomeric 5-HT(2A) receptors were simulated by molecular dynamics for 40 ns each. The trajectories were clustered and representative structures of six clusters for each system were generated. Inspection of the these representative structures clearly indicate an effect of the dimerization interface on the topology of the binding pocket. Docking studies allowed to generate receiver operating characteristic curves for a set of 5-HT(2A) ligands, indicating that different complexes prefer different classes of 5-HT(2A) ligands. This study clearly indicates that the presence of a dimerization interface must explicitly be considered when studying G-protein coupled receptors known to exist as dimers. Molecular dynamics simulation and cluster analysis are appropriate tools to study the phenomenon.

An integrated strategy for improving contrast, durability, and portability of a Pocket Colposcope for cervical cancer screening and diagnosis

PubMed Central

Mueller, Jenna; Asma, Betsy; Asiedu, Mercy; Krieger, Marlee S.; Chitalia, Rhea; Dahl, Denali; Taylor, Peyton; Schmitt, John W.; Ramanujam, Nimmi

2018-01-01

Introduction We have previously developed a portable Pocket Colposcope for cervical cancer screening in resource-limited settings. In this manuscript we report two different strategies (cross-polarization and an integrated reflector) to improve image contrast levels achieved with the Pocket Colposcope and evaluate the merits of each strategy compared to a standard-of-care digital colposcope. The desired outcomes included reduced specular reflection (glare), increased illumination beam pattern uniformity, and reduced electrical power budget. In addition, anti-fogging and waterproofing features were incorporated to prevent the Pocket Colposcope from fogging in the vaginal canal and to enable rapid disinfection by submersion in chemical agents. Methods Cross-polarization (Generation 3 Pocket Colposcope) and a new reflector design (Generation 4 Pocket Colposcope) were used to reduce glare and improve contrast. The reflector design (including the angle and height of the reflector sidewalls) was optimized through ray-tracing simulations. Both systems were characterized with a series of bench tests to assess specular reflection, beam pattern uniformity, and image contrast. A pilot clinical study was conducted to compare the Generation 3 and 4 Pocket Colposcopes to a standard-of-care colposcope (Leisegang Optik 2). Specifically, paired images of cervices were collected from the standard-of-care colposcope and either the Generation 3 (n = 24 patients) or the Generation 4 (n = 32 patients) Pocket Colposcopes. The paired images were blinded by device, randomized, and sent to an expert physician who provided a diagnosis for each image. Corresponding pathology was obtained for all image pairs. The primary outcome measures were the level of agreement (%) and κ (kappa) statistic between the standard-of-care colposcope and each Pocket Colposcope (Generation 3 and Generation 4). Results Both generations of Pocket Colposcope had significantly higher image contrast when compared to the standard-of-care colposcope. The addition of anti-fog and waterproofing features to the Generation 3 and 4 Pocket Colposcope did not impact image quality based on qualitative and quantitative metrics. The level of agreement between the Generation 3 Pocket Colposcope and the standard-of-care colposcope was 75.0% (kappa = 0.4000, p = 0.0028, n = 24). This closely matched the level of agreement between the Generation 4 Pocket Colposcope and the standard-of-care colposcope which was also 75.0% (kappa = 0.4941, p = 0.0024, n = 32). Conclusion Our results indicate that the Generation 3 and 4 Pocket Colposcopes perform comparably to the standard-of-care colposcope, with the added benefit of being low-cost and waterproof, which is ideal for use in resource-limited settings. Additionally, the reflector significantly reduces the electrical requirements of the Generation 4 Pocket Colposcope enhancing portability without altering performance compared to the Generation 3 system. PMID:29425225

Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations

PubMed Central

Johnson, David K.; Karanicolas, John

2015-01-01

Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein-bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal structures. Next, we find that the ensembles generated using different members of this protein family are overlapping but distinct, and that the activity of a given compound against a particular family member (ligand selectivity) can be predicted from whether the corresponding ensemble samples a complementary surface pocket. Finally, we find that each ensemble includes certain surface pockets that are not shared by any other family member: while no inhibitors have yet been identified to take advantage of these pockets, we expect that chemical scaffolds complementing these “distinct” pockets will prove highly selective for their targets. The opportunity to achieve target selectivity within a protein family by exploiting differences in surface fluctuations represents a new paradigm that may facilitate design of family-selective small-molecule inhibitors of protein-protein interactions. PMID:25706586

Impact of source height on the characteristic of U-shaped channel tunnel field-effect transistor

NASA Astrophysics Data System (ADS)

Yang, Zhaonian; Zhang, Yue; Yang, Yuan; Yu, Ningmei

2017-11-01

Tunnel field-effect transistor (TFET) is very attractive in replacing a MOSFET, particularly for low-power nanoelectronic circuits. The U-shaped channel TFET (U-TFET) was proposed to improve the drain-source current with a reduced footprint. In this work, the impact of the source height (HS) on the characteristic of the U-shaped channel tunnel field-effect transistor (U-TFET) is investigated by using TCAD simulation. It is found that with a fixed gate height (HG) the drain-source current has a negative correlation with HS. This is because when the gate region is deeper than the source region, the electric field near the corner of the tunneling junction can be enhanced and the tunneling rate is increased. When HS becomes very thin, the drain-source current is limited by the source region volume. The U-TFET with an n+ pocket is also studied and the same trend is observed.

The Hexamer Structure of the Rift Valley Fever Virus Nucleoprotein Suggests a Mechanism for its Assembly into Ribonucleoprotein Complexes

PubMed Central

Ferron, François; Li, Zongli; Danek, Eric I.; Luo, Dahai; Wong, Yeehwa; Coutard, Bruno; Lantez, Violaine; Charrel, Rémi; Canard, Bruno; Walz, Thomas; Lescar, Julien

2011-01-01

Rift Valley fever virus (RVFV), a Phlebovirus with a genome consisting of three single-stranded RNA segments, is spread by infected mosquitoes and causes large viral outbreaks in Africa. RVFV encodes a nucleoprotein (N) that encapsidates the viral RNA. The N protein is the major component of the ribonucleoprotein complex and is also required for genomic RNA replication and transcription by the viral polymerase. Here we present the 1.6 Å crystal structure of the RVFV N protein in hexameric form. The ring-shaped hexamers form a functional RNA binding site, as assessed by mutagenesis experiments. Electron microscopy (EM) demonstrates that N in complex with RNA also forms rings in solution, and a single-particle EM reconstruction of a hexameric N-RNA complex is consistent with the crystallographic N hexamers. The ring-like organization of the hexamers in the crystal is stabilized by circular interactions of the N terminus of RVFV N, which forms an extended arm that binds to a hydrophobic pocket in the core domain of an adjacent subunit. The conformation of the N-terminal arm differs from that seen in a previous crystal structure of RVFV, in which it was bound to the hydrophobic pocket in its own core domain. The switch from an intra- to an inter-molecular interaction mode of the N-terminal arm may be a general principle that underlies multimerization and RNA encapsidation by N proteins from Bunyaviridae. Furthermore, slight structural adjustments of the N-terminal arm would allow RVFV N to form smaller or larger ring-shaped oligomers and potentially even a multimer with a super-helical subunit arrangement. Thus, the interaction mode between subunits seen in the crystal structure would allow the formation of filamentous ribonucleocapsids in vivo. Both the RNA binding cleft and the multimerization site of the N protein are promising targets for the development of antiviral drugs. PMID:21589902

A modeling of elementary passes taking into account the firing angle in abrasive water jet machining of titanium alloy

NASA Astrophysics Data System (ADS)

Bui, Van-Hung; Gilles, Patrick; Cohen, Guillaume; Rubio, Walter

2018-05-01

The use of titanium alloys in the aeronautical and high technology domains is widespread. The high strength and the low mass are two outstanding characteristics of titanium alloys which permit to produce parts for these domains. As other hard materials, it is challenging to generate 3D surfaces (e.g. pockets) when using conventional cutting methods. The development of Abrasive Water Jet Machining (AWJM) technology shows the capability to cut any kind of materials and it seems to be a good solution for such titanium materials with low specific force, low deformation of parts and low thermal shocks. Applying this technology for generating 3D surfaces requires to adopt a modelling approach. However, a general methodology results in complex models due to a lot of parameters of the machining process and based on numerous experiments. This study introduces an extended geometry model of an elementary pass when changing the firing angle during machining Ti-6AL-4V titanium alloy with a given machine configuration. Several experiments are conducted to observe the influence of major kinematic operating parameters, i.e. jet inclination angle (α) (perpendicular to the feed direction) and traverse speed (Vf). The material exposure time and the erosion capability of abrasives particles are affected directly by a variation of the traverse speed (Vf) and firing angle (α). These variations lead to different erosion rates along the kerf profile characterized by the depth and width of cut. A comparison demonstrated an efficiency of the proposed model for depth and width of elementary passes. Based on knowledge of the influence of both firing angle and traverse speed on the elementary pass shape, the proposed model allows to develop the simulation of AWJM process and paves a way for milling flat bottom pockets and 3D complex shapes.

Pockets of Hope: How Students and Teachers Change the World. Series in Language and Ideology.

ERIC Educational Resources Information Center

de los Reyes, Eileen; Gozemba, Patricia A.

This book presents case studies of six "pockets of hope," democratic educational projects in which empowered students and their teachers actively engage with relevant academic and social problems. Although seemingly very different, the projects share a core commitment to democratic pedagogy and demonstrate practices consistent with…

Fabrication and Testing of a Modular Micro-Pocket Fission Detector Instrumentation System for Test Nuclear Reactors

NASA Astrophysics Data System (ADS)

Reichenberger, Michael A.; Nichols, Daniel M.; Stevenson, Sarah R.; Swope, Tanner M.; Hilger, Caden W.; Roberts, Jeremy A.; Unruh, Troy C.; McGregor, Douglas S.

2018-01-01

Advancements in nuclear reactor core modeling and computational capability have encouraged further development of in-core neutron sensors. Measurement of the neutron-flux distribution within the reactor core provides a more complete understanding of the operating conditions in the reactor than typical ex-core sensors. Micro-Pocket Fission Detectors have been developed and tested previously but have been limited to single-node operation and have utilized highly specialized designs. The development of a widely deployable, multi-node Micro-Pocket Fission Detector assembly will enhance nuclear research capabilities. A modular, four-node Micro-Pocket Fission Detector array was designed, fabricated, and tested at Kansas State University. The array was constructed from materials that do not significantly perturb the neutron flux in the reactor core. All four sensor nodes were equally spaced axially in the array to span the fuel-region of the reactor core. The array was filled with neon gas, serving as an ionization medium in the small cavities of the Micro-Pocket Fission Detectors. The modular design of the instrument facilitates the testing and deployment of numerous sensor arrays. The unified design drastically improved device ruggedness and simplified construction from previous designs. Five 8-mm penetrations in the upper grid plate of the Kansas State University TRIGA Mk. II research nuclear reactor were utilized to deploy the array between fuel elements in the core. The Micro-Pocket Fission Detector array was coupled to an electronic support system which has been specially developed to support pulse-mode operation. The Micro-Pocket Fission Detector array composed of four sensors was used to monitor local neutron flux at a constant reactor power of 100 kWth at different axial locations simultaneously. The array was positioned at five different radial locations within the core to emulate the deployment of multiple arrays and develop a 2-dimensional measurement of neutron flux in the reactor core.

Solution structure of the strawberry allergen Fra a 1

PubMed Central

Seutter von Loetzen, Christian; Schweimer, Kristian; Schwab, Wilfried; Rösch, Paul; Hartl-Spiegelhauer, Olivia

2012-01-01

The PR10 family protein Fra a 1E from strawberry (Fragaria x ananassa) is down-regulated in white strawberry mutants, and transient RNAi (RNA interference)-mediated silencing experiments confirmed that Fra a 1 is involved in fruit pigment synthesis. In the present study, we determined the solution structure of Fra a 1E. The protein fold is identical with that of other members of the PR10 protein family and consists of a seven-stranded antiparallel β-sheet, two short V-shaped α-helices and a long C-terminal α-helix that encompass a hydrophobic pocket. Whereas Fra a 1E contains the glycine-rich loop that is highly conserved throughout the protein family, the volume of the hydrophobic pocket and the size of its entrance are much larger than expected. The three-dimensional structure may shed some light on its physiological function and may help to further understand the role of PR10 proteins in plants. PMID:22913709

Pocket-depths-related effectiveness of an intrapocket anaesthesia gel in periodontal maintenance patients.

PubMed

Derman, S H M; Lowden, C E; Kaus, P; Noack, M J

2014-05-01

The aim of this study was to determine the impact of the pocket depth on the effectiveness of an intrapocket anaesthesia gel during SRP in periodontal maintenance patients. Effectiveness was measured by pain levels during SRP via visual analogue scale (VAS) and verbal rating scale (VRS). Secondary endpoint was the evaluation of patients' preferred choice of anaesthesia for SRP. A total of 638 patients undergoing the periodontal maintenance programme and with the need for SRP participated in this observational study. After SRP, patients filled in questionnaires to record pain levels experienced and anaesthesia preference for future use. Mann-Whitney U-test was used to analyse intergroup difference in pain perception and anaesthesia choice. Overall, increasing pocket depths were accompanied by higher pain levels, irrespective of maximum or commonest pocket depths (P < 0.05). For SRP procedures, patients definitely prefer the anaesthesia gel (72.4%). In this study, an effectiveness of local anaesthesia gel (lidocaine/prilocaine) related to pocket depths was found in periodontal maintenance patients during SRP. Increasing pocket depths were accompanied by increasing procedural pain levels. Nevertheless, the anaesthesia gel is well accepted and in the majority of cases was found to be the preferred option for future SRP treatments. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Analysis of the distributional impact of out-of-pocket health payments: evidence from a public health insurance program for the poor in Mexico.

PubMed

Garcia-Diaz, Rocio; Sosa-Rubi, Sandra G; Sosa-Rub, Sandra G

2011-07-01

Many governments have health programs focused on improving health among the poor and these have an impact on out-of-pocket health payments made by individuals. Therefore, one of the objectives of these programs is to reach the poorest and reduce their out-of-pocket expenditure. In this paper we propose the distributional poverty impact approach to measure the poverty impact of out-of-pocket health payments of different health financing policies. This approach is comparable to the impoverishment methodology proposed by Wagstaff and van Doorslaer (2003) that compares poverty indices before and after out-of-pocket health payments. In order to escape the specification of a particular poverty index, we use the marginal dominance approach that uses non-intersecting curves and can rank poverty reducing health financing policies. We present an empirical application of the out-of-pocket health payments for an innovative social financing policy implemented in Mexico named Seguro Popular. The paper finds evidence that Seguro Popular program has a better distributional poverty impact when families face illness when compared to other poverty reducing policies. The empirical dominance approach uses data from Mexico in 2006 and considers international poverty standards of $2 per person per day. Copyright © 2011 Elsevier B.V. All rights reserved.

Accelerometer's position independent physical activity recognition system for long-term activity monitoring in the elderly.

PubMed

Khan, Adil Mehmood; Lee, Young-Koo; Lee, Sungyoung; Kim, Tae-Seong

2010-12-01

Mobility is a good indicator of health status and thus objective mobility data could be used to assess the health status of elderly patients. Accelerometry has emerged as an effective means for long-term physical activity monitoring in the elderly. However, the output of an accelerometer varies at different positions on a subject's body, even for the same activity, resulting in high within-class variance. Existing accelerometer-based activity recognition systems thus require firm attachment of the sensor to a subject's body. This requirement makes them impractical for long-term activity monitoring during unsupervised free-living as it forces subjects into a fixed life pattern and impede their daily activities. Therefore, we introduce a novel single-triaxial-accelerometer-based activity recognition system that reduces the high within-class variance significantly and allows subjects to carry the sensor freely in any pocket without its firm attachment. We validated our system using seven activities: resting (lying/sitting/standing), walking, walking-upstairs, walking-downstairs, running, cycling, and vacuuming, recorded from five positions: chest pocket, front left trousers pocket, front right trousers pocket, rear trousers pocket, and inner jacket pocket. Its simplicity, ability to perform activities unimpeded, and an average recognition accuracy of 94% make our system a practical solution for continuous long-term activity monitoring in the elderly.

Detailed conformation dynamics and activation process of wild type c-Abl and T315I mutant

NASA Astrophysics Data System (ADS)

Yang, Li-Jun; Zhao, Wen-Hua; Liu, Qian

2014-10-01

Bcr-Abl is an important target for therapy against chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). The synergistic effect between myristyl pocket and the ATP pocket has been found. But its detailed information based on molecular level still has not been achieved. In this study, conventional molecular dynamics (CMD) and target molecular dynamics (TMD) simulations were performed to explore the effect of T315I mutation on dynamics and activation process of Abl containing the N-terminal cap (Ncap). The CMD simulation results reveal the increasing flexibility of ATP pocket in kinase domain (KD) after T315I mutation which confirms the disability of ATP-pocket inhibitors to the Abl-T315I mutant. On the contrary, the T315I mutation decreased the flexibility of remote helix αI which suggests the synergistic effect between them. The mobility of farther regions containing Ncap, SH3, SH2 and SH2-KD linker were not affected by T315I mutation. The TMD simulation results show that the activation process of wild type Abl and Abl-T315I mutant experienced global conformation change. Their differences were elucidated by the activation motion of subsegments including A-loop, P-loop and Ncap. Besides, the T315I mutation caused decreasing energy barrier and increasing intermediate number in activation process, which results easier activation process. The TMD and CMD results indicate that a drug targeting only the ATP pocket is not enough to inhibit the Abl-T315I mutant. An effective way to inhibit the abnormal activity of Abl-T315I mutant is to combine the ATP-pocket inhibitors with inhibitors binding at non-ATP pockets mainly related to Ncap, SH2-KD linker and myristyl pocket.

Full pockets, empty lives: a psychoanalytic exploration of the contemporary culture of greed.

PubMed

Wachtel, Paul L

2003-06-01

This paper offers a psychoanalytic exploration of the dynamics of greed in individual lives and ways that those dynamics both reflect and influence the surrounding culture. The paper discusses the contradictions associated with the consumerist pursuit of wealth and goods, and finds evidence for the failure of such pursuit to provide the satisfaction that is anticipated. It also examines the implications for psychoanalytic theorizing on the ways in which ongoing social forces and institutions contribute to shaping the psyche.

Habitat associations of vertebrate prey within the controlled area study zone

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

Marr, N.V.; Brandt, C.A.; Fitzner, R.E.

1988-03-01

Twelve study locations were established in nine habitat types in the vicinity of the proposed reference repository location. Eight species of small mammals were captured. Great Basin pocket mice (Perognathus parvus) comprised the majority of individuals captured, followed by deer mice (Peromyscus maniculatus), Northern pocket gopher (Thomomys talpoides), Western harvest mouse (Reithrodontomys megalotus), Grasshopper mouse (Onychomys leucogaster), Montane vole, (Microtus montanus), House mouse (Mus musculus), and the Bushy-tailed woodrat (Neotoma cinerea). Pocket mice were captured in all habitats sampled; deer mice were obtained in all habitats save hopsage and nearly pure cheatgrass stands. The highese capture rates were found inmore » bitterbrush and riparian habitats. Capture sex ratios for both pocket mice and deer mice were significantly different from equality. Body weights for deer mice and pocket mice exhibited a great deal of heterogeneity across trap sites, although only the heterogeneity for pocket mice was significant. In general, body weights for both species were greater in the sagebrush habitats than elsewhere. These differences are interpreted in light of habitat evaluation methodologies. Six species of reptiles and one species of amphibian were captured. Side-blotched lizards (Uta stansburiana) were by far the most frequently captured species. The predominant snakes captured were the yellow-bellied racer (Coluber constrictor) and the Great Basin gopher snake (Pituophis melanoleucus). Two Great Basin spadefoot toads (Scaphiopus intermontanus) captured at the Rattlesnake Springs trap site. Species diversity was quite low (Shannon-Wiener H )equals) 1.03). Side-blotched lizards were found in all habitats save near the talus on Gable Mountain and on the gravel pad site. The only other lizard species (northern sagebrush lizard (Sceloporus graciosus) and short-horned lizard (Phrynosoma douglasii)) were obtained in bitterbrush habitat. 20 refs., 1 fig., 9 tabs.« less

Quantifying Queensland patients with cancer health service usage and costs: study protocol

PubMed Central

Callander, Emily; Topp, Stephanie M; Larkins, Sarah; Sabesan, Sabe

2017-01-01

Introduction The overall mortality rate for cancer has declined in Australia. However, socioeconomic inequalities exist and the out-of-pocket costs incurred by patients in Australia are high compared with some European countries. There is currently no readily available data set to provide a systematic means of measuring the out-of-pocket costs incurred by patients with cancer within Australia. The primary aim of the project is to quantify the direct out-of-pocket healthcare expenditure of individuals in the state of Queensland, who are diagnosed with cancer. Methods and analysis This project will build Australia's first model (called CancerCostMod) of out-of-pocket healthcare expenditure of patients with cancer using administrative data from Queensland Cancer Registry, for all individuals diagnosed with any cancer in Queensland between 1 July 2011 and 30 June 2012, linked to their Admitted Patient Data Collection, Emergency Department Information System, Medicare Benefits Schedule and Pharmaceutical Benefits Scheme records from 1 July 2011 to 30 June 2015. No identifiable information will be provided to the authors. The project will use a combination of linear and logistic regression modelling, Cox proportional hazards modelling and machine learning to identify differences in survival, total health system expenditure, total out-of-pocket expenditure and high out-of-pocket cost patients, adjusting for demographic and clinical confounders, and income group, Indigenous status and geographic location. Results will be analysed separately for different types of cancer. Ethics and dissemination Human Research Ethics approval has been obtained from the Townsville Hospital and Health Service Human Research Ethics Committee (HREC/16/QTHS/110) and James Cook University Human Research Ethics Committee (H6678). Permission to waive consent has been sought from Queensland Health under the Public Health Act 2005. PMID:28119391

Patterns and determinants of communal latrine usage in urban poverty pockets in Bhopal, India.

PubMed

Biran, A; Jenkins, M W; Dabrase, P; Bhagwat, I

2011-07-01

To explore and explain patterns of use of communal latrine facilities in urban poverty pockets. Six poverty pockets with communal latrine facilities representing two management models (Sulabh and municipal) were selected. Sampling was random and stratified by poverty pocket population size. A seventh, community-managed facility was also included. Data were collected by exit interviews with facility users and by interviews with residents from a randomly selected representative sample of poverty pocket households, on social, economic and demographic characteristics of households, latrine ownership, defecation practices, costs of using the facility and distance from the house to the facility. A tally of facility users was kept for 1 day at each facility. Data were analysed using logistic regression modelling to identify determinants of communal latrine usage. Communal latrines differed in their facilities, conditions, management and operating characteristics, and rates of usage. Reported usage rates among non-latrine-owning households ranged from 15% to 100%. There was significant variation in wealth, occupation and household structure across the poverty pockets as well as in household latrine ownership. Households in pockets with municipal communal latrine facilities appeared poorer. Households in pockets with Sulabh-managed communal facilities were significantly more likely to own a household latrine. Determinants of communal facility usage among households without a latrine were access and convenience (distance and opening hours), facility age, cleanliness/upkeep and cost. The ratio of male to female users was 2:1 across all facilities for both adults and children. Provision of communal facilities reduces but does not end the problem of open defecation in poverty pockets. Women appear to be relatively poorly served by communal facilities and, cost is a barrier to use by poorer households. Results suggest improving facility convenience and access and modifying fee structures could lead to increased rates of usage. Attention to possible barriers to usage at household level associated particularly with having school-age children and with pre-school childcare needs may also be warranted. © 2011 Blackwell Publishing Ltd.

Evolutionary plasticity of the NHL domain underlies distinct solutions to RNA recognition.

PubMed

Kumari, Pooja; Aeschimann, Florian; Gaidatzis, Dimos; Keusch, Jeremy J; Ghosh, Pritha; Neagu, Anca; Pachulska-Wieczorek, Katarzyna; Bujnicki, Janusz M; Gut, Heinz; Großhans, Helge; Ciosk, Rafal

2018-04-19

RNA-binding proteins regulate all aspects of RNA metabolism. Their association with RNA is mediated by RNA-binding domains, of which many remain uncharacterized. A recently reported example is the NHL domain, found in prominent regulators of cellular plasticity like the C. elegans LIN-41. Here we employ an integrative approach to dissect the RNA specificity of LIN-41. Using computational analysis, structural biology, and in vivo studies in worms and human cells, we find that a positively charged pocket, specific to the NHL domain of LIN-41 and its homologs (collectively LIN41), recognizes a stem-loop RNA element, whose shape determines the binding specificity. Surprisingly, the mechanism of RNA recognition by LIN41 is drastically different from that of its more distant relative, the fly Brat. Our phylogenetic analysis suggests that this reflects a rapid evolution of the domain, presenting an interesting example of a conserved protein fold that acquired completely different solutions to RNA recognition.

KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry

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

Lu, Jia; Harrison, Rane A.; Li, Lianbo

KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basismore » for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.« less

The genus Krithe (Ostracoda) from the Campanian and Maastrichtian (Upper Cretaceous) of the northern US Gulf Coastal Plain

USGS Publications Warehouse

Puckett, T.M.

1997-01-01

The ostracode genus Krithe is one of the most common genera in the Upper Cretaceous (late Santonian to Maastrichtian) deposits of the northern Gulf Coastal Plain of North America. Although it is never abundant, the genus occurs in sediments that were deposited under a wide range of palaeoenvironments, including nearshore sandy marls to offshore, nearly pure, chalk. The taxonomy of this taxon has been problematical, and what is herein considered to be a single species, K. cushmani, has been referred to in the literature under five different names. Two morphotypes were observed: relatively large individuals with 'mushroom'-shaped vestibules collected from chalk, and smaller individuals with pocket-shaped vestibules collected from nearshore deposits. Species of Krithe have been hypothesized to be useful in estimating dissolved oxygen concentration in ancient ocean floors, based on details of their morphology. Whereas the relationship between size and environment corroborates with previous predictions (larger individuals live in deeper water), the morphology of the vestibules contradicts predictions (the larger vestibules occur in the nearshore deposits and the smaller, more constricted vestibules occur in the chalk). A causal relationship between environment and morphology is discussed.

Characterization of the allosteric binding pocket of human liver fructose-1,6-bisphosphatase by protein crystallography and inhibitor activity studies.

PubMed

Iversen, L F; Brzozowski, M; Hastrup, S; Hubbard, R; Kastrup, J S; Larsen, I K; Naerum, L; Nørskov-Lauridsen, L; Rasmussen, P B; Thim, L; Wiberg, F C; Lundgren, K

1997-05-01

The structures of three complexes of human fructose-1,6-bisphosphatase (FB) with the allosteric inhibitor AMP and two AMP analogues have been determined and all fully refined. The data used for structure determination were collected at cryogenic temperature (110 K), and with the use of synchrotron radiation. The structures reveal a common mode of binding for AMP and formycine monophosphate (FMP). 5-Amino-4-carboxamido-1 beta-D-5-phosphate-ribofuranosyl-1H-imidazole (AICAR-P) shows an unexpected mode of binding to FB, different from that of the other two ligands. The imidazole ring of AICAR-P is rotated 180 degrees compared to the AMP and FMP bases. This rotation results in a slightly different hydrogen bonding pattern and minor changes in the water structure in the binding pocket. Common features of binding are seen for the ribose and phosphate moieties of all three compounds. Although binding in a different mode, AICAR-P is still capable of making all the important interactions with the residues building the allosteric binding pocket. The IC50 values of AMP, FMP, and AICAR-P were determined to be 1.7, 1.4, and 20.9 microM, respectively. Thus, the approximately 10 times lower potency of AICAR-P is difficult to explain solely from the variations observed in the binding pocket. Only one water molecule in the allosteric binding pocket was found to be conserved in all four subunits in all three structures. This water molecule coordinates to a phosphate oxygen atom and the N7 atom of the AMP molecule, and to similarly situated atoms in the FMP and AICAR-P complexes. This implies an important role of the conserved water molecule in binding of the ligand.

Characterization of the allosteric binding pocket of human liver fructose-1,6-bisphosphatase by protein crystallography and inhibitor activity studies.

PubMed Central

Iversen, L. F.; Brzozowski, M.; Hastrup, S.; Hubbard, R.; Kastrup, J. S.; Larsen, I. K.; Naerum, L.; Nørskov-Lauridsen, L.; Rasmussen, P. B.; Thim, L.; Wiberg, F. C.; Lundgren, K.

1997-01-01

The structures of three complexes of human fructose-1,6-bisphosphatase (FB) with the allosteric inhibitor AMP and two AMP analogues have been determined and all fully refined. The data used for structure determination were collected at cryogenic temperature (110 K), and with the use of synchrotron radiation. The structures reveal a common mode of binding for AMP and formycine monophosphate (FMP). 5-Amino-4-carboxamido-1 beta-D-5-phosphate-ribofuranosyl-1H-imidazole (AICAR-P) shows an unexpected mode of binding to FB, different from that of the other two ligands. The imidazole ring of AICAR-P is rotated 180 degrees compared to the AMP and FMP bases. This rotation results in a slightly different hydrogen bonding pattern and minor changes in the water structure in the binding pocket. Common features of binding are seen for the ribose and phosphate moieties of all three compounds. Although binding in a different mode, AICAR-P is still capable of making all the important interactions with the residues building the allosteric binding pocket. The IC50 values of AMP, FMP, and AICAR-P were determined to be 1.7, 1.4, and 20.9 microM, respectively. Thus, the approximately 10 times lower potency of AICAR-P is difficult to explain solely from the variations observed in the binding pocket. Only one water molecule in the allosteric binding pocket was found to be conserved in all four subunits in all three structures. This water molecule coordinates to a phosphate oxygen atom and the N7 atom of the AMP molecule, and to similarly situated atoms in the FMP and AICAR-P complexes. This implies an important role of the conserved water molecule in binding of the ligand. PMID:9144768

Use of a pocket compression device for the prevention and treatment of pocket hematoma after pacemaker and defibrillator implantation (STOP-HEMATOMA-I).

PubMed

Turagam, Mohit K; Nagarajan, Darbhamulla V; Bartus, Krzysztof; Makkar, Akash; Swarup, Vijay

2017-08-01

Pocket hematoma is a recognized complication after placement of cardiac implantable electronic devices and is associated with increased device infection, length of hospitalization, and morbidity especially with uninterrupted antiplatelet agents and anticoagulants. We assessed the use of a post-surgical vest to decrease the incidence of pocket hematoma in patients undergoing device implantation with uninterrupted antiplatelet and anticoagulants. In this observational study, a vest was used by 20 consecutive patients who were compared to 20 age-, gender-, procedure-matched patients who received standard care. All patients were continued on antiplatelet and anticoagulants in the perioperative period. The pocket was assessed at post procedure day 0, 2, and 7, respectively. There were no significant differences in the baseline characteristics between both groups. Baseline mean international normalized ratio (INR) was significantly higher in the vest group when compared with the control group (2.7 ± 0.4 vs. 2.2 ± 0.3 = <0.001). The incidence of pocket hematoma was significantly lower in the vest group than the control group (0 vs 30%, p = 0.02) at the end of 7 days. Control group had a total of six hematomas with one patient requiring evacuation and blood transfusion. The vest group had three hematomas on day 2 that resolved by day 7. The risk of moderate or large pocket hematoma is significantly reduced with the use of this vest in high-risk patients undergoing implantable devices on uninterrupted antiplatelet and anticoagulants.

MSPocket: an orientation-independent algorithm for the detection of ligand binding pockets.

PubMed

Zhu, Hongbo; Pisabarro, M Teresa

2011-02-01

Identification of ligand binding pockets on proteins is crucial for the characterization of protein functions. It provides valuable information for protein-ligand docking and rational engineering of small molecules that regulate protein functions. A major number of current prediction algorithms of ligand binding pockets are based on cubic grid representation of proteins and, thus, the results are often protein orientation dependent. We present the MSPocket program for detecting pockets on the solvent excluded surface of proteins. The core algorithm of the MSPocket approach does not use any cubic grid system to represent proteins and is therefore independent of protein orientations. We demonstrate that MSPocket is able to achieve an accuracy of 75% in predicting ligand binding pockets on a test dataset used for evaluating several existing methods. The accuracy is 92% if the top three predictions are considered. Comparison to one of the recently published best performing methods shows that MSPocket reaches similar performance with the additional feature of being protein orientation independent. Interestingly, some of the predictions are different, meaning that the two methods can be considered complementary and combined to achieve better prediction accuracy. MSPocket also provides a graphical user interface for interactive investigation of the predicted ligand binding pockets. In addition, we show that overlap criterion is a better strategy for the evaluation of predicted ligand binding pockets than the single point distance criterion. The MSPocket source code can be downloaded from http://appserver.biotec.tu-dresden.de/MSPocket/. MSPocket is also available as a PyMOL plugin with a graphical user interface.

Burden of common multiple-morbidity constellations on out-of-pocket medical expenditures among older adults.

PubMed

Schoenberg, Nancy E; Kim, Hyungsoo; Edwards, William; Fleming, Steven T

2007-08-01

On average, adults aged 60 years or older have 2.2 chronic diseases, contributing to the over 60 million Americans with multiple morbidities. We aimed to understand the financial implications of the most frequent multiple morbidities among older adults. We analyzed Health and Retirement Study data, determining out-of-pocket medical expenses from 1998 and 2002 separately and examining differences in the impact of multiple-morbidity constellations on these expenses. We paid particular attention to the most common disease constellations - hypertension, arthritis, and heart disease. An increasing prevalence of multiple morbidity (58% compared with 70% of adults had two or more chronic conditions in 1998 and 2002, respectively) was accompanied by escalating out-of-pocket expenditures (2,164 dollars in 1998, increasing by 104% to 3,748 dollars in 2002). Individuals with two, three, and four chronic conditions had health care expenditure increases of 41%, 85%, and 100%, respectively, over 4 years. Such patterns were particularly noticeable among the oldest old, those with higher educational attainment, and women, although having supplementary health insurance or Medicaid mitigated these expenses. Finally, there were significant differences in out-of-pocket expenditure levels among the multiple-morbidity combinations. Increasing rates of multiple morbidities in conjunction with escalating health care costs and stable or declining incomes among elders warrant creative attention from providers, researchers, and policy makers. Further understanding how specific multiple-morbidity constellations impact out-of-pocket spending moves us closer to effective interventions to support vulnerable elders.

Treatment of fingertip amputation: comparison of results between microsurgical replantation and pocket principle.

PubMed

Yabe, Tetsuji; Tsuda, Tomoyuki; Hirose, Shunsuke; Ozawa, Toshiyuki

2012-05-01

In this article, a comparison of replantation using microsurgical replantation (replantation) and the Brent method and its modification (pocket principle) in the treatment of fingertip amputation is reported. As a classification of amputation level, we used Ishikawa's subzone classification of fingertip amputation, and the cases of amputations only in subzone 2 were included in this study. Between these two groups, there was no statistical difference in survival rate, postoperative atrophy, or postoperative range of motion. In terms of sensory recovery, some records were lost and exact study was difficult. But there was no obvious difference between these cases. In our comparison of microsurgical replantation versus the pocket principle in treatment of subzone 2 fingertip amputation, there was no difference in postoperative results. Each method has pros and cons, and the surgeon should choose which technique to use based on his or her understanding of the characteristics of both methods. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Computational analysis of protein-protein interfaces involving an alpha helix: insights for terphenyl-like molecules binding.

PubMed

Isvoran, Adriana; Craciun, Dana; Martiny, Virginie; Sperandio, Olivier; Miteva, Maria A

2013-06-14

Protein-Protein Interactions (PPIs) are key for many cellular processes. The characterization of PPI interfaces and the prediction of putative ligand binding sites and hot spot residues are essential to design efficient small-molecule modulators of PPI. Terphenyl and its derivatives are small organic molecules known to mimic one face of protein-binding alpha-helical peptides. In this work we focus on several PPIs mediated by alpha-helical peptides. We performed computational sequence- and structure-based analyses in order to evaluate several key physicochemical and surface properties of proteins known to interact with alpha-helical peptides and/or terphenyl and its derivatives. Sequence-based analysis revealed low sequence identity between some of the analyzed proteins binding alpha-helical peptides. Structure-based analysis was performed to calculate the volume, the fractal dimension roughness and the hydrophobicity of the binding regions. Besides the overall hydrophobic character of the binding pockets, some specificities were detected. We showed that the hydrophobicity is not uniformly distributed in different alpha-helix binding pockets that can help to identify key hydrophobic hot spots. The presence of hydrophobic cavities at the protein surface with a more complex shape than the entire protein surface seems to be an important property related to the ability of proteins to bind alpha-helical peptides and low molecular weight mimetics. Characterization of similarities and specificities of PPI binding sites can be helpful for further development of small molecules targeting alpha-helix binding proteins.

Interconnected Cavernous Structure of Bacterial Fruiting Bodies

DOE PAGES

Harvey, Cameron W.; Du, Huijing; Xu, Zhiliang; ...

2012-12-27

The formation of spore-filled fruiting bodies by myxobacteria is a fascinating case of multicelular self-organization by bacteria. The organization of Myxococcus xanthus into fruiting bodies has long been studied not only as an important example of collective motion of bacteria, but also as a simplified model for developmental morphogenesis. Sporulation within the nascent fruiting body requires signaling between moving cells in order that the rod-shaped self-propelled cells differentiate into spores at the appropriate time. Probing the three-dimensional structure of myxobacteria fruiting bodies has previously presented a challenge due to Imitations at different imaging methods. A new technique using Infrared Opticalmore » Coherence Tomography (OCT) revealed previously unknown details of the Internal structure of M. xanthus fruiting bodies consisting of interconnected pockets of relative nigh and low spore density regions. Here, to make sense of the experimentally observed structure, modeling and computer simulations were used to test a hypothesized mechanism that could produce high density pockets of spores. The mechanism consists of self-propelled cells aligning with each other and signaling by end-to-end contact to coordinate the process of differentiation resulting in a pattern of clusters observed in the experiment. The Integration of novel OCT experimental techniques with computational simulations can provide new insight Into the mechanisms that can give rise to the pattern formation seen In other biological systems such as dlctyostelids, social amoeba known to form multicellular aggregates observed as slugs under starvation conditions.« less

Measuring the shapes of macromolecules – and why it matters

PubMed Central

Li, Jie; Mach, Paul; Koehl, Patrice

2013-01-01

The molecular basis of life rests on the activity of biological macromolecules, mostly nucleic acids and proteins. A perhaps surprising finding that crystallized over the last handful of decades is that geometric reasoning plays a major role in our attempt to understand these activities. In this paper, we address this connection between geometry and biology, focusing on methods for measuring and characterizing the shapes of macromolecules. We briefly review existing numerical and analytical approaches that solve these problems. We cover in more details our own work in this field, focusing on the alpha shape theory as it provides a unifying mathematical framework that enable the analytical calculations of the surface area and volume of a macromolecule represented as a union of balls, the detection of pockets and cavities in the molecule, and the quantification of contacts between the atomic balls. We have shown that each of these quantities can be related to physical properties of the molecule under study and ultimately provides insight on its activity. We conclude with a brief description of new challenges for the alpha shape theory in modern structural biology. PMID:24688748

Effect of Uniform Design on the Speed of Combat Tourniquet Application: A Simulation Study.

PubMed

Higgs, Andrew R; Maughon, Michael J; Ruland, Robert T; Reade, Michael C

2016-08-01

Tourniquets are issued to deployed members of both the United States (U.S. military and the Australian Defence Force (ADF). The ease of removing the tourniquet from the pocket of the combat uniform may influence its time to application. The ADF uniform uses buttons to secure the pocket, whereas the U.S. uniform uses a hook and loop fastener system. National differences in training may influence the time to and effectiveness of tourniquet application. To compare the time taken to retrieve and apply a tourniquet from the pocket of the Australian and the U.S. combat uniform and compare the effectiveness of tourniquet application. Twenty participants from both nations were randomly selected. Participants were timed on their ability to remove a tourniquet from their pockets and then apply it effectively. The U.S. personnel removed their tourniquets in shorter time (median 2.5 seconds) than Australians (median 5.72 seconds, p < 0.0001). ADF members (mean 41.36 seconds vs. 58.87 seconds, p < 0.037) applied the tourniquet more rapidly once removed from the pocket and trended to apply it more effectively (p = 0.1). The closure system of pockets on the combat uniform might influence the time taken to apply a tourniquet. Regular training might also reduce the time taken to apply a tourniquet effectively. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

Molecular Determinants of Magnolol Targeting Both RXRα and PPARγ

PubMed Central

Chen, Lili; Chen, Jing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

2011-01-01

Nuclear receptors retinoic X receptor α (RXRα) and peroxisome proliferator activated receptor γ (PPARγ) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRα and PPARγ is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRα and PPARγ. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy. Although magnolol can bind and activate both of these two nuclear receptors, the transactivation assays indicate that magnolol exhibits biased agonism on the transcription of PPAR-response element (PPRE) mediated by RXRα:PPARγ heterodimer, instead of RXR-response element (RXRE) mediated by RXRα:RXRα homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXRα and PPARγ ligand-binding domains (LBDs) with magnolol. Structural analyses reveal that magnolol adopts its two 5-allyl-2-hydroxyphenyl moieties occupying the acidic and hydrophobic cavities of RXRα L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPARγ Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXRα and PPARγ are determined. As the first report on the dual agonist targeting RXRα and PPARγ with receptor-ligand complex structures, our results are thus expected to help inspect the potential pharmacological mechanism for magnolol functions, and supply useful hits for nuclear receptor multi-target ligand design. PMID:22140563

Crystal structure of the solute-binding protein BxlE from Streptomyces thermoviolaceus OPC-520 complexed with xylobiose.

PubMed

Tomoo, Koji; Miki, Yasuhiro; Morioka, Hideaki; Seike, Kiho; Ishida, Toshimasa; Ikenishi, Sadao; Miyamoto, Katsushiro; Hasegawa, Tomokazu; Yamano, Akihito; Hamada, Kensaku; Tsujibo, Hiroshi

2017-06-01

BxlE from Streptomyces thermoviolaceus OPC-520 is a xylo-oligosaccharide (mainly xylobiose)-binding protein that serves as the initial receptor for the bacterial ABC-type xylo-oligosaccharide transport system. To determine the ligand-binding mechanism of BxlE, X-ray structures of ligand-free (open form) and ligand (xylobiose)-bound (closed form) BxlE were determined at 1.85 Å resolution. BxlE consists of two globular domains that are linked by two β-strands, with the cleft at the interface of the two domains creating the ligand-binding pocket. In the ligand-free open form, this pocket consists of a U-shaped and negatively charged groove located between the two domains. In the xylobiose-bound closed form of BxlE, both the N and C domains move to fold the ligand without conformational changes in either domain. Xylobiose is buried in the groove and wrapped by the N-domain mainly via hydrogen bond interactions and by the C-domain primarily via non-polar interactions with Trp side chains. In addition to the concave shape matching the binding of xylobiose, an inter-domain salt bridge between Asp-47 and Lys-294 limits the space in the ligand-binding site. This domain-stabilized mechanism of ligand binding to BxlE is a unique feature that is not observed with other solute-binding proteins. © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Formation of superheavy elements in the capture of very heavy ions at high excitation energies

NASA Astrophysics Data System (ADS)

Royer, G.

2013-05-01

The potential barriers governing the reactions 58Fe+244Pu, 238U+64Ni, and 238U+72Ge have been determined from a liquid-drop model taking into account the proximity energy, shell energies, rotational energy, and deformation of the incoming nuclei in the quasimolecular shape valley. Double-humped potential barriers appear in these entrance channels. The external saddle-point corresponds to two touching ellipsoidal nuclei when the shell and pairing effects are taken into account, while the inner barrier is due to the shell effects at the vicinity of the spherical shape of the composite system. Between them, a large potential pocket exists and persists at very high angular momenta allowing the capture of very heavy ions at high excitation energies.

Occupation of the cytochrome P450 substrate pocket by diverse compounds at general anesthesia concentrations.

PubMed

LaBella, F S; Stein, D; Queen, G

1998-10-02

Each of a diverse array of compounds, at concentrations reported to effect general anesthesia, when added to liver microsomes, forms a complex with cytochromes P450 to generate, with reference to a cuvette containing microsomes only, a characteristic absorbance-difference spectrum. This spectrum results from a change in the electron-spin state of the heme iron atom induced upon entry by the anesthetic molecule into the enzyme catalytic pocket. The difference spectrum, representing the anesthetic-P450 complex, is characteristic of substances that are substrates for the enzyme. For the group of compounds as a whole, the magnitudes of the absorbance-difference spectra vary only about twofold, although the anesthetic potencies vary by several orders of magnitude. The dissociation constants (Ks), calculated from absorbance data and representing affinities of the anesthetics for P450, agree closely with the respective EC50 (concentration that effects anesthesia in 50% of individuals) values, and with the respective Ki (concentration that inhibits P450 catalytic activities half-maximally) values reported by us previously. The absorbance complex resulting from the occupation of the catalytic pocket by endogenous substrates, androstenedione and arachidonic acid, is inhibited, competitively, by anesthetics. Occupation of and perturbation of the heme catalytic pocket by anesthetic, as monitored by the absorbance-difference spectrum, is rapidly reversible. The presumed in vivo consequences of perturbation by general anesthetics of heme proteins is suppression of the generation of chemical signals that determine cell sensitivity and response.

A review of MEMS micropropulsion technologies for CubeSats and PocketQubes

NASA Astrophysics Data System (ADS)

Silva, Marsil A. C.; Guerrieri, Daduí C.; Cervone, Angelo; Gill, Eberhard

2018-02-01

CubeSats have been extensively used in the past decade as scientific tools, technology demonstrators and for education. Recently, PocketQubes have emerged as an interesting and even smaller alternative to CubeSats. However, both satellite types often lack some key capabilities, such as micropropulsion, in order to further extend the range of applications of these small satellites. This paper reviews the current development status of micropropulsion systems fabricated with MEMS (micro electro-mechanical systems) and silicon technology intended to be used in CubeSat or PocketQube missions and compares different technologies with respect to performance parameters such as thrust, specific impulse, and power as well as in terms of operational complexity. More than 30 different devices are analyzed and divided into 7 main categories according to the working principle. A specific outcome of the research is the identification of the current status of MEMS technologies for micropropulsion including key opportunities and challenges.

A fossil biting midge (Diptera: Ceratopogonidae) from early Eocene Indian amber with a complex pheromone evaporator

NASA Astrophysics Data System (ADS)

Stebner, Frauke; Szadziewski, Ryszard; Rühr, Peter T.; Singh, Hukam; Hammel, Jörg U.; Kvifte, Gunnar Mikalsen; Rust, Jes

2016-10-01

The life-like fidelity of organisms captured in amber is unique among all kinds of fossilization and represents an invaluable source for different fields of palaeontological and biological research. One of the most challenging aspects in amber research is the study of traits related to behaviour. Here, indirect evidence for pheromone-mediated mating behaviour is recorded from a biting midge (Ceratopogonidae) in 54 million-year-old Indian amber. Camptopterohelea odora n. sp. exhibits a complex, pocket shaped structure on the wings, which resembles the wing folds of certain moth flies (Diptera: Psychodidae) and scent organs that are only known from butterflies and moths (Lepidoptera) so far. Our studies suggests that pheromone releasing structures on the wings have evolved independently in biting midges and might be much more widespread in fossil as well as modern insects than known so far.

A fossil biting midge (Diptera: Ceratopogonidae) from early Eocene Indian amber with a complex pheromone evaporator.

PubMed

Stebner, Frauke; Szadziewski, Ryszard; Rühr, Peter T; Singh, Hukam; Hammel, Jörg U; Kvifte, Gunnar Mikalsen; Rust, Jes

2016-10-04

The life-like fidelity of organisms captured in amber is unique among all kinds of fossilization and represents an invaluable source for different fields of palaeontological and biological research. One of the most challenging aspects in amber research is the study of traits related to behaviour. Here, indirect evidence for pheromone-mediated mating behaviour is recorded from a biting midge (Ceratopogonidae) in 54 million-year-old Indian amber. Camptopterohelea odora n. sp. exhibits a complex, pocket shaped structure on the wings, which resembles the wing folds of certain moth flies (Diptera: Psychodidae) and scent organs that are only known from butterflies and moths (Lepidoptera) so far. Our studies suggests that pheromone releasing structures on the wings have evolved independently in biting midges and might be much more widespread in fossil as well as modern insects than known so far.

A fossil biting midge (Diptera: Ceratopogonidae) from early Eocene Indian amber with a complex pheromone evaporator

PubMed Central

Stebner, Frauke; Szadziewski, Ryszard; Rühr, Peter T.; Singh, Hukam; Hammel, Jörg U.; Kvifte, Gunnar Mikalsen; Rust, Jes

2016-01-01

The life-like fidelity of organisms captured in amber is unique among all kinds of fossilization and represents an invaluable source for different fields of palaeontological and biological research. One of the most challenging aspects in amber research is the study of traits related to behaviour. Here, indirect evidence for pheromone-mediated mating behaviour is recorded from a biting midge (Ceratopogonidae) in 54 million-year-old Indian amber. Camptopterohelea odora n. sp. exhibits a complex, pocket shaped structure on the wings, which resembles the wing folds of certain moth flies (Diptera: Psychodidae) and scent organs that are only known from butterflies and moths (Lepidoptera) so far. Our studies suggests that pheromone releasing structures on the wings have evolved independently in biting midges and might be much more widespread in fossil as well as modern insects than known so far. PMID:27698490

PL-PatchSurfer: a novel molecular local surface-based method for exploring protein-ligand interactions.

PubMed

Hu, Bingjie; Zhu, Xiaolei; Monroe, Lyman; Bures, Mark G; Kihara, Daisuke

2014-08-27

Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer). PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD). We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets.

PL-PatchSurfer: A Novel Molecular Local Surface-Based Method for Exploring Protein-Ligand Interactions

PubMed Central

Hu, Bingjie; Zhu, Xiaolei; Monroe, Lyman; Bures, Mark G.; Kihara, Daisuke

2014-01-01

Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer). PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD). We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets. PMID:25167137

Out-of-pocket medical expenses for inpatient care among beneficiaries of the National Health Insurance Program in the Philippines.

PubMed

Tobe, Makoto; Stickley, Andrew; del Rosario, Rodolfo B; Shibuya, Kenji

2013-08-01

OBJECTIVE The National Health Insurance Program (NHIP) in the Philippines is a social health insurance system partially subsidized by tax-based financing which offers benefits on a fee-for-service basis up to a fixed ceiling. This paper quantifies the extent to which beneficiaries of the NHIP incur out-of-pocket expenses for inpatient care, and examines the characteristics of beneficiaries making these payments and the hospitals in which these payments are typically made. METHODS Probit and ordinary least squares regression analyses were carried out on 94 531 insurance claims from Benguet province and Baguio city during the period 2007 to 2009. RESULTS Eighty-six per cent of claims involved an out-of-pocket payment. The median figure for out-of-pocket payments was Philippine Pesos (PHP) 3016 (US$67), with this figure varying widely [inter-quartile range (IQR): PHP 9393 (US$209)]. Thirteen per cent of claims involved very large out-of-pocket payments exceeding PHP 19 213 (US$428)-the equivalent of 10% of the average annual household income in the region. Membership type, disease severity, age and residential location of the patient, length of hospitalization, and ownership and level of the hospital were all significantly associated with making out-of-pocket payments and/or the size of these payments. CONCLUSION Although the current NHIP reduces the size of out-of-pocket payments, NHIP beneficiaries are not completely free from the risk of large out-of-pocket payments (as the size of these payments varies widely and can be extremely large), despite NHIP's attempts to mitigate this by setting different benefit ceilings based on the level of the hospital and the severity of the disease. To reduce these large out-of-pocket payments and to increase financial risk protection further, it is essential to ensure more investment for health from social health insurance and/or tax-based government funding as well as shifting the provider payment mechanism from a fee-for-service to a case-based payment method (which up until now has only been partially implemented).

Effect of baclofen on the acid pocket at the gastroesophageal junction.

PubMed

Scarpellini, E; Boecxstaens, V; Farré, R; Bisschops, R; Dewulf, D; Gasbarrini, A; Pauwels, A; Blondeau, K; Tack, J

2015-07-01

Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 ± 0.7 vs. 0.3 ± 0.4 cm at 60 minutes, 2.2 ± 0.6 vs. 0.2 ± 0.6 at 90 minutes, and 1.5 ± 0.5 vs. 0.7 ± 0.7 cm at 120 minutes, all P < 0.05). Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure. © 2014 International Society for Diseases of the Esophagus.

Tertiary structure prediction and identification of druggable pocket in the cancer biomarker – Osteopontin-c

PubMed Central

2014-01-01

Background Osteopontin (Eta, secreted sialoprotein 1, opn) is secreted from different cell types including cancer cells. Three splice variant forms namely osteopontin-a, osteopontin-b and osteopontin-c have been identified. The main astonishing feature is that osteopontin-c is found to be elevated in almost all types of cancer cells. This was the vital point to consider it for sequence analysis and structure predictions which provide ample chances for prognostic, therapeutic and preventive cancer research. Methods Osteopontin-c gene sequence was determined from Breast Cancer sample and was translated to protein sequence. It was then analyzed using various software and web tools for binding pockets, docking and druggability analysis. Due to the lack of homological templates, tertiary structure was predicted using ab-initio method server – I-TASSER and was evaluated after refinement using web tools. Refined structure was compared with known bone sialoprotein electron microscopic structure and docked with CD44 for binding analysis and binding pockets were identified for drug designing. Results Signal sequence of about sixteen amino acid residues was identified using signal sequence prediction servers. Due to the absence of known structures of similar proteins, three dimensional structure of osteopontin-c was predicted using I-TASSER server. The predicted structure was refined with the help of SUMMA server and was validated using SAVES server. Molecular dynamic analysis was carried out using GROMACS software. The final model was built and was used for docking with CD44. Druggable pockets were identified using pocket energies. Conclusions The tertiary structure of osteopontin-c was predicted successfully using the ab-initio method and the predictions showed that osteopontin-c is of fibrous nature comparable to firbronectin. Docking studies showed the significant similarities of QSAET motif in the interaction of CD44 and osteopontins between the normal and splice variant forms of osteopontins and binding pockets analyses revealed several pockets which paved the way to the identification of a druggable pocket. PMID:24401206

Household out-of-pocket medical expenditures and national health insurance in Taiwan: income and regional inequality

PubMed Central

Chu, Tu-Bin; Liu, Tsai-Ching; Chen, Chin-Shyan; Tsai, Yi-Wen; Chiu, Wen-Ta

2005-01-01

Background Unequal geographical distribution of medical care resources and insufficient healthcare coverage have been two long-standing problems with Taiwan's public health system. The implementation of National Health Insurance (NHI) attempted to mitigate the inequality in health care use. This study examines the degree to which Taiwan's National Health Insurance (NHI) has reduced out-of-pocket medical expenditures in households in different regions and varying levels of income. Methods Data used in this study were drawn from the 1994 and 1996 Surveys of Family Income and Expenditure. We pooled the data from 1994 and 1996 and included a year dummy variable (NHI), equal to 1 if the household data came from 1996 in order to assess the impact of NHI on household out-of-pocket medical care expenditures shortly after its implementation in 1995. Results An individual who was older, female, married, unemployed, better educated, richer, head of a larger family household, or living in the central and eastern areas was more likely to have greater household out-of-pocket medical expenditures. NHI was found to have effectively reduced household out-of-pocket medical expenditures by 23.08%, particularly for more affluent households. With the implementation of NHI, lower and middle income quintiles had smaller decreases in out-of-pocket medical expenditure. NHI was also found to have reduced household out-of-pocket medical expenditures more for households in eastern Taiwan. Conclusion Although NHI was established to create free medical care for all, further effort is needed to reduce the medical costs for certain disadvantaged groups, particularly the poor and aborigines, if equality is to be achieved. PMID:16137336

Intracranial surgical operative apparatus

NASA Technical Reports Server (NTRS)

Sheldon, Charles H. (Inventor); Frazer, Robert E. (Inventor); Lutes, Harold R. (Inventor)

1983-01-01

Apparatus for operating on the brain with minimal disturbances thereto, including a bullet-shaped expandable device with an end that can be closed for insertion through a small hole in the brain. The device can be expanded after insertion to leave an air pocket through which to extend viewing and cutting devices which enable operation on tumors or the like that lie at the end of the expanded device. A set of probes of varying diameters are also provided, to progressively enlarge a passage leading to the tumor, prior to inserting the expandable device.

Voroprot: an interactive tool for the analysis and visualization of complex geometric features of protein structure.

PubMed

Olechnovic, Kliment; Margelevicius, Mindaugas; Venclovas, Ceslovas

2011-03-01

We present Voroprot, an interactive cross-platform software tool that provides a unique set of capabilities for exploring geometric features of protein structure. Voroprot allows the construction and visualization of the Apollonius diagram (also known as the additively weighted Voronoi diagram), the Apollonius graph, protein alpha shapes, interatomic contact surfaces, solvent accessible surfaces, pockets and cavities inside protein structure. Voroprot is available for Windows, Linux and Mac OS X operating systems and can be downloaded from http://www.ibt.lt/bioinformatics/voroprot/.

Rotary engine research

NASA Astrophysics Data System (ADS)

1992-06-01

A development history is presented for NASA's 1983-1991 Rotary Engine Enablement Program, emphasizing the CFD approaches to various problems that were instituted from 1987 to the end of the program. In phase I, a test rig was built to intensively clarify and characterize the stratified-charge rotary engine concept. In phase II, a high pressure, electronically controlled fuel injection system was tested. In phase III, the testing of improved fuel injectors led to the achievement of the stipulated 5 hp/cu inch specific power goal. CFD-aided design of advanced rotor-pocket shapes led to additional performance improvements.

How Will the Affordable Care Act's Cost-Sharing Reductions Affect Consumers' Out-of-Pocket Costs in 2016?

PubMed

Collins, Sara R; Gunja, Munira; Beutel, Sophie

2016-03-01

Health insurers selling plans in the Affordable Care Act's market­places are required to reduce cost-sharing in silver plans for low- and moderate-income people earning between 100 percent and 250 percent of the federal pov­erty level. In 2016, as many as 7 million Americans may have plans with these cost-sharing reductions. In the largest markets in the 38 states using the federal website for marketplace enrollment, the cost-sharing reductions substantially lower projected out-of-pocket costs for people who qualify for them. However, the degree to which consumers' out-of-pocket spending will fall varies by plan and how much health care they use. This is because insurers use deductibles, out-of-pocket limits, and copayments in different combinations to lower cost-sharing for eligible enrollees. In 2017, marketplace insurers will have the option of offering standard plans, which may help simplify consumers' choices and lead to more equal cost-sharing.

Quantifying Queensland patients with cancer health service usage and costs: study protocol.

PubMed

Callander, Emily; Topp, Stephanie M; Larkins, Sarah; Sabesan, Sabe; Bates, Nicole

2017-01-24

The overall mortality rate for cancer has declined in Australia. However, socioeconomic inequalities exist and the out-of-pocket costs incurred by patients in Australia are high compared with some European countries. There is currently no readily available data set to provide a systematic means of measuring the out-of-pocket costs incurred by patients with cancer within Australia. The primary aim of the project is to quantify the direct out-of-pocket healthcare expenditure of individuals in the state of Queensland, who are diagnosed with cancer. This project will build Australia's first model (called CancerCostMod) of out-of-pocket healthcare expenditure of patients with cancer using administrative data from Queensland Cancer Registry, for all individuals diagnosed with any cancer in Queensland between 1 July 2011 and 30 June 2012, linked to their Admitted Patient Data Collection, Emergency Department Information System, Medicare Benefits Schedule and Pharmaceutical Benefits Scheme records from 1 July 2011 to 30 June 2015. No identifiable information will be provided to the authors. The project will use a combination of linear and logistic regression modelling, Cox proportional hazards modelling and machine learning to identify differences in survival, total health system expenditure, total out-of-pocket expenditure and high out-of-pocket cost patients, adjusting for demographic and clinical confounders, and income group, Indigenous status and geographic location. Results will be analysed separately for different types of cancer. Human Research Ethics approval has been obtained from the Townsville Hospital and Health Service Human Research Ethics Committee (HREC/16/QTHS/110) and James Cook University Human Research Ethics Committee (H6678). Permission to waive consent has been sought from Queensland Health under the Public Health Act 2005. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Grain-scale alignment of melt in sheared partially molten rocks: implications for viscous anisotropy

NASA Astrophysics Data System (ADS)

Pec, Matej; Quintanilla-Terminel, Alejandra; Holtzman, Benjamin; Zimmerman, Mark; Kohlstedt, David

2016-04-01

Presence of melt significantly influences rheological properties of partially molten rocks by providing fast diffusional pathways. Under stress, melt aligns at the grain scale and this alignment induces viscous anisotropy in the deforming aggregate. One of the consequences of viscous anisotropy is melt segregation into melt-rich sheets oriented at low angle to the shear plane on much larger scales than the grain scale. The magnitude and orientation of viscous anisotropy with respect to the applied stress are important parameters for constitutive models (Takei and Holtzman 2009) that must be constrained by experimental studies. In this contribution, we analyze the shape preferred orientation (SPO) of individual grain-scale melt pockets in deformed partially molten mantle rocks. The starting materials were obtained by isostatically hot-pressing olivine + basalt and olivine + chromite + basalt powders. These partially molten rocks were deformed in general shear or torsion at a confining pressure, Pc = 300 MPa, temperature, T = 1200° - 1250° C, and strain rates of 10-3 - 10-5 s-1to finite shear strains, γ, of 0.5 - 5. After the experiment, high resolution backscattered electron images were obtained using a SEM equipped with a field emission gun. Individual melt pockets were segmented and their SPO analyzed using the paror and surfor methods and Fourier transforms (Heilbronner and Barret 2014). Melt segregation into melt-rich sheets inclined at 15° -20° antithetic with respect to the shear plane occurs in three-phase system (olivine + chromite + basalt) and in two-phase systems (olivine + basalt) twisted to high strain. The SPO of individual melt pockets within the melt-rich bands is moderately strong (b/a ≈ 0.8) and is always steeper (20° -40°) than the average melt-rich band orientation. In the two-phase system (olivine + basalt) sheared to lower strains, no distinct melt-rich sheets are observed. Individual grain-scale melt pockets are oriented at 45° -55° antithetic with respect to the shear plane (i.e., sub-perpendicular to σ3) with a strong SPO (b/a ≈ 0.7) that decreases with increasing finite strain. Our observations of melt alignment at low strains are in agreement with observations performed on analogue materials (borneol, Takei 2010) and provide further constraints for the orientation of viscous anisotropy in the Earth's mantle. The systematic difference in grain-scale melt alignment between samples in which melt segregation did and did not occur - irrespective of the deformation geometry and mineralogy - suggests that melt segregation into bands leads to local stress rotation within the samples.

Self-Cooling Gradient Shell for Body Armor

DTIC Science & Technology

2012-05-10

Silica gel 2.1 Filter paper pocket (no absorbent) 2.0 2 g Silica gel (150-Å pore size) + 2 g sodium polyacrylate (SPA) in filter paper pocket 2.7...layer of filter paper improved the temperature difference by an additional 0.5 °C. More-absorbent materials, such as sodium polyacrylate (SPA) or... sodium polyacrylate SPM scanning probe microscopy µm micrometer Wm-2 watts per square meter °C degrees Celsius

Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family

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

Liban, Tyler J.; Medina, Edgar M.; Tripathi, Sarvind

The retinoblastoma protein (Rb) and the homologous pocket proteins p107 and p130 negatively regulate cell proliferation by binding and inhibiting members of the E2F transcription factor family. The structural features that distinguish Rb from other pocket proteins have been unclear but are critical for understanding their functional diversity and determining why Rb has unique tumor suppressor activities. We describe here important differences in how the Rb and p107 C-terminal domains (CTDs) associate with the coiled-coil and marked-box domains (CMs) of E2Fs. We find that although CTD–CM binding is conserved across protein families, Rb and p107 CTDs show clear preferences formore » different E2Fs. A crystal structure of the p107 CTD bound to E2F5 and its dimer partner DP1 reveals the molecular basis for pocket protein–E2F binding specificity and how cyclin-dependent kinases differentially regulate pocket proteins through CTD phosphorylation. Our structural and biochemical data together with phylogenetic analyses of Rb and E2F proteins support the conclusion that Rb evolved specific structural motifs that confer its unique capacity to bind with high affinity those E2Fs that are the most potent activators of the cell cycle.« less

Clinical tests of an ultrasonic periodontal probe

NASA Astrophysics Data System (ADS)

Hinders, Mark K.; Lynch, John E.; McCombs, Gayle B.

2002-05-01

A new ultrasonic periodontal probe has been developed that offers the potential for earlier detection of periodontal disease activity, non-invasive diagnosis, and greater reliability of measurement. A comparison study of the ultrasonic probe to both a manual probe, and a controlled-force probe was conducted to evaluate its clinical effectiveness. Twelve patients enrolled into this study. Two half-month examinations were conducted on each patient, scheduled one hour apart. A one-way analysis of variance was performed to compare the results for the three sets of probing depth measurements, followed by a repeated measures analysis to assess the reproducibility of the different probing techniques. These preliminary findings indicate that manual and ultrasonic probing measure different features of the pocket. Therefore, it is not obvious how the two depth measurements correspond to each other. However, both methods exhibited a similar tendency toward increasing pocket depths as Gingival Index scores increased. Based on the small sample size, further studies need to be conducted using a larger population of patients exhibiting a wider range of disease activity. In addition, studies that allow histological examination of the pocket after probing will help further evaluate the clinical effectiveness the ultrasonic probe. Future studies will also aid in the development of more effective automated feature recognition algorithms that convert the ultrasonic echoes into pocket depth readings.

Crystallographic Study of a Novel Sub-Nanomolar Inhibitor Provides Insight on the Binding Interactions of Alkenyldiarylmethanes with Human Immunodeficiency Virus-1 (HIV-1) Reverse Transcriptase†

PubMed Central

Cullen, Matthew D.; Ho, William C.; Bauman, Joseph D.; Das, Kalyan; Arnold, Eddy; Hartman, Tracy L.; Watson, Karen M.; Buckheit, Robert W.; Pannecouque, Christophe; De Clercq, Erik; Cushman, Mark

2009-01-01

Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor-RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the backside of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC50 ≤ nM). ADAM 4 was designed to be hydrolytically stable in blood plasma, and an investigation of its hydrolysis in rat plasma demonstrated it has a significantly prolonged half-life in comparison to ADAM lead compounds 1 and 2. PMID:19775161

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

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

Mandal, Mihirbaran; Wu, Yusheng; Misiaszek, Jeffrey

2016-04-14

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'–S2'' pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4),more » which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.« less

Chemotaxis of Amoeba proteus in the developing pH gradient within a pocket-like chamber studied with the computer assisted method.

PubMed

Korohoda, W; Golda, J; Sroka, J; Wojnarowicz, A; Jochym, P; Madeja, Z

1997-01-01

A new "U" shaped, pocket-like chamber was used to observe the chemotactic responses of individual cells. This method permits monitoring of both the development of the concentration gradient of a tested substance and cell locomotion. We investigated the chemotactic responses of Amoeba proteus and observed that the amoebae moved in positively and negatively developing [H+] gradients towards the solution of lower pH in a pH range 5.75-7.75. The chemotactic response of amoebae to [H+] gradients required the presence of extracellular calcium ions. It was blocked and random locomotion was restored by the replacement of calcium with magnesium in the cell medium. Time-lapse video recording and data processing were accomplished with computer-assisted methods. This made it possible to compare selected methods of data presentation and analysis for cells locomoting in isotropic and anisotropic conditions. The cell trajectories were determined and displayed in circular diagrams, lengths of cell tracks and final cell displacements were estimated and a few parameters characterizing cell locomotion were computed.

SABRE: ligand/structure-based virtual screening approach using consensus molecular-shape pattern recognition.

PubMed

Wei, Ning-Ning; Hamza, Adel

2014-01-27

We present an efficient and rational ligand/structure shape-based virtual screening approach combining our previous ligand shape-based similarity SABRE (shape-approach-based routines enhanced) and the 3D shape of the receptor binding site. Our approach exploits the pharmacological preferences of a number of known active ligands to take advantage of the structural diversities and chemical similarities, using a linear combination of weighted molecular shape density. Furthermore, the algorithm generates a consensus molecular-shape pattern recognition that is used to filter and place the candidate structure into the binding pocket. The descriptor pool used to construct the consensus molecular-shape pattern consists of four dimensional (4D) fingerprints generated from the distribution of conformer states available to a molecule and the 3D shapes of a set of active ligands computed using SABRE software. The virtual screening efficiency of SABRE was validated using the Database of Useful Decoys (DUD) and the filtered version (WOMBAT) of 10 DUD targets. The ligand/structure shape-based similarity SABRE algorithm outperforms several other widely used virtual screening methods which uses the data fusion of multiscreening tools (2D and 3D fingerprints) and demonstrates a superior early retrieval rate of active compounds (EF(0.1%) = 69.0% and EF(1%) = 98.7%) from a large size of ligand database (∼95,000 structures). Therefore, our developed similarity approach can be of particular use for identifying active compounds that are similar to reference molecules and predicting activity against other targets (chemogenomics). An academic license of the SABRE program is available on request.

F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins.

PubMed

Abualrous, Esam T; Fritzsche, Susanne; Hein, Zeynep; Al-Balushi, Mohammed S; Reinink, Peter; Boyle, Louise H; Wellbrock, Ursula; Antoniou, Antony N; Springer, Sebastian

2015-04-01

The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype. Also watch the Video Abstract. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The 13C-Pocket Structure In AGB Models: Constraints From Zirconium Isotope Abundances In Single Mainstream SiC Grains

DOE PAGES

Liu, Nan; Gallino, Roberto; Bisterzo, Sara; ...

2014-06-04

In this paper, we present postprocess asymptotic giant branch (AGB) nucleosynthesis models with different 13C-pocket internal structures to better explain zirconium isotope measurements in mainstream presolar SiC grains by Nicolussi et al. and Barzyk et al. We show that higher-than-solar 92Zr/ 94Zr ratios can be predicted by adopting a 13C-pocket with a flat 13C profile, instead of the previous decreasing-with-depth 13C profile. Finally, the improved agreement between grain data for zirconium isotopes and AGB models provides additional support for a recent proposal of a flat 13C profile based on barium isotopes in mainstream SiC grains by Liu et al.

How Medicaid Expansion Affected Out-of-Pocket Health Care Spending for Low-Income Families.

PubMed

Glied, Sherry; Chakraborty, Ougni; Russo, Therese

2017-08-01

ISSUE. Prior research shows that low-income residents of states that expanded Medicaid under the Affordable Care Act are less likely to experience financial barriers to health care access, but the impact on out-of-pocket spending has not yet been measured. GOAL. Assess how the Medicaid expansion affected out-of-pocket health care spending for low-income families compared to those in states that did not expand and consider whether effects differed in states that expanded under conventional Medicaid rules vs. waiver programs. METHODS. Analysis of the Consumer Expenditure Survey 2010–2015. KEY FINDINGS AND CONCLUSIONS. Compared to families in nonexpansion states, low-income families in states that did expand Medicaid saved an average of $382 in annual spending on health care. In these states, low-income families were less like to report any out-of-pocket spending on insurance premiums or medical care than were similar families in nonexpansion states. For families that did have some out-of-pocket spending, spending levels were lower in states that expanded Medicaid. Low-income families in Medicaid expansion states were also much less likely to have catastrophically high spending levels. The form of coverage expansion — conventional Medicaid or waiver rules — did not have a statistically significant effect on these outcomes.

Signature of Microbial Dysbiosis in Periodontitis.

PubMed

Meuric, Vincent; Le Gall-David, Sandrine; Boyer, Emile; Acuña-Amador, Luis; Martin, Bénédicte; Fong, Shao Bing; Barloy-Hubler, Frederique; Bonnaure-Mallet, Martine

2017-07-15

Periodontitis is driven by disproportionate host inflammatory immune responses induced by an imbalance in the composition of oral bacteria; this instigates microbial dysbiosis, along with failed resolution of the chronic destructive inflammation. The objectives of this study were to identify microbial signatures for health and chronic periodontitis at the genus level and to propose a model of dysbiosis, including the calculation of bacterial ratios. Published sequencing data obtained from several different studies (196 subgingival samples from patients with chronic periodontitis and 422 subgingival samples from healthy subjects) were pooled and subjected to a new microbiota analysis using the same Visualization and Analysis of Microbial Population Structures (VAMPS) pipeline, to identify microbiota specific to health and disease. Microbiota were visualized using CoNet and Cytoscape. Dysbiosis ratios, defined as the percentage of genera associated with disease relative to the percentage of genera associated with health, were calculated to distinguish disease from health. Correlations between the proposed dysbiosis ratio and the periodontal pocket depth were tested with a different set of data obtained from a recent study, to confirm the relevance of the ratio as a potential indicator of dysbiosis. Beta diversity showed significant clustering of periodontitis-associated microbiota, at the genus level, according to the clinical status and independent of the methods used. Specific genera ( Veillonella , Neisseria , Rothia , Corynebacterium , and Actinomyces ) were highly prevalent (>95%) in health, while other genera ( Eubacterium , Campylobacter , Treponema , and Tannerella ) were associated with chronic periodontitis. The calculation of dysbiosis ratios based on the relative abundance of the genera found in health versus periodontitis was tested. Nonperiodontitis samples were significantly identifiable by low ratios, compared to chronic periodontitis samples. When applied to a subgingival sample set with well-defined clinical data, the method showed a strong correlation between the dysbiosis ratio, as well as a simplified ratio ( Porphyromonas , Treponema , and Tannerella to Rothia and Corynebacterium ), and pocket depth. Microbial analysis of chronic periodontitis can be correlated with the pocket depth through specific signatures for microbial dysbiosis. IMPORTANCE Defining microbiota typical of oral health or chronic periodontitis is difficult. The evaluation of periodontal disease is currently based on probing of the periodontal pocket. However, the status of pockets "on the mend" or sulci at risk of periodontitis cannot be addressed solely through pocket depth measurements or current microbiological tests available for practitioners. Thus, a more specific microbiological measure of dysbiosis could help in future diagnoses of periodontitis. In this work, data from different studies were pooled, to improve the accuracy of the results. However, analysis of multiple species from different studies intensified the bacterial network and complicated the search for reproducible microbial signatures. Despite the use of different methods in each study, investigation of the microbiota at the genus level showed that some genera were prevalent (up to 95% of the samples) in health or disease, allowing the calculation of bacterial ratios (i.e., dysbiosis ratios). The correlation between the proposed ratios and the periodontal pocket depth was tested, which confirmed the link between dysbiosis ratios and the severity of the disease. The results of this work are promising, but longitudinal studies will be required to improve the ratios and to define the microbial signatures of the disease, which will allow monitoring of periodontal pocket recovery and, conceivably, determination of the potential risk of periodontitis among healthy patients. Copyright © 2017 American Society for Microbiology.

Numerical Modeling of Large-Scale Rocky Coastline Evolution

NASA Astrophysics Data System (ADS)

Limber, P.; Murray, A. B.; Littlewood, R.; Valvo, L.

2008-12-01

Seventy-five percent of the world's ocean coastline is rocky. On large scales (i.e. greater than a kilometer), many intertwined processes drive rocky coastline evolution, including coastal erosion and sediment transport, tectonics, antecedent topography, and variations in sea cliff lithology. In areas such as California, an additional aspect of rocky coastline evolution involves submarine canyons that cut across the continental shelf and extend into the nearshore zone. These types of canyons intercept alongshore sediment transport and flush sand to abyssal depths during periodic turbidity currents, thereby delineating coastal sediment transport pathways and affecting shoreline evolution over large spatial and time scales. How tectonic, sediment transport, and canyon processes interact with inherited topographic and lithologic settings to shape rocky coastlines remains an unanswered, and largely unexplored, question. We will present numerical model results of rocky coastline evolution that starts with an immature fractal coastline. The initial shape is modified by headland erosion, wave-driven alongshore sediment transport, and submarine canyon placement. Our previous model results have shown that, as expected, an initial sediment-free irregularly shaped rocky coastline with homogeneous lithology will undergo smoothing in response to wave attack; headlands erode and mobile sediment is swept into bays, forming isolated pocket beaches. As this diffusive process continues, pocket beaches coalesce, and a continuous sediment transport pathway results. However, when a randomly placed submarine canyon is introduced to the system as a sediment sink, the end results are wholly different: sediment cover is reduced, which in turn increases weathering and erosion rates and causes the entire shoreline to move landward more rapidly. The canyon's alongshore position also affects coastline morphology. When placed offshore of a headland, the submarine canyon captures local sediment, increases weathering and erosion around the headland, and eventually changes the headland into an embayment! Improvements to our modeling approach include refining the initial conditions. To create a fractal, immature rocky coastline, self-similar river networks with random side branches were drawn on the shoreline domain. River networks and side branches were scaled according to Horton's law and Tokunaga statistics, respectively, and each river pathway was assigned a simple exponential longitudinal profile. Topography was generated around the river networks to create drainage basins and, on a larger scale, represent a mountainous, fluvially-sculpted landscape. The resultant morphology was then flooded to a given elevation, leaving a fractal rocky coastline. In addition to the simulated terrain, actual digital elevation models will also be used to derive the initial conditions. Elevation data from different mountainous geomorphic settings such as the decaying Appalachian Mountains or actively uplifting Sierra Nevada can be effectively flooded to a given sea level, resulting in a fractal and immature coastline that can be input to the numerical model. This approach will offer insight into how rocky coastlines in different geomorphic settings evolve, and provide a useful complement to results using the simulated terrain.

Reconstructing the diet of a 505-million-year-old arthropod: Sidneyia inexpectans from the Burgess Shale fauna.

PubMed

Zacaï, Axelle; Vannier, Jean; Lerosey-Aubril, Rudy

2016-03-01

The feeding ecology of the 505-million-year-old arthropod Sidneyia inexpectans from the middle Cambrian (Series 3, Stage 5) Burgess Shale fauna (British Columbia, Canada) is revealed by three lines of evidence: the structure of its digestive system, the fossilized contents of its gut and the functional anatomy of its appendages. The digestive tract of Sidneyia is straight, tubular and relatively narrow in the trunk region. It is enlarged into a pear-shaped area in the cephalic region and stretches notably to form a large pocket in the abdomen. The mouth is ventral, posteriorly directed and leads to the midgut via a short tubular structure interpreted as the oesophagus. Anteriorly, three pairs of glands with internal, branching tubular structures open into the digestive tract. These glands have equivalents in various Cambrian arthropod taxa (e.g. naraoiids) and modern arthropods. Their primary function was most likely to digest and assimilate food. The abdominal pocket of Sidneyia concentrates undigested skeletal elements and various residues. It is interpreted here as the functional analogue of the stercoral pocket of some extant terrestrial arachnids (e.g. Araneae, Solifugae), whose primary function is to store food residuals and excretory material until defecation. Analysis of the gut contents indicates that Sidneyia fed largely on small ptychopariid trilobites, brachiopods, possibly agnostids, worms and other undetermined animals. Sidneyia was primarily a durophagous carnivore with predatory and/or scavenging habits, feeding on small invertebrates that lived at the water-sediment interface. There is no evidence for selective feeding. Its food items (e.g. living prey or dead material) were grasped and manipulated ventrally by its anterior appendages, then macerated into ingestible fragments and conveyed to the mouth via the converging action of strong molar-like gnathobases. Digestion probably took place within the anterior midgut via enzymes secreted in the glands. Residues were transported through the digestive tract into the abdominal pocket. The storage of faeces suggests infrequent feeding. The early diagenetic three-dimensional preservation of the digestive glands and abdominal pocket may be due to the capacity of Sidneyia to store Phosphorus and Calcium (e.g. spherites) in its digestive tissues during life as do, for example, modern horseshoe crabs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Assessment of Drug Binding Potential of Pockets in the NS2B/NS3 Dengue Virus Protein

NASA Astrophysics Data System (ADS)

Amelia, F.; Iryani; Sari, P. Y.; Parikesit, A. A.; Bakri, R.; Toepak, E. P.; Tambunan, U. S. F.

2018-04-01

Every year an endemic dengue fever estimated to affect over 390 million cases in over 128 countries occurs. However, the antigen types which stimulate the human immune response are variable, as a result, neither effective vaccines nor antiviral treatments have been successfully developed for this disease. The NS2B/NS3 protease of the dengue virus (DENV) responsible for viral replication is a potential drug target. The ligand-enzyme binding site determination is a key role in the success of virtual screening of new inhibitors. The NS2B/NS3 protease of DENV (PDB ID: 2FOM) has two pockets consisting of 37 (Pocket 1) and 27 (Pocket 2) amino acid residues in each pocket. In this research, we characterized the amino acid residues for binding sites in NS3/NS2B based on the hydrophobicity, the percentage of charged residues, volume, depth, ΔGbinding, hydrogen bonding and bond length. The hydrophobic percentages of both pockets are high, 59 % (Pocket 1) and 41% (Pocket 2) and the percentage of charged residues in Pocket 1 and 2 are 22% and 48%, and the pocket volume is less than 700 Å3. An interaction analysis using molecular docking showed that interaction between the ligand complex and protein in Pocket 1 is more negative than Pocket 2. As a result, Pocket 1 is the better potential target for a ligand to inhibit the action of NS2B/NS3 DENV.

Association Between Availability of a Price Transparency Tool and Outpatient Spending.

PubMed

Desai, Sunita; Hatfield, Laura A; Hicks, Andrew L; Chernew, Michael E; Mehrotra, Ateev

2016-05-03

There is increasing interest in using price transparency tools to decrease health care spending. To measure the association between offering a health care price transparency tool and outpatient spending. Two large employers represented in multiple market areas across the United States offered an online health care price transparency tool to their employees. One introduced it on April 1, 2011, and the other on January 1, 2012. The tool provided users information about what they would pay out of pocket for services from different physicians, hospitals, or other clinical sites. Using a matched difference-in-differences design, outpatient spending among employees offered the tool (n=148,655) was compared with that among employees from other companies not offered the tool (n=295,983) in the year before and after it was introduced. Availability of a price transparency tool. Annual outpatient spending, outpatient out-of-pocket spending, use rates of the tool. Mean outpatient spending among employees offered the tool was $2021 in the year before the tool was introduced and $2233 in the year after. In comparison, among controls, mean outpatient spending changed from $1985 to $2138. After adjusting for demographic and health characteristics, being offered the tool was associated with a mean $59 (95% CI, $25-$93) increase in outpatient spending. Mean outpatient out-of-pocket spending among those offered the tool was $507 in the year before introduction of the tool and $555 in the year after. Among the comparison group, mean outpatient out-of-pocket spending changed from $490 to $520. Being offered the price transparency tool was associated with a mean $18 (95% CI, $12-$25) increase in out-of-pocket spending after adjusting for relevant factors. In the first 12 months, 10% of employees who were offered the tool used it at least once. Among employees at 2 large companies, offering a price transparency tool was not associated with lower health care spending. The tool was used by only a small percentage of eligible employees.

Ti6Al4V Superplastic Forming for the Production of an Aircraft Part

NASA Astrophysics Data System (ADS)

Filice, L.; Gagliardi, F.; Lazzaro, S.; Rosa, R.

2011-05-01

Titanium and its alloys have grown their importance in the automotive and aerospace industries becoming strategic materials; this is due to their mechanical properties that, perfectly, meet the needs of the above said industrial field. For example, they are characterized by a high strength vs. weight ratio that is directly related to fuel saving impacting on both economic and environmental aspects. A weakness point of these materials is linked to their workability that entails significant manufacturing costs. Taking into account these issues, it is easy to understand the reasons for the development of net shape technologies, like hot forming (HF) or superplastic forming (SPF) in order to reduce the price of titanium components. In the work here introduced, a cockpit section, known as "Pocket Support", was produced through SPF. More in detail, the influence that the strain rate can have on the quality of the final part was highlighted; for this reason, two different pressure-time curves were tested monitoring the accuracy and wall thinning of the realized parts. The experimental campaign was carried out using an ACB superplastic forming press located in the Somma Vesuviana DEMA plant. The dimension of the obtained components were checked through the structural light technique (Gray Code-Phase Shifting); in particular, a cloud of points was obtained and, subsequently, used to rebuild the actual surface of the Pocket Support. In this way, a comparison between the CAD model and the real part was possible. Moreover, the thickness distribution along a critical section was analyzed by means of a coordinate measuring machine.

Coastal geomorphological study of pocket beaches in Crete, with the use of planview indices.

NASA Astrophysics Data System (ADS)

Alexandrakis, George; Karditsa, Aikaterini; Poulos, Serafim; Kampanis, Nikos

2013-04-01

The formation of pocket beaches is a result of a large number of processes and mechanisms that vary on space and time scales. This study aims in defining the planform characteristics of pocket beaches in Crete Isl. and to determine their sheltering effect, embaymentization and their status of equilibrium. Thus, data from 30 pocket beaches along the coastline of Crete, with different geomorphological and hydrodynamical setting, were collected. Planform parameters were applied and coastal planview indices from the bibliography were applied. The parameters included: length and orientation of the headlands between the pocket beach; length between the bay entrance and the center of the beach; lengths of the i) embayed shoreline, ii) embayed beach, iii) beach segment located at the shadow of a headland; linear distance and orientation between the edges of the embayed beach; direction of the incident wave energy flux; wave crest obliquity to the control line; beach area, maximum beach width and headland orientation and river/ torrent catchment areas in beach zones that an active river system existed (Bowman et al.2009). For the morphological mapping of the study areas, 1:5000 orthophoto maps were used. Wave regime has been calculated with the use of prognostic equations and utilising local wind data (mean annual frequency of wind speed and direction), provided by the Wind and Wave Atlas of the Eastern Mediterranean Sea. The diffraction and refraction of the waves has been simulated with the use of numerical models. The study shows that Cretan pocket beaches display a wide range of indentation, suggesting that is the result of several parameters that include tectonics, coastal hydrodynamics and river catchment areas. The more indented bays are, the shorter their beaches become, while low-indented pocket beaches are the widest and the longest ones. Beaches with headland with large length appear to be more protected and receive smaller amount of wave energy. Most of the Cretan pocket beaches have limited sediment supply for the mainland, while they appear to be in an unstable status. D. Bowman, J. Guillén, L. López, V. Pellegrino (2009), Planview Geometry and morphological characteristics of pocket beaches on the Catalan coast (Spain). Geomorphology, 108, 191-199

Nearshore hydrodynamics at pocket beaches with contrasting wave exposure in southern Portugal

NASA Astrophysics Data System (ADS)

Horta, João; Oliveira, Sónia; Moura, Delminda; Ferreira, Óscar

2018-05-01

Pocket beaches on rocky coasts with headlands that control hydro-sedimentary processes are considered to be constrained sedimentary systems, generally with limited sediment inputs. Pocket beaches face severe changes over time. Under worst-case scenarios, these changes can result in the loss of the beach, causing waves to directly attack adjacent cliffs. Studies of nearshore hydrodynamics can help to understand such changes and optimise sediment nourishment procedures. The present work contributes to the knowledge of hydrodynamic forcing mechanisms at pocket beaches by providing a comprehensive description of the nearshore circulation at two beaches with contrasting wave exposures. Two pocket beaches in southern Portugal were studied by combining field measurements of waves and currents with numerical models (STWAVE and BOUSS-2D). The aim of this analysis was to evaluate nearshore hydrodynamics under different wave exposure forcing conditions (e.g. variable wave heights/directions and different tidal levels). The results show that the beach circulation can rapidly shift from longshore-to rip-dominated depending on changes in both the offshore wave direction and tidal levels. Waves with higher obliquity (for both low and moderate wave energy conditions) tend to generate longshore circulation in all considered tidal stages, while waves with lower obliquity tend to produce rip flow with higher-velocity rip currents during low to intermediate tidal stages. The results indicate that the location and intensity of rip currents strongly depend on geomorphological constraints, that is, the control exerted by shore platforms. A larger morphological control is observed at mean sea level because most platforms are submerged/exposed during high/low tide and therefore exert less control on nearshore circulation.

The Impact of Medicare Part D on the Proportion of Out-of-Pocket Prescription Drug Costs Among Older Adults With Diabetes.

PubMed

Choi, Yoon Jeong; Jia, Haomiao; Gross, Tal; Weinger, Katie; Stone, Patricia W; Smaldone, Arlene M

2017-04-01

The purpose of this study was to evaluate the impact of Medicare Part D on reducing the financial burden of prescription drugs in older adults with diabetes. Using Medical Expenditure Panel Survey data (2000-2011), interrupted time series and difference-in-difference analyses were used to examine out-of-pocket costs for prescription drugs in 4,664 Medicare beneficiaries (≥65 years of age) compared with 2,938 younger, non-Medicare adults (50-60 years) with diabetes and to estimate the causal effects of Medicare Part D. Part D enrollment of Medicare beneficiaries with diabetes gradually increased from 45.7% (2006) to 52.4% (2011). Compared with years 2000-2005, out-of-pocket pharmacy costs decreased by 13.5% (SE 2.1) for all Medicare beneficiaries with diabetes following Part D implementation; on average, Part D beneficiaries had 5.3% (0.8) lower costs compared with those without Part D. Compared with a younger group with diabetes, out-of-pocket pharmacy costs decreased by 19.4% (1.7) for Medicare beneficiaries after Part D. Part D beneficiaries with diabetes who experienced the coverage gap decreased from 60.1% (2006) to 40.9% (2011) over this period. These findings demonstrate that although Medicare Part D has been effective in reducing the out-of-pocket cost burden of prescription drugs, approximately two out of five Part D beneficiaries with diabetes experienced the coverage gap in 2011. Future research is needed to examine the impact of Affordable Care Act provisions to close the coverage gap on the cost burden of prescription drugs for Medicare beneficiaries with diabetes. © 2017 by the American Diabetes Association.

Evaluation of the turbine pocket spirometer.

PubMed Central

Gunawardena, K A; Houston, K; Smith, A P

1987-01-01

A compact electronic spirometer, the turbine pocket spirometer, which measures the FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF) in a single expiration, was compared with the Vitalograph and the Wright peak flow meter in 99 subjects (FEV1 range 0.40-5.50 litres; FVC 0.58-6.48 l; PEF 40-650 l min-1). The mean differences between the machines were small--0.05 l for FEV1, 0.05 l for FVC, and 11.6 l min-1 for PEF, with the limits of agreement at +/- 0.25 l, +/- 0.48 l, and +/- 52.2 l min-1 respectively. The wide limits of agreement for the PEF comparison were probably because of the difference in the technique of blowing: a fast, long blow was used for the pocket spirometer and a short, sharp one for the Wright peak flow meter. The FEV1 and FVC showed a proportional bias of around 4-5% in favour of the Vitalograph. The repeatability coefficient for the pocket spirometer FEV1 was 0.18 l, for FVC 0.22 l, and for PEF 31 l min-1. These compared well with the repeatability coefficients of the Vitalograph and the Wright peak flow meter, which gave values of 0.18 l, 0.28 l, and 27 l min-1 respectively. At flow rates of over 600 l min-1 the resistance of the pocket spirometer marginally exceeded the American Thoracic Society recommendations. The machine is easy to operate and portable, and less expensive than the Vitalograph and Wright peak flow meter combined. It can be recommended for general use. Images PMID:3686460

Association Between the Duration of Periodontitis and Increased Cardiometabolic Risk Factors: A 9-Year Cohort Study.

PubMed

Morita, Toyoko; Yamazaki, Yoji; Fujiharu, Chika; Ishii, Takanori; Seto, Misae; Nishinoue, Norihide; Sasaki, Yoshiyuki; Nakai, Kumiko; Tanaka, Hideki; Kawato, Takayuki; Maeno, Masao

2016-12-01

Epidemiological studies have reported that periodontitis and cardiometabolic disease such as cardiovascular disease and type 2 diabetes are associated; however, there have been very few prospective cohort studies on this topic. Therefore, we conducted a 9-year follow-up study to examine the relationship between the duration of periodontitis and cardiometabolic risk factors, including hypertension, hyperglycemia, dyslipidemia, and obesity. The study participants comprised 572 adult industrial workers (417 men and 155 women; mean age, 37.4 years) who had undergone annual medical and dental health examinations from 2003 to 2012; the evaluation of the four cardiometabolic risk factors in 2003 revealed normal values in all the participants. We investigated the relationship between the cumulative duration of the presence of periodontal pockets, which is a major symptom of periodontitis, and the presence of cardiometabolic risk factors after 9 years using multiple logistic regression analysis. The odds ratio (OR) for the presence of ≥1 cardiometabolic risk factor in participants with a cumulative duration of periodontal pockets for ≥6 years was significantly higher than that in participants without pockets. The ORs for the onset of obesity, hypertension, dyslipidemia, and hyperglycemia were higher in participants with a cumulative duration of periodontal pockets for ≥6 years than those in participants without pockets or in participants with a cumulative duration of periodontal pockets for ≤5 years, and all the differences, except dyslipidemia, were significant. Chronic periodontitis was significantly associated with having cardiometabolic risk factors during the 9-year observation period, suggesting that the risk of cardiometabolic disease might increase in people who have untreated periodontitis.

Community-level effect of the reproductive health vouchers program on out-of-pocket spending on family planning and safe motherhood services in Kenya.

PubMed

Obare, Francis; Warren, Charlotte; Kanya, Lucy; Abuya, Timothy; Bellows, Ben

2015-08-25

Although vouchers can protect individuals in low-income countries from financial catastrophe and impoverishment arising from out-of-pocket expenditures on healthcare, their effectiveness in achieving this goal depends on whether both service and transport costs are subsidized as well as other factors such as service availability in a given locality and community perceptions about the quality of care. This paper examines the community-level effect of the reproductive health vouchers program on out-of-pocket expenditure on family planning, antenatal, delivery and postnatal care services in Kenya. Data are from two rounds of cross-sectional household surveys in voucher and non-voucher sites. The first survey was conducted between May 2010 and July 2011 among 2,933 women aged 15-49 years while the second survey took place between July and October 2012 among 3,094 women of similar age groups. The effect of the program on out-of-pocket expenditure is determined by difference-in-differences estimation. Analysis entails comparison of changes in proportions, means and medians as well as estimation of multivariate linear regression models with interaction terms between indicators for study site (voucher or non-voucher) and period of study (2010-2011 or 2012). There were significantly greater declines in the proportions of women from voucher sites that paid for antenatal, delivery and postnatal care services at health facilities compared to those from non-voucher sites. The changes were also consistent with increased uptake of the safe motherhood voucher in intervention sites over time. There was, however, no significant difference in changes in the proportions of women from voucher and non-voucher sites that paid for family planning services. The results further show that there were significant differences in changes in the amount paid for family planning and antenatal care services by women from voucher compared to those from non-voucher sites. Although there were greater declines in the average amount paid for delivery and postnatal care services by women from voucher compared to those from non-voucher sites, the difference-in-differences estimates were not statistically significant. The reproductive health vouchers program in Kenya significantly contributed to reductions in the proportions of women in the community that paid out-of-pocket for safe motherhood services at health facilities.

Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

PubMed

Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

2013-01-01

Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket properties for ligand binding.

Insights into an Original Pocket-Ligand Pair Classification: A Promising Tool for Ligand Profile Prediction

PubMed Central

Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A.; Villoutreix, Bruno O.; Camproux, Anne-Claude

2013-01-01

Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket properties for ligand binding. PMID:23840299

Dosimetric Effects of Air Pockets Around High-Dose Rate Brachytherapy Vaginal Cylinders

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

Richardson, Susan, E-mail: srichardson@radonc.wustl.ed; Palaniswaamy, Geethpriya; Grigsby, Perry W.

2010-09-01

Purpose: Most physicians use a single-channel vaginal cylinder for postoperative endometrial cancer brachytherapy. Recent published data have identified air pockets between the vaginal cylinders and the vaginal mucosa. The purpose of this research was to evaluate the incidence, size, and dosimetric effects of these air pockets. Methods and Materials: 25 patients receiving postoperative vaginal cuff brachytherapy with a high-dose rate vaginal cylinders were enrolled in this prospective data collection study. Patients were treated with 6 fractions of 200 to 400 cGy per fraction prescribed at 5 mm depth. Computed tomography simulation for brachytherapy treatment planning was performed for each fraction.more » The quantity, volume, and dosimetric impact of the air pockets surrounding the cylinder were quantified. Results: In 25 patients, a total of 90 air pockets were present in 150 procedures (60%). Five patients had no air pockets present during any of their treatments. The average number of air pockets per patient was 3.6, with the average total air pocket volume being 0.34 cm{sup 3} (range, 0.01-1.32 cm{sup 3}). The average dose reduction to the vaginal mucosa at the air pocket was 27% (range, 9-58%). Ten patients had no air pockets on their first fraction but air pockets occurred in subsequent fractions. Conclusion: Air pockets between high-dose rate vaginal cylinder applicators and the vaginal mucosa are present in the majority of fractions of therapy, and their presence varies from patient to patient and fraction to fraction. The existence of air pockets results in reduced radiation dose to the vaginal mucosa.« less

Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex.

PubMed

Fan, Q R; Long, E O; Wiley, D C

2001-05-01

Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells. We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to its class I MHC ligand, HLA-Cw4. The KIR2DL1-HLA-Cw4 interface exhibits charge and shape complementarity. Specificity is mediated by a pocket in KIR2DL1 that hosts the Lys80 residue of HLA-Cw4. Many residues conserved in HLA-C and in KIR2DL receptors make different interactions in KIR2DL1-HLA-Cw4 and in a previously reported KIR2DL2-HLA-Cw3 complex. A dimeric aggregate of KIR-HLA-C complexes was observed in one KIR2DL1-HLA-Cw4 crystal. Most of the amino acids that differ between human and chimpanzee KIRs with HLA-C specificities form solvent-accessible clusters outside the KIR-HLA interface, which suggests undiscovered interactions by KIRs.

[Substrate specificities of bile salt hydrolase 1 and its mutants from Lactobacillus salivarius].

PubMed

Bi, Jie; Fang, Fang; Qiu, Yuying; Yang, Qingli; Chen, Jian

2014-03-01

In order to analyze the correlation between critical residues in the catalytic centre of BSH and the enzyme substrate specificity, seven mutants of Lactobacillus salivarius bile salt hydrolase (BSH1) were constructed by using the Escherichia coli pET-20b(+) gene expression system, rational design and site-directed mutagenesis. These BSH1 mutants exhibited different hydrolytic activities against various conjugated bile salts through substrate specificities comparison. Among the residues being tested, Cys2 and Thr264 were deduced as key sites for BSH1 to catalyze taurocholic acid and glycocholic acid, respectively. Moreover, Cys2 and Thr264 were important for keeping the catalytic activity of BSH1. The high conservative Cys2 was not the only active site, other mutant amino acid sites were possibly involved in substrate binding. These mutant residues might influence the space and shape of the substrate-binding pockets or the channel size for substrate passing through and entering active site of BSH1, thus, the hydrolytic activity of BSH1 was changed to different conjugated bile salt.

Comparison of full-mouth disinfection and quadrant-wise scaling in the treatment of adult chronic periodontitis: a systematic review and meta-analysis.

PubMed

Fang, H; Han, M; Li, Q-L; Cao, C Y; Xia, R; Zhang, Z-H

2016-08-01

Scaling and root planing are widely considered as effective methods for treating chronic periodontitis. A meta-analysis published in 2008 showed no statistically significant differences between full-mouth disinfection (FMD) or full-mouth scaling and root planing (FMS) and quadrant scaling and root planing (Q-SRP). The FMD approach only resulted in modest additional improvements in several indices. Whether differences exist between these two approaches requires further validation. Accordingly, a study was conducted to further validate whether FMD with antiseptics or FMS without the use of antiseptics within 24 h provides greater clinical improvement than Q-SRP in patients with chronic periodontitis. Medline (via OVID), EMBASE (via OVID), PubMed and CENTRAL databases were searched up to 27 January 2015. Randomized controlled trials comparing FMD or FMS with Q-SRP after at least 3 mo were included. Meta-analysis was performed to obtain the weighted mean difference (WMD), together with the corresponding 95% confidence intervals. Thirteen articles were included in the meta-analysis. The WMD of probing pocket depth reduction was 0.25 mm (p < 0.05) for FMD vs. Q-SRP in single-rooted teeth with moderate pockets, and clinical attachment level gain in single- and multirooted teeth with moderate pockets was 0.33 mm (p < 0.05) for FMD vs. Q-SRP. Except for those, no statistically significant differences were found in the other subanalyses of FMD vs. Q-SRP, FMS vs. Q-SRP and FMD vs. FMS. Therefore, the meta-analysis results showed that FMD was better than Q-SRP for achieving probing pocket depth reduction and clinical attachment level gain in moderate pockets. Additionally, regardless of the treatment, no serious complications were observed. FMD, FMS and Q-SRP are all effective for the treatment of adult chronic periodontitis, and they do not lead to any obvious discomfort among patients. Moreover, FMD had modest additional clinical benefits over Q-SRP, so we prefer to recommend FMD as the first choice for the treatment of adult chronic periodontitis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Jack Rabbit Pretest Shadowplate Drawings For TATB IHE Model Development

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

Hart, M M; McDaniel, D W

The Jack Rabbit Pretest (PT) series consisted of 5 focused hydrodynamic experiments 2021E PT3, PT4, PT5, PT6, and PT7. They were fired in March and April of 2008 at the Contained Firing Facility, Site 300, Lawrence Livermore National Laboratory, Livermore, California. These experiments measured deadzone formation and impulse gradients created during the detonation of TATB based insensitive high explosive. When setting up computer simulations of the Jack Rabbit Pretest series, the modeler or code developer can execute simulations with increasing degrees of refinement using detail found in the shadowplate design. The easiest way to get started is by treating themore » shadowplate in each experiment as a monolithic homogeneous piece of stainless steel. The simulation of detonation would begin as a point initiation below the center, bottom surface of the shadowplate. The detonation running through the ultrafine TATB booster can be simulated using program burn and then switched over to a reactive flow detonation model as the detonation front crosses the boundary into the main charge LX-17 IHE. A modeler wanting to further refine the simulation and progression of shock through the shadowplate can use the more detailed shadowplate design information presented in this document. The source drawings are included in Appendix A of this document. Their titles and drawing numbers are listed. Each experiment's shadowplate consists of two major components. A 303 stainless steel shape that defines the outer dimensions of shadowplate and a cylindrical 303 stainless steel detonator housing that is located in a closely machined pocket in the shape. The SIMPLE ASSY drawing accurately represents the dimensions of the outer shape, it's machined cylindrical pocket, and detonator body which is treated as a monolithic, homogeneous piece of stainless steel. The detonator body cross section shows an accurately dimensioned void where the slapper flyer barrel, LX-16 (pressed PETN) pellet, and pellet can flyer barrel are located. The FULL ASSY drawing accurately represents the dimensions of the outer shadowplate shape and it's machined pocket. The detonator dimensions and materials are detailed in cross section and exploded view. All diameters, thicknesses, and materials are called out in the drawing. You will notice that the detonator includes a multilayer slapper assembly with two layers of electrically insulating Kapton sandwiching the copper foil bridge circuit. The Kapton insulated circuit is sandwiched between two thin stainless steel sheets. This slapper assembly is secured to the detonator body with two screws. There is a 0.25 mm gap between the slapper assembly and the outer shadowplate shape. The stainless steel detonator body contains an off-center titanium wheel. This titanium wheel is secured to the detonator body with one screw and two pins to maintain position and orientation of the pellet can assembly in the center of the detonator body. The titanium wheel contains a tantalum/tungsten washer and pellet can assembly. The pellet can assembly consists of a pressed LX-16 initiator pellet contained in an extruded aluminum foil can. It may be useful for the modeler to include some of the details of the shadowplate and detonator design to further refine simulations of the Jack Rabbit Pretest experiments. These details may be relevant to the progression of shock originating from the PETN initiation pellet and ultrafine TATB booster that propagates through the shadowplate.« less

Influence of GTP/GDP and magnesium ion on the solvated structure of the protein FtsZ: a molecular dynamics study.

PubMed

Jamous, Carla; Basdevant, Nathalie; Ha-Duong, Tap

2014-01-01

We present here a structural analysis of ten extensive all-atom molecular dynamics simulations of the monomeric protein FtsZ in various binding states. Since the polymerization and GTPase activities of FtsZ depend on the nature of a bound nucleotide as well as on the presence of a magnesium ion, we studied the structural differences between the average conformations of the following five systems: FtsZ-Apo, FtsZ-GTP, FtsZ-GDP, FtsZ-GTP-Mg, and FtsZ-GDP-Mg. The in silico solvated average structure of FtsZ-Apo significantly differs from the crystallographic structure 1W59 of FtsZ which was crystallized in a dimeric form without nucleotide and magnesium. The simulated Apo form of the protein also clearly differs from the FtsZ structures when it is bound to its ligand, the most important discrepancies being located in the loops surrounding the nucleotide binding pocket. The three average structures of FtsZ-GTP, FtsZ-GDP, and FtsZ-GTP-Mg are overall similar, except for the loop T7 located at the opposite side of the binding pocket and whose conformation in FtsZ-GDP notably differs from the one in FtsZ-GTP and FtsZ-GTP-Mg. The presence of a magnesium ion in the binding pocket has no impact on the FtsZ conformation when it is bound to GTP. In contrast, when the protein is bound to GDP, the divalent cation causes a translation of the nucleotide outwards the pocket, inducing a significant conformational change of the loop H6-H7 and the top of helix H7.

Reply to “Comment on ‘Magnetotransport signatures of a single nodal electron pocket constructed from Fermi arcs' ”

DOE PAGES

Harrison, N.; Sebastian, S. E.

2017-10-12

In this paper, we provide arguments relating to those recently made in a comment by Chakravarty and Wang, who question the validity of our proposed charge-density wave Fermi surface reconstruction model and its relation to sign changes in the Hall effect. First, we show that the form of rounding of the vertices (i.e. sharp corners) of the reconstructed electron pocket, as used in our model calculations of the Hall coefficient, is consistent with Bragg reflection from the periodic potential of a charge-density wave, rather than being arbitrarily chosen. Second, we provide further justifications for why an oscillatory transport scattering timemore » provides a useful means for modeling Shubnikov–de Haas oscillations in the Hall effect, in the situation where a Fermi surface pocket departs from the ideal circular form. Third and finally, we discuss recent experimental evidence gathered from two different families of underdoped cuprates supporting the existence of a single electron pocket produced by biaxial charge-density wave order as a universal phenomena.« less

Estimating annual medical and out-of-pocket expenditures associated with traumatic injuries in the United States.

PubMed

Alghnam, Suliman; Vanness, David J; Gaskin, Darrell J; Thorpe, Roland J; Castillo, Renan

2016-02-01

Every year, as many as 31 million Americans sustain traumatic injuries, leaving survivors with risks of disabilities and health settings with staggering medical costs. Little is known on the societal burden of injuries in terms of medical and out-of-pocket expenditures. Therefore, we used a nationally representative sample to evaluate the association between injuries and health expenditures among a nationally representative US sample. This study used years 2006 to 2010 (Panels 11-14; n = 53,065) of the Medical Expenditure Panel Survey. Each panel was followed up for 2 years. Total expenditures included insurance payments and out-of-pocket costs. Two-part models were constructed to examine differences in annual medical expenditures between injured and noninjured populations controlling for confounding effects. A total of 4,210 individuals (7.9%) reported injuries representing 21.5 million individuals. Injured individuals were more likely to be males, to be white, and to report higher medical expenditures in the second year than the reference population (p < 0.01). Adjusted analyses showed that reporting any injury was associated with $2,577 (95% confidence interval [CI], $2,049-$3,103) and $186 (95% CI, $142-$230) increase in total and out-of-pocket costs, respectively. While a moderate or severe injury was associated with $4,779 (95% CI, $3,947-$5,610) increase in the average of medical expenditures and $256 (95% CI, $190-$322) increase in out-of-pocket costs adjusting for covariates. Our adjusted national medical cost of injuries was estimated at $56 billion and out-of-pocket cost to be approximately $4 billion. Injuries pose a substantial burden on medical expenditures in the United States. Investment in injury prevention can facilitate reducing medical expenditures and save resources. Prevention programs may use the out-of-pocket findings to highlight injury burden on individual's prosperity and thus facilitate engagement of the public in prevention. Economic and evaluation study, level III.

Biomarker-based diagnosis of pacemaker and implantable cardioverter defibrillator pocket infections: A prospective, multicentre, case-control evaluation

PubMed Central

Vrazic, Hrvoje; Haller, Bernhard; Braun, Siegmund; Petzold, Tobias; Ott, Ilka; Lennerz, Agnes; Michel, Jonathan; Blažek, Patrick; Deisenhofer, Isabel; Whittaker, Peter; Kolb, Christof

2017-01-01

Background The use of cardiac implantable electronic devices (CIED) has risen steadily, yet the rate of cardiac device infections (CDI) has disproportionately increased. Amongst all cardiac device infections, the pocket infection is the most challenging diagnosis. Therefore, we aimed to improve diagnosis of such pocket infection by identifying relevant biomarkers. Methods We enrolled 25 consecutive patients with invasively and microbiologically confirmed pocket infection. None of the patients had any confounding conditions. Pre-operative levels of 14 biomarkers were compared in infected and control (n = 50) patients. Our selected biomarkers included white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), lipopolysaccharide binding protein, high-sensitivity C-reactive protein (HS-CRP), polymorphonuclear-elastase, presepsin, various interleukins, tumor necrosis factor α (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF). Results Of the 25 patients with isolated pocket infection (70±13years, 76% male, 40% ICDs), none presented with leukocytosis. In contrast, they had higher serum levels of HS-CRP (p = 0.019) and PCT (p = 0.010) than control patients. Median PCT-level was 0.06 ng/mL (IQR 0.03–0.07 ng/mL) in the study group versus 0.03 ng/mL (IQR 0.02–0.04 ng/mL) in controls. An optimized PCT cut-off value of 0.05 ng/mL suggests pocket infection with a sensitivity of 60% and specificity of 82%. In addition TNF-α- and GM-CSF-levels were lower in the study group. Other biomarkers did not differ between groups. Conclusion Diagnosis of isolated pocket infections requires clinical awareness, physical examination, evaluation of blood cultures and echocardiography assessment. Nevertheless, measurement of PCT- and HS-CRP-levels can aid diagnosis. However, no conclusion can be drawn from normal WBC-values. Clinical trial registration clinicaltrials.gov identifier: NCT01619267 PMID:28264059

Pocket money, eating behaviors, and weight status among Chinese children: The Childhood Obesity Study in China mega-cities.

PubMed

Li, Miao; Xue, Hong; Jia, Peng; Zhao, Yaling; Wang, Zhiyong; Xu, Fei; Wang, Youfa

2017-07-01

Both the obesity rate and pocket money are rising among children in China. This study examined family correlates of children's pocket money, associations of pocket money with eating behaviors and weight status, and how the associations may be modified by schools' unhealthy food restrictions in urban China. Data were collected in 2015 from 1648 students in 16 primary and middle schools in four mega-cities in China (4 schools/city): Beijing, Shanghai, Nanjing, and Xi'an. Cluster robust negative binomial regression models were fit to assess family correlates of pocket money, associations of pocket money with child eating behaviors and weight outcomes, and possible modifying effects of schools' unhealthy food restrictions. Sixty-nine percent of students received pocket money weekly. Students received more pocket money if mothers frequently ate out of home (IRR=2.28 [1.76, 2.94]) and/or family rarely had dinner together (IRR=1.42, 95%=[1.01, 1.99]). Students got less pocket money if parents were concerned about child's future health due to unhealthy eating (IRR=0.56 [0.32,0.98]). Students with more pocket money more frequently consumed (by 25-89%) sugary beverages, snacks, fast food, or at street food stalls, and were 45-90% more likely to be overweight/obese. Associations of pocket money with unhealthy eating and overweight/obesity were weaker in schools with unhealthy food restrictions. Pocket money is a risk factor for unhealthy eating and obesity in urban China. School policies may buffer pocket money's negative influence on students' eating and weight status. Copyright © 2017. Published by Elsevier Inc.

Structural Characterization and Determinants of Specificity of Single-Chain Antibody Inhibitors of Membrane-Type Serine Protease 1

DTIC Science & Technology

2008-03-01

Colman, P. M. (1993). Shape complementarity at protein / protein interfaces . J Mol Biol 234, 946-50. 26. Huang, M., Syed, R., Stura, E. A., Stone, M. J...Å2 of surface area (Table 1). In the apo MT-SP1 structure20, Asp96 forms the bottom of the S4 pocket, allowing a positively charged substrate P4...of surface area that E2 buries on MT-SP1 is larger than the typical antibody/ protein antigen interaction, which averages about 875 Å2 26; 27. This

An Empirical Analysis of Rural-Urban Differences in Out-Of-Pocket Health Expenditures in a Low-Income Society of China.

PubMed

Wang, Lidan; Wang, Anjue; Zhou, Detong; FitzGerald, Gerry; Ye, Dongqing; Jiang, Qicheng

2016-01-01

The paper examines whether out-of-pocket health care expenditure also has regional discrepancies, comparing to the equity between urban and rural areas, and across households. Sampled data were derived from Urban Household Survey and Rural Household Survey data for 2011/2012 for Anhui Province, and 11049 households were included in this study. The study compared differences in out-of-pocket expenditure on health care between regions (urban vs. rural areas) and years (2011 vs. 2012) using two-sample t-test, and also investigated the degree of inequality using Lorenz and concentration curves. Approximately 5% and 8% of total household consumption expenditure was spent on health care for urban and rural populations, respectively. In 2012, the wealthiest 20% of urban and rural population contributed 49.7% and 55.8% of urban and rural total health expenditure respectively, while the poorest 20% took only 4.7% and 4.4%. The concentration curve for out-of-pocket expenditure in 2012 fell below the corresponding concentration curve for 2011 for both urban and rural areas, and the difference between curves for rural areas was greater than that for urban areas. A substantial and increasing gap in health care expenditures existed between urban and rural areas in Anhui. The health care financing inequality merits ample attention, with need for policymaking to focus on improving the accessibility to essential health care services, particularly for rural and poor residents. This study may provide useful information on low income areas of China.

An Empirical Analysis of Rural-Urban Differences in Out-Of-Pocket Health Expenditures in a Low-Income Society of China

PubMed Central

Wang, Lidan; Wang, Anjue; Zhou, Detong; FitzGerald, Gerry; Ye, Dongqing; Jiang, Qicheng

2016-01-01

Objective The paper examines whether out-of-pocket health care expenditure also has regional discrepancies, comparing to the equity between urban and rural areas, and across households. Method Sampled data were derived from Urban Household Survey and Rural Household Survey data for 2011/2012 for Anhui Province, and 11049 households were included in this study. The study compared differences in out-of-pocket expenditure on health care between regions (urban vs. rural areas) and years (2011 vs. 2012) using two-sample t-test, and also investigated the degree of inequality using Lorenz and concentration curves. Result Approximately 5% and 8% of total household consumption expenditure was spent on health care for urban and rural populations, respectively. In 2012, the wealthiest 20% of urban and rural population contributed 49.7% and 55.8% of urban and rural total health expenditure respectively, while the poorest 20% took only 4.7% and 4.4%. The concentration curve for out-of-pocket expenditure in 2012 fell below the corresponding concentration curve for 2011 for both urban and rural areas, and the difference between curves for rural areas was greater than that for urban areas. Conclusion A substantial and increasing gap in health care expenditures existed between urban and rural areas in Anhui. The health care financing inequality merits ample attention, with need for policymaking to focus on improving the accessibility to essential health care services, particularly for rural and poor residents. This study may provide useful information on low income areas of China. PMID:27223811

Skin in the game: Does paying for obesity treatment out of pocket lead to better outcomes compared to insurance coverage?

PubMed

Ard, Jamy D; Emery, Matt; Cook, Miranda; Hale, Erica; Frain, Annette; Lewis, Kristina H; Song, Eunyoung

2017-06-01

To determine whether insurance coverage for medical weight loss treatment was associated with different program engagement and weight loss outcomes compared to those who paid out of pocket. One-year outcomes from an academic medical weight management program were used to compare two groups: employees (n = 480) with insurance coverage ("covered") versus nonemployees (n = 463) who paid out of pocket ("self-pay"). Demographics and weight were abstracted from medical records. Socioeconomic status was estimated using neighborhood demographics. Group differences in weight were analyzed using generalized linear modeling adjusted for age, baseline BMI, sex, program type, and neighborhood socioeconomic status. Covered patients were younger (46.5 ± 10.6 vs. 51.6 ± 12.5) with a lower BMI (38.5 ± 7.5 vs. 41.3 ± 9.9) compared to self-pay (P < 0.001). Self-pay patients resided in higher annual per capita income neighborhoods (+$4,545, P < 0.001). Program dropout was lower for covered patients (12.7% vs. 17.6%, P = 0.03). There was no significant difference in 12-month weight loss between groups in adjusted models; covered patients lost 13.4%, compared to 13.6% for self-pay. Data from an academic medical weight management program suggest that individuals with access to insurance coverage for nonsurgical obesity treatment have lower levels of attrition and similar levels of participation and outcomes as those who pay out of pocket. © 2017 The Obesity Society.

Accurate de novo design of hyperstable constrained peptides

PubMed Central

Bhardwaj, Gaurav; Mulligan, Vikram Khipple; Bahl, Christopher D.; Gilmore, Jason M.; Harvey, Peta J.; Cheneval, Olivier; Buchko, Garry W.; Pulavarti, Surya V.S.R.K.; Kaas, Quentin; Eletsky, Alexander; Huang, Po-Ssu; Johnsen, William A.; Greisen, Per; Rocklin, Gabriel J.; Song, Yifan; Linsky, Thomas W.; Watkins, Andrew; Rettie, Stephen A.; Xu, Xianzhong; Carter, Lauren P.; Bonneau, Richard; Olson, James M.; Coutsias, Evangelos; Correnti, Colin E.; Szyperski, Thomas; Craik, David J.; Baker, David

2016-01-01

Summary Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for de novo design of conformationally-restricted peptides, and the use of these methods to design 15–50 residue disulfide-crosslinked and heterochiral N-C backbone-cyclized peptides. These peptides are exceptionally stable to thermal and chemical denaturation, and twelve experimentally-determined X-ray and NMR structures are nearly identical to the computational models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs. PMID:27626386

A Novel Antiviral Target Structure Involved in the RNA Binding, Dimerization, and Nuclear Export Functions of the Influenza A Virus Nucleoprotein

PubMed Central

Yamada, Kazunori; Kondoh, Yasumitsu; Hikono, Hirokazu; Osada, Hiroyuki; Tomii, Kentaro; Saito, Takehiko; Aida, Yoko

2015-01-01

Developing antiviral therapies for influenza A virus (IAV) infection is an ongoing process because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. The ideal strategy is to develop drugs that target well-conserved, functionally restricted, and unique surface structures without affecting host cell function. We recently identified the antiviral compound, RK424, by screening a library of 50,000 compounds using cell-based infection assays. RK424 showed potent antiviral activity against many different subtypes of IAV in vitro and partially protected mice from a lethal dose of A/WSN/1933 (H1N1) virus in vivo. Here, we show that RK424 inhibits viral ribonucleoprotein complex (vRNP) activity, causing the viral nucleoprotein (NP) to accumulate in the cell nucleus. In silico docking analysis revealed that RK424 bound to a small pocket in the viral NP. This pocket was surrounded by three functionally important domains: the RNA binding groove, the NP dimer interface, and nuclear export signal (NES) 3, indicating that it may be involved in the RNA binding, oligomerization, and nuclear export functions of NP. The accuracy of this binding model was confirmed in a NP-RK424 binding assay incorporating photo-cross-linked RK424 affinity beads and in a plaque assay evaluating the structure-activity relationship of RK424. Surface plasmon resonance (SPR) and pull-down assays showed that RK424 inhibited both the NP-RNA and NP-NP interactions, whereas size exclusion chromatography showed that RK424 disrupted viral RNA-induced NP oligomerization. In addition, in vitro nuclear export assays confirmed that RK424 inhibited nuclear export of NP. The amino acid residues comprising the NP pocket play a crucial role in viral replication and are highly conserved in more than 7,000 NP sequences from avian, human, and swine influenza viruses. Furthermore, we found that the NP pocket has a surface structure different from that of the pocket in host molecules. Taken together, these results describe a promising new approach to developing influenza virus drugs that target a novel pocket structure within NP. PMID:26222066

α clustering with a hollow structure: Geometrical structure of α clusters from platonic solids to fullerene shape

NASA Astrophysics Data System (ADS)

Tohsaki, Akihiro; Itagaki, Naoyuki

2018-01-01

We study α -cluster structure based on the geometric configurations with a microscopic framework, which takes full account of the Pauli principle, and which also employs an effective internucleon force including finite-range three-body terms suitable for microscopic α -cluster models. Here, special attention is focused upon the α clustering with a hollow structure; all the α clusters are put on the surface of a sphere. All the platonic solids (five regular polyhedra) and the fullerene-shaped polyhedron coming from icosahedral structure are considered. Furthermore, two configurations with dual polyhedra, hexahedron-octahedron and dodecahedron-icosahedron, are also scrutinized. When approaching each other from large distances with these symmetries, α clusters create certain local energy pockets. As a consequence, we insist on the possible existence of α clustering with a geometric shape and hollow structure, which is favored from Coulomb energy point of view. Especially, two configurations, that is, dual polyhedra of dodecahedron-icosahedron and fullerene, have a prominent hollow structure compared with the other six configurations.

An Augmented Pocketome: Detection and Analysis of Small-Molecule Binding Pockets in Proteins of Known 3D Structure.

PubMed

Bhagavat, Raghu; Sankar, Santhosh; Srinivasan, Narayanaswamy; Chandra, Nagasuma

2018-03-06

Protein-ligand interactions form the basis of most cellular events. Identifying ligand binding pockets in proteins will greatly facilitate rationalizing and predicting protein function. Ligand binding sites are unknown for many proteins of known three-dimensional (3D) structure, creating a gap in our understanding of protein structure-function relationships. To bridge this gap, we detect pockets in proteins of known 3D structures, using computational techniques. This augmented pocketome (PocketDB) consists of 249,096 pockets, which is about seven times larger than what is currently known. We deduce possible ligand associations for about 46% of the newly identified pockets. The augmented pocketome, when subjected to clustering based on similarities among pockets, yielded 2,161 site types, which are associated with 1,037 ligand types, together providing fold-site-type-ligand-type associations. The PocketDB resource facilitates a structure-based function annotation, delineation of the structural basis of ligand recognition, and provides functional clues for domains of unknown functions, allosteric proteins, and druggable pockets. Copyright © 2018 Elsevier Ltd. All rights reserved.

Visualizing electron pockets in cuprate superconductors

NASA Astrophysics Data System (ADS)

Das, Tanmoy; Markiewicz, R. S.; Bansil, A.; Balatsky, A. V.

2012-06-01

Fingerprints of the electron pocket in cuprates have been obtained only in numerous magnetotransport measurements, but its absence in spectroscopic observations poses a long-standing mystery. We develop a theoretical tool to provide ways to detect electron pockets via spectroscopies including scanning tunneling microscopy (STM) spectra, inelastic neutron scattering (INS), and angle-resolved photoemission spectroscopy (ARPES). We show that the quasiparticle-interference (QPI) pattern, measured by STM, shows an additional seven q vectors associated with the scattering on the electron pocket than that on the hole pocket. Furthermore, the Bogolyubov quasiparticle scatterings of the electron pocket lead to a second magnetic resonance mode in the INS spectra at a higher resonance energy. Finally, we reanalyze some STM, INS, and ARPES experimental data of several cuprates which dictates the direct fingerprints of electron pockets in these systems.

Air Entrainment in Steady Breaking Waves

NASA Astrophysics Data System (ADS)

Li, C. Y.; Duncan, J. H.; Wenz, A.; Full, O. E.

1997-11-01

Air entrainment due to steady breaking waves generated by fully submerged hydrofoils moving at constant speed and angle of attack is investigated experimentally. Three hydrofoils with the same shape (NACA 0012) but different chords (15, 20 and 30 cm) are used with Froude scaled operating conditions to generate the breaking waves. In this way, the effect of scale due to the combined influence of surface tension and viscosity on the bubble entrainment process is investigated. The bubbles are measured from plan-view and side-view 35-mm photographs of the wake. It is found that the number and average size of the bubbles increases dramatically with scale. High-speed movies of the turbulent breaking region that rides on the forward face of the wave are also used to observe bubble entrainment events. It is found that the bubbles are entrained periodically when the leading edge of the breaking region rushes forward and plunges over a pocket of air. This plunging process appears to become more frequent and more violent as the scale of the breaker increases.

Molecular basis for defect in Alix-binding by alternatively spliced isoform of ALG-2 (ALG-2DeltaGF122) and structural roles of F122 in target recognition.

PubMed

Inuzuka, Tatsutoshi; Suzuki, Hironori; Kawasaki, Masato; Shibata, Hideki; Wakatsuki, Soichi; Maki, Masatoshi

2010-08-06

ALG-2 (a gene product of PDCD6) belongs to the penta-EF-hand (PEF) protein family and Ca2+-dependently interacts with various intracellular proteins including mammalian Alix, an adaptor protein in the ESCRT system. Our previous X-ray crystal structural analyses revealed that binding of Ca2+ to EF3 enables the side chain of R125 to move enough to make a primary hydrophobic pocket (Pocket 1) accessible to a short fragment of Alix. The side chain of F122, facing a secondary hydrophobic pocket (Pocket 2), interacts with the Alix peptide. An alternatively spliced shorter isoform, designated ALG-2DeltaGF122, lacks Gly121Phe122 and does not bind Alix, but the structural basis of the incompetence has remained to be elucidated. We solved the X-ray crystal structure of the PEF domain of ALG-2DeltaGF122 in the Ca2+-bound form and compared it with that of ALG-2. Deletion of the two residues shortened alpha-helix 5 (alpha5) and changed the configuration of the R125 side chain so that it partially blocked Pocket 1. A wall created by the main chain of 121-GFG-123 and facing the two pockets was destroyed. Surprisingly, however, substitution of F122 with Ala or Gly, but not with Trp, increased the Alix-binding capacity in binding assays. The F122 substitutions exhibited different effects on binding of ALG-2 to other known interacting proteins, including TSG101 (Tumor susceptibility gene 101) and annexin A11. The X-ray crystal structure of the F122A mutant revealed that removal of the bulky F122 side chain not only created an additional open space in Pocket 2 but also abolished inter-helix interactions with W95 and V98 (present in alpha4) and that alpha5 inclined away from alpha4 to expand Pocket 2, suggesting acquirement of more appropriate positioning of the interacting residues to accept Alix. We found that the inability of the two-residue shorter ALG-2 isoform to bind Alix is not due to the absence of bulky side chain of F122 but due to deformation of a main-chain wall facing pockets 1 and 2. Moreover, a residue at the position of F122 contributes to target specificity and a smaller side chain is preferable for Alix binding but not favored to bind annexin A11.

Rogue waves and large deviations in deep sea.

PubMed

Dematteis, Giovanni; Grafke, Tobias; Vanden-Eijnden, Eric

2018-01-30

The appearance of rogue waves in deep sea is investigated by using the modified nonlinear Schrödinger (MNLS) equation in one spatial dimension with random initial conditions that are assumed to be normally distributed, with a spectrum approximating realistic conditions of a unidirectional sea state. It is shown that one can use the incomplete information contained in this spectrum as prior and supplement this information with the MNLS dynamics to reliably estimate the probability distribution of the sea surface elevation far in the tail at later times. Our results indicate that rogue waves occur when the system hits unlikely pockets of wave configurations that trigger large disturbances of the surface height. The rogue wave precursors in these pockets are wave patterns of regular height, but with a very specific shape that is identified explicitly, thereby allowing for early detection. The method proposed here combines Monte Carlo sampling with tools from large deviations theory that reduce the calculation of the most likely rogue wave precursors to an optimization problem that can be solved efficiently. This approach is transferable to other problems in which the system's governing equations contain random initial conditions and/or parameters.

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

Xu, J.; Ghimire, N. J.; Jiang, J. S.

Extremely large magnetoresistance (XMR) was recently discovered in YSb but its origin, along with that of many other XMR materials, is an active subject of debate. Here we demonstrate that YSb, with a cubic crystalline lattice and anisotropic bulk electron Fermi pockets, can be an excellent candidate for revealing the origin of XMR. We carried out angle dependent Shubnikov – de Haas quantum oscillation measurements to determine the volume and shape of the Fermi pockets. In addition, by investigating both Hall and longitudinal magnetoresistivities, we reveal that the origin of XMR in YSb lies in its carrier high mobility withmore » a diminishing Hall factor that is obtained from the ratio of the Hall and longitudinal magentoresistivities. The high mobility leads to a strong magnetic field dependence of the longitudinal magnetoconductivity while a diminishing Hall factor reveals the latent XMR hidden in the longitudinal magnetoconductivity whose inverse has a nearly quadratic magnetic-field dependence. The Hall factor highlights the deviation of the measured magnetoresistivity from its full potential value and provides a general formulation to reveal the origin of XMR behavior in high mobility materials and of nonsaturating MR behavior as a whole. Our approach can be readily applied to other XMR materials.« less

Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein-Ligand Contacts.

PubMed

Monaco, Serena; Tailford, Louise E; Juge, Nathalie; Angulo, Jesus

2017-11-27

Saturation transfer difference (STD) NMR spectroscopy is extensively used to obtain epitope maps of ligands binding to protein receptors, thereby revealing structural details of the interaction, which is key to direct lead optimization efforts in drug discovery. However, it does not give information about the nature of the amino acids surrounding the ligand in the binding pocket. Herein, we report the development of the novel method differential epitope mapping by STD NMR (DEEP-STD NMR) for identifying the type of protein residues contacting the ligand. The method produces differential epitope maps through 1) differential frequency STD NMR and/or 2) differential solvent (D 2 O/H 2 O) STD NMR experiments. The two approaches provide different complementary information on the binding pocket. We demonstrate that DEEP-STD NMR can be used to readily obtain pharmacophore information on the protein. Furthermore, if the 3D structure of the protein is known, this information also helps in orienting the ligand in the binding pocket. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

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

Adhikary, Suraj; Eichman, Brandt F.

DNA glycosylases specialized for the repair of alkylation damage must identify, with fine specificity, a diverse array of subtle modifications within DNA. The current mechanism involves damage sensing through interrogation of the DNA duplex, followed by more specific recognition of the target base inside the active site pocket. To better understand the physical basis for alkylpurine detection, we determined the crystal structure of Schizosaccharomyces pombe Mag1 (spMag1) in complex with DNA and performed a mutational analysis of spMag1 and the close homologue from Saccharomyces cerevisiae (scMag). Despite strong homology, spMag1 and scMag differ in substrate specificity and cellular alkylation sensitivity,more » although the enzymological basis for their functional differences is unknown. We show that Mag preference for 1,N{sup 6}-ethenoadenine ({var_epsilon}A) is influenced by a minor groove-interrogating residue more than the composition of the nucleobase-binding pocket. Exchanging this residue between Mag proteins swapped their {var_epsilon}A activities, providing evidence that residues outside the extrahelical base-binding pocket have a role in identification of a particular modification in addition to sensing damage.« less

Sonographic findings of ruptured epidermal inclusion cysts in superficial soft tissue: emphasis on shapes, pericystic changes, and pericystic vascularity.

PubMed

Jin, Wook; Ryu, Kyung Nam; Kim, Gou Young; Kim, Hyun Cheol; Lee, Jae Hoon; Park, Ji Seon

2008-02-01

The purpose of this study was to retrospectively evaluate the sonographic findings of ruptured epidermal inclusion cysts in superficial soft tissue, with an emphasis on shapes, pericystic changes, and pericystic vascularity. The cases of 61 patients with surgically confirmed epidermal inclusion cysts were reviewed, and 13 patients were found to have ruptured cysts. The Ethics Committees of our institutions did not require patient approval or informed patient consent for this retrospective study. We evaluated the shapes, sizes, locations, pericystic changes, and pericystic vascularity for the 13 cases. The shapes of the ruptured epidermal inclusion cysts were classified into 3 types: with lobulations (type I, 2 cases), with protrusions (type II, 8 cases), and with abscess pocket formations (type III, 3 cases). The mean long diameter of the cysts was 3 cm. Common sites of ruptured epidermal inclusion cysts were the plantar surface of the metatarsophalangeal joint (4 cases) and buttocks (3 cases). Pericystic changes were noted in all of the type II and III cysts. Increased vascularity on color Doppler sonography was prominent in 3 type II cysts and 3 type III cysts. Deep abscess formation was noted in the epidermal inclusion cysts, especially for the type III cysts. A ruptured epidermal inclusion cyst visualized by sonography had variable shapes; the sonographic findings can be useful for obtaining a correct diagnosis of a ruptured epidermal inclusion cyst.

Tetanus Neurotoxin Neutralizing Antibodies Screened from a Human Immune scFv Antibody Phage Display Library.

PubMed

Wang, Han; Yu, Rui; Fang, Ting; Yu, Ting; Chi, Xiangyang; Zhang, Xiaopeng; Liu, Shuling; Fu, Ling; Yu, Changming; Chen, Wei

2016-09-11

Tetanus neurotoxin (TeNT) produced by Clostridium tetani is one of the most poisonous protein substances. Neutralizing antibodies against TeNT can effectively prevent and cure toxicosis. Using purified Hc fragments of TeNT (TeNT-Hc) as an antigen, three specific neutralizing antibody clones recognizing different epitopes were selected from a human immune scFv antibody phage display library. The three antibodies (2-7G, 2-2D, and S-4-7H) can effectively inhibit the binding between TeNT-Hc and differentiated PC-12 cells in vitro. Moreover, 2-7G inhibited TeNT-Hc binding to the receptor via carbohydrate-binding sites of the W pocket while 2-2D and S-4-7H inhibited binding of the R pocket. Although no single mAb completely protected mice from the toxin, they could both prolong survival when challenged with 20 LD50s (50% of the lethal dose) of TeNT. When used together, the mAbs completely neutralized 1000 LD50s/mg Ab, indicating their high neutralizing potency in vivo. Antibodies recognizing different carbohydrate-binding pockets could have higher synergistic toxin neutralization activities than those that recognize the same pockets. These results could lead to further production of neutralizing antibody drugs against TeNT and indicate that using TeNT-Hc as an antigen for screening human antibodies for TeNT intoxication therapy from human immune antibody library was convenient and effective.

Patient Preferences Regarding Colorectal Cancer Screening: Test Features and Cost Willing to Pay Out of Pocket.

PubMed

Moreno, Courtney C; Weiss, Paul S; Jarrett, Thomas L; Roberts, David L; Mittal, Pardeep K; Votaw, John R

2016-01-01

The purpose of this investigation was to evaluate whether test features would make an individual more or less likely to undergo colorectal cancer screening and how much an individual would be willing to pay out of pocket for a screening test. The methods include an administration of a survey to consecutive adult patients of a general medicine clinic. The survey consisted of Likert-scale questions assessing the patients' likelihood of choosing a screening test based on various test characteristics. Additional questions measured the patients' age, race, gender, and maximum out-of-pocket cost they would be willing to pay. Chi-square tests were used to assess the associations between the likelihood questions and the various demographic characteristics. In results, survey response rate was 88.8% (213 of 240). Respondents were 48.4% female (103 of 213), 51.6% male (110 of 213), 82.6% White (176 of 213), 11.3% African-American (24 of 213), and 6.1% other (13 of 213). Risk of internal injury and light exposure to radiation were the least desirable test features. Light sedation was the only test feature that most respondents (54.8%) indicated would make them likely or very likely to undergo a colorectal cancer screening test. The vast majority of respondents (86.8%) were willing to pay less than $200 out of pocket for a colorectal cancer screening test. There was no statistically significant difference in the responses of males and females, or in the responses of individuals of different races or different ages regarding test features, or the amount individuals were willing to pay for a screening test. To conclude, survey results suggest that patient education emphasizing the low complication rate of computed tomographic colonography (CTC), the minimal risks associated with the low-level radiation exposure resulting from CTC, and the benefits of a sedation-free test (eg, no risk of sedation-related complication and no need for a driver) may increase patient acceptance of CTC. Additionally, an out-of-pocket cost of <$200 would be preferable from the patient perspective. Copyright © 2015 Mosby, Inc. All rights reserved.

24 CFR 570.466 - Additional application submission requirements for Pockets of Poverty-employment opportunities.

Code of Federal Regulations, 2011 CFR

2011-04-01

... requirements for Pockets of Poverty-employment opportunities. 570.466 Section 570.466 Housing and Urban... application submission requirements for Pockets of Poverty—employment opportunities. Applicants for Action Grants under the Pockets of Poverty provision must describe the number and, to the extent possible, the...

24 CFR 570.466 - Additional application submission requirements for Pockets of Poverty-employment opportunities.

Code of Federal Regulations, 2013 CFR

2013-04-01

... requirements for Pockets of Poverty-employment opportunities. 570.466 Section 570.466 Housing and Urban... application submission requirements for Pockets of Poverty—employment opportunities. Applicants for Action Grants under the Pockets of Poverty provision must describe the number and, to the extent possible, the...

24 CFR 570.466 - Additional application submission requirements for Pockets of Poverty-employment opportunities.

Code of Federal Regulations, 2012 CFR

2012-04-01

... requirements for Pockets of Poverty-employment opportunities. 570.466 Section 570.466 Housing and Urban... application submission requirements for Pockets of Poverty—employment opportunities. Applicants for Action Grants under the Pockets of Poverty provision must describe the number and, to the extent possible, the...

24 CFR 570.466 - Additional application submission requirements for Pockets of Poverty-employment opportunities.

Code of Federal Regulations, 2014 CFR

2014-04-01

... requirements for Pockets of Poverty-employment opportunities. 570.466 Section 570.466 Housing and Urban... application submission requirements for Pockets of Poverty—employment opportunities. Applicants for Action Grants under the Pockets of Poverty provision must describe the number and, to the extent possible, the...

24 CFR 570.466 - Additional application submission requirements for Pockets of Poverty-employment opportunities.

Code of Federal Regulations, 2010 CFR

2010-04-01

... requirements for Pockets of Poverty-employment opportunities. 570.466 Section 570.466 Housing and Urban... application submission requirements for Pockets of Poverty—employment opportunities. Applicants for Action Grants under the Pockets of Poverty provision must describe the number and, to the extent possible, the...

[Analysis of breath hydrogen (H2) in diagnosis of gastrointestinal function: validation of a pocket breath H2 test analyzer].

PubMed

Braden, B; Braden, C P; Klutz, M; Lembcke, B

1993-04-01

Breath hydrogen (H2) analysis, as used in gastroenterologic function tests, requires a stationary analysis system equipped with a gaschromatograph or an electrochemical sensor cell. Now a portable breath H2-analyzer has been miniaturized to pocket size (104 mm x 62 mm x 29 mm). The application of this device in clinical practice has been assessed in comparison to the standard GMI-exhaled monitor. The pocket analyzer showed a linear response to standards with H2-concentrations ranging from 0-100 ppm (n = 7), which was not different from the GMI-apparatus. The correlation of both methods during clinical application (lactose tolerance tests, mouth-to-coecum transit time determined with lactulose) was excellent (Y = 1.08 X + 0.96; r = 0.959). Using the new device, both, analysis (3 s vs. 90 s) and the reset-time (43 s vs. 140 s) were shorter whereas calibration was more feasible with the GMI-apparatus. It is concluded, that the considerably cheaper pocket-sized breath H2-analyzer is as precise and sensitive as the GMI-exhaled monitor, and thus presents a valid alternative for H2-breath tests.

Enhancing an appointment diary on a pocket computer for use by people after brain injury.

PubMed

Wright, P; Rogers, N; Hall, C; Wilson, B; Evans, J; Emslie, H

2001-12-01

People with memory loss resulting from brain injury benefit from purpose-designed memory aids such as appointment diaries on pocket computers. The present study explores the effects of extending the range of memory aids and including games. For 2 months, 12 people who had sustained brain injury were loaned a pocket computer containing three purpose-designed memory aids: diary, notebook and to-do list. A month later they were given another computer with the same memory aids but a different method of text entry (physical keyboard or touch-screen keyboard). Machine order was counterbalanced across participants. Assessment was by interviews during the loan periods, rating scales, performance tests and computer log files. All participants could use the memory aids and ten people (83%) found them very useful. Correlations among the three memory aids were not significant, suggesting individual variation in how they were used. Games did not increase use of the memory aids, nor did loan of the preferred pocket computer (with physical keyboard). Significantly more diary entries were made by people who had previously used other memory aids, suggesting that a better understanding of how to use a range of memory aids could benefit some people with brain injury.

Structural Analysis of the Complex between Penta-EF-Hand ALG-2 Protein and Sec31A Peptide Reveals a Novel Target Recognition Mechanism of ALG-2

PubMed Central

Takahashi, Takeshi; Kojima, Kyosuke; Zhang, Wei; Sasaki, Kanae; Ito, Masaru; Suzuki, Hironori; Kawasaki, Masato; Wakatsuki, Soichi; Takahara, Terunao; Shibata, Hideki; Maki, Masatoshi

2015-01-01

ALG-2, a 22-kDa penta-EF-hand protein, is involved in cell death, signal transduction, membrane trafficking, etc., by interacting with various proteins in mammalian cells in a Ca2+-dependent manner. Most known ALG-2-interacting proteins contain proline-rich regions in which either PPYPXnYP (type 1 motif) or PXPGF (type 2 motif) is commonly found. Previous X-ray crystal structural analysis of the complex between ALG-2 and an ALIX peptide revealed that the peptide binds to the two hydrophobic pockets. In the present study, we resolved the crystal structure of the complex between ALG-2 and a peptide of Sec31A (outer shell component of coat complex II, COPII; containing the type 2 motif) and found that the peptide binds to the third hydrophobic pocket (Pocket 3). While amino acid substitution of Phe85, a Pocket 3 residue, with Ala abrogated the interaction with Sec31A, it did not affect the interaction with ALIX. On the other hand, amino acid substitution of Tyr180, a Pocket 1 residue, with Ala caused loss of binding to ALIX, but maintained binding to Sec31A. We conclude that ALG-2 recognizes two types of motifs at different hydrophobic surfaces. Furthermore, based on the results of serial mutational analysis of the ALG-2-binding sites in Sec31A, the type 2 motif was newly defined. PMID:25667979

Exploration of the conformational landscape in pregnane X receptor reveals a new binding pocket

PubMed Central

Chandran, Aneesh

2016-01-01

Abstract Ligand‐regulated pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a central role in xenobiotic metabolism. Despite its critical role in drug metabolism, PXR activation can lead to adverse drug‐drug interactions and early stage metabolism of drugs. Activated PXR can induce cancer drug resistance and enhance the onset of malignancy. Since promiscuity in ligand binding makes it difficult to develop competitive inhibitors targeting PXR ligand binding pocket (LBP), it is essential to identify allosteric sites for effective PXR antagonism. Here, molecular dynamics (MD) simulation studies unravelled the existence of two different conformational states, namely “expanded” and “contracted”, in apo PXR ligand binding domain (LBD). Ligand binding events shifted this conformational equilibrium and locked the LBD in a single “ligand‐adaptable” conformational state. Ensemble‐based computational solvent mapping identified a transiently open potential small molecule binding pocket between α5 and α8 helices, named “α8 pocket”, whose opening‐closing mechanism directly correlated with the conformational shift in LBD. A virtual hit identified through structure‐based virtual screening against α8 pocket locks the pocket in its open conformation. MD simulations further revealed that the presence of small molecule at allosteric site disrupts the LBD dynamics and locks the LBD in a “tightly‐contracted” conformation. The molecular details provided here could guide new structural studies to understand PXR activation and antagonism. PMID:27515410

Bacterial Community and PHB-Accumulating Bacteria Associated with the Wall and Specialized Niches of the Hindgut of the Forest Cockchafer (Melolontha hippocastani).

PubMed

Alonso-Pernas, Pol; Arias-Cordero, Erika; Novoselov, Alexey; Ebert, Christina; Rybak, Jürgen; Kaltenpoth, Martin; Westermann, Martin; Neugebauer, Ute; Boland, Wilhelm

2017-01-01

A characterization of the bacterial community of the hindgut wall of two larval and the adult stages of the forest cockchafer ( Melolontha hippocastani ) was carried out using amplicon sequencing of the 16S rRNA gene fragment. We found that, in second-instar larvae, Caulobacteraceae and Pseudomonadaceae showed the highest relative abundances, while in third-instar larvae, the dominant families were Porphyromonadaceae and Bacteroidales-related. In adults, an increase of the relative abundance of Bacteroidetes, Proteobacteria (γ- and δ- classes) and the family Enterococcaceae (Firmicutes) was observed. This suggests that the composition of the hindgut wall community may depend on the insect's life stage. Additionally, specialized bacterial niches hitherto very poorly described in the literature were spotted at both sides of the distal part of the hindgut chamber. We named these structures "pockets." Amplicon sequencing of the 16S rRNA gene fragment revealed that the pockets contained a different bacterial community than the surrounding hindgut wall, dominated by Alcaligenaceae and Micrococcaceae-related families. Poly-β-hydroxybutyrate (PHB) accumulation in the pocket was suggested in isolated Achromobacter sp. by Nile Blue staining, and confirmed by gas chromatography-mass spectrometry analysis (GC-MS) on cultured bacterial mass and whole pocket tissue. Raman micro-spectroscopy allowed to visualize the spatial distribution of PHB accumulating bacteria within the pocket tissue. The presence of this polymer might play a role in the colonization of these specialized niches.

Is there foul play in the leaf pocket? The metagenome of floating fern Azolla reveals endophytes that do not fix N2 but may denitrify.

PubMed

Dijkhuizen, Laura W; Brouwer, Paul; Bolhuis, Henk; Reichart, Gert-Jan; Koppers, Nils; Huettel, Bruno; Bolger, Anthony M; Li, Fay-Wei; Cheng, Shifeng; Liu, Xin; Wong, Gane Ka-Shu; Pryer, Kathleen; Weber, Andreas; Bräutigam, Andrea; Schluepmann, Henriette

2018-01-01

Dinitrogen fixation by Nostoc azollae residing in specialized leaf pockets supports prolific growth of the floating fern Azolla filiculoides. To evaluate contributions by further microorganisms, the A. filiculoides microbiome and nitrogen metabolism in bacteria persistently associated with Azolla ferns were characterized. A metagenomic approach was taken complemented by detection of N 2 O released and nitrogen isotope determinations of fern biomass. Ribosomal RNA genes in sequenced DNA of natural ferns, their enriched leaf pockets and water filtrate from the surrounding ditch established that bacteria of A. filiculoides differed entirely from surrounding water and revealed species of the order Rhizobiales. Analyses of seven cultivated Azolla species confirmed persistent association with Rhizobiales. Two distinct nearly full-length Rhizobiales genomes were identified in leaf-pocket-enriched samples from ditch grown A. filiculoides. Their annotation revealed genes for denitrification but not N 2 -fixation. 15 N 2 incorporation was active in ferns with N. azollae but not in ferns without. N 2 O was not detectably released from surface-sterilized ferns with the Rhizobiales. N 2 -fixing N. azollae, we conclude, dominated the microbiome of Azolla ferns. The persistent but less abundant heterotrophic Rhizobiales bacteria possibly contributed to lowering O 2 levels in leaf pockets but did not release detectable amounts of the strong greenhouse gas N 2 O. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Grid-Free 2D Plasma Simulations of the Complex Interaction Between the Solar Wind and Small, Near-Earth Asteroids

NASA Technical Reports Server (NTRS)

Zimmerman, M. I.; Farrell, W. M.; Poppe, A. R.

2014-01-01

We present results from a new grid-free 2D plasma simulation code applied to a small, unmagnetized body immersed in the streaming solar wind plasma. The body was purposely modeled as an irregular shape in order to examine photoemission and solar wind plasma flow in high detail on the dayside, night-side, terminator and surface-depressed 'pocket' regions. Our objective is to examine the overall morphology of the various plasma interaction regions that form around a small body like a small near-Earth asteroid (NEA). We find that the object obstructs the solar wind flow and creates a trailing wake region downstream, which involves the interplay between surface charging and ambipolar plasma expansion. Photoemission is modeled as a steady outflow of electrons from illuminated portions of the surface, and under direct illumination the surface forms a non-monotonic or ''double-sheath'' electric potential upstream of the body, which is important for understanding trajectories and equilibria of lofted dust grains in the presence of a complex asteroid geometry. The largest electric fields are found at the terminators, where ambipolar plasma expansion in the body-sized night-side wake merges seamlessly with the thin photoelectric sheath on the dayside. The pocket regions are found to be especially complex, with nearby sunlit regions of positive potential electrically connected to unlit negative potentials and forming adjacent natural electric dipoles. For objects near the surface, we find electrical dissipation times (through collection of local environmental solar wind currents) that vary over at least 5 orders of magnitude: from 39 Micro(s) inside the near-surface photoelectron cloud under direct sunlight to less than 1 s inside the particle-depleted night-side wake and shadowed pocket regions

Equity in health care financing: The case of Malaysia.

PubMed

Yu, Chai Ping; Whynes, David K; Sach, Tracey H

2008-06-09

Equitable financing is a key objective of health care systems. Its importance is evidenced in policy documents, policy statements, the work of health economists and policy analysts. The conventional categorisations of finance sources for health care are taxation, social health insurance, private health insurance and out-of-pocket payments. There are nonetheless increasing variations in the finance sources used to fund health care. An understanding of the equity implications would help policy makers in achieving equitable financing. The primary purpose of this paper was to comprehensively assess the equity of health care financing in Malaysia, which represents a new country context for the quantitative techniques used. The paper evaluated each of the five financing sources (direct taxes, indirect taxes, contributions to Employee Provident Fund and Social Security Organization, private insurance and out-of-pocket payments) independently, and subsequently by combined the financing sources to evaluate the whole financing system. Cross-sectional analyses were performed on the Household Expenditure Survey Malaysia 1998/99, using Stata statistical software package. In order to assess inequality, progressivity of each finance sources and the whole financing system was measured by Kakwani's progressivity index. Results showed that Malaysia's predominantly tax-financed system was slightly progressive with a Kakwani's progressivity index of 0.186. The net progressive effect was produced by four progressive finance sources (in the decreasing order of direct taxes, private insurance premiums, out-of-pocket payments, contributions to EPF and SOCSO) and a regressive finance source (indirect taxes). Malaysia's two tier health system, of a heavily subsidised public sector and a user charged private sector, has produced a progressive health financing system. The case of Malaysia exemplifies that policy makers can gain an in depth understanding of the equity impact, in order to help shape health financing strategies for the nation.

An Inserted α/β Subdomain Shapes the Catalytic Pocket of Lactobacillus johnsonii Cinnamoyl Esterase

PubMed Central

Vu, Clara; Xu, Xiaohui; Cui, Hong; Molloy, Sara; Savchenko, Alexei; Yakunin, Alexander; Gonzalez, Claudio F.

2011-01-01

Background Microbial enzymes produced in the gastrointestinal tract are primarily responsible for the release and biochemical transformation of absorbable bioactive monophenols. In the present work we described the crystal structure of LJ0536, a serine cinnamoyl esterase produced by the probiotic bacterium Lactobacillus johnsonii N6.2. Methodology/Principal Findings We crystallized LJ0536 in the apo form and in three substrate-bound complexes. The structure showed a canonical α/β fold characteristic of esterases, and the enzyme is dimeric. Two classical serine esterase motifs (GlyXSerXGly) can be recognized from the amino acid sequence, and the structure revealed that the catalytic triad of the enzyme is formed by Ser106, His225, and Asp197, while the other motif is non-functional. In all substrate-bound complexes, the aromatic acyl group of the ester compound was bound in the deepest part of the catalytic pocket. The binding pocket also contained an unoccupied area that could accommodate larger ligands. The structure revealed a prominent inserted α/β subdomain of 54 amino acids, from which multiple contacts to the aromatic acyl groups of the substrates are made. Inserts of this size are seen in other esterases, but the secondary structure topology of this subdomain of LJ0536 is unique to this enzyme and its closest homolog (Est1E) in the Protein Databank. Conclusions The binding mechanism characterized (involving the inserted α/β subdomain) clearly differentiates LJ0536 from enzymes with similar activity of a fungal origin. The structural features herein described together with the activity profile of LJ0536 suggest that this enzyme should be clustered in a new group of bacterial cinnamoyl esterases. PMID:21876742

An inserted α/β subdomain shapes the catalytic pocket of Lactobacillus johnsonii cinnamoyl esterase.

PubMed

Lai, Kin-Kwan; Stogios, Peter J; Vu, Clara; Xu, Xiaohui; Cui, Hong; Molloy, Sara; Savchenko, Alexei; Yakunin, Alexander; Gonzalez, Claudio F

2011-01-01

Microbial enzymes produced in the gastrointestinal tract are primarily responsible for the release and biochemical transformation of absorbable bioactive monophenols. In the present work we described the crystal structure of LJ0536, a serine cinnamoyl esterase produced by the probiotic bacterium Lactobacillus johnsonii N6.2. We crystallized LJ0536 in the apo form and in three substrate-bound complexes. The structure showed a canonical α/β fold characteristic of esterases, and the enzyme is dimeric. Two classical serine esterase motifs (GlyXSerXGly) can be recognized from the amino acid sequence, and the structure revealed that the catalytic triad of the enzyme is formed by Ser(106), His(225), and Asp(197), while the other motif is non-functional. In all substrate-bound complexes, the aromatic acyl group of the ester compound was bound in the deepest part of the catalytic pocket. The binding pocket also contained an unoccupied area that could accommodate larger ligands. The structure revealed a prominent inserted α/β subdomain of 54 amino acids, from which multiple contacts to the aromatic acyl groups of the substrates are made. Inserts of this size are seen in other esterases, but the secondary structure topology of this subdomain of LJ0536 is unique to this enzyme and its closest homolog (Est1E) in the Protein Databank. The binding mechanism characterized (involving the inserted α/β subdomain) clearly differentiates LJ0536 from enzymes with similar activity of a fungal origin. The structural features herein described together with the activity profile of LJ0536 suggest that this enzyme should be clustered in a new group of bacterial cinnamoyl esterases.

ARPES study of the evolution of band structure and charge density wave properties in RTe3 ( R=Y , La, Ce, Sm, Gd, Tb, and Dy)

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

Hussain, Zahid; Brouet, Veronique; Yang, Wanli

2008-01-16

We present a detailed angle-resolved photoemission spectroscopy (ARPES) investigation of the RTe3 family, which sets this system as an ideal"textbook" example for the formation of a nesting driven charge density wave (CDW). This family indeed exhibits the full range of phenomena that can be associated to CDWinstabilities, from the opening of large gaps on the best nested parts of Fermi surface (up to 0.4 eV), to the existence of residual metallic pockets. ARPES is the best suited technique to characterize these features, thanks to its unique ability to resolve the electronic structure in k space. An additional advantage of RTe3more » is that theband structure can be very accurately described by a simple two dimensional tight-binding (TB) model, which allows one to understand and easily reproduce many characteristics of the CDW. In this paper, we first establish the main features of the electronic structure by comparing our ARPES measurements with the linear muffin-tinorbital band calculations. We use this to define the validity and limits of the TB model. We then present a complete description of the CDW properties and of their strong evolution as a function of R. Using simple models, we are able to reproduce perfectly the evolution of gaps in k space, the evolution of the CDW wave vector with R, and the shape of the residual metallic pockets. Finally, we give an estimation of the CDWinteraction parameters and find that the change in the electronic density of states n (EF), due to lattice expansion when different R ions are inserted, has the correct order of magnitude to explain the evolution of the CDW properties.« less

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2.

PubMed

Mpakali, Anastasia; Giastas, Petros; Mathioudakis, Nikolas; Mavridis, Irene M; Saridakis, Emmanuel; Stratikos, Efstratios

2015-10-23

Endoplasmic reticulum (ER) aminopeptidases process antigenic peptide precursors to generate epitopes for presentation by MHC class I molecules and help shape the antigenic peptide repertoire and cytotoxic T-cell responses. To perform this function, ER aminopeptidases have to recognize and process a vast variety of peptide sequences. To understand how these enzymes recognize substrates, we determined crystal structures of ER aminopeptidase 2 (ERAP2) in complex with a substrate analogue and a peptidic product to 2.5 and 2.7 Å, respectively, and compared them to the apo-form structure determined to 3.0 Å. The peptides were found within the internal cavity of the enzyme with no direct access to the outside solvent. The substrate analogue extends away from the catalytic center toward the distal end of the internal cavity, making interactions with several shallow pockets along the path. A similar configuration was evident for the peptidic product, although decreasing electron density toward its C terminus indicated progressive disorder. Enzymatic analysis confirmed that visualized interactions can either positively or negatively impact in vitro trimming rates. Opportunistic side-chain interactions and lack of deep specificity pockets support a limited-selectivity model for antigenic peptide processing by ERAP2. In contrast to proposed models for the homologous ERAP1, no specific recognition of the peptide C terminus by ERAP2 was evident, consistent with functional differences in length selection and self-activation between these two enzymes. Our results suggest that ERAP2 selects substrates by sequestering them in its internal cavity and allowing opportunistic interactions to determine trimming rates, thus combining substrate permissiveness with sequence bias. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Current switching ratio optimization using dual pocket doping engineering

NASA Astrophysics Data System (ADS)

Dash, Sidhartha; Sahoo, Girija Shankar; Mishra, Guru Prasad

2018-01-01

This paper presents a smart idea to maximize current switching ratio of cylindrical gate tunnel FET (CGT) by growing pocket layers in both source and channel region. The pocket layers positioned in the source and channel of the device provides significant improvement in ON-state and OFF-state current respectively. The dual pocket doped cylindrical gate TFET (DP-CGT) exhibits much superior performance in term of drain current, transconductance and current ratio as compared to conventional CGT, channel pocket doped CGT (CP-CGT) and source pocket doped CGT (SP-CGT). Further, the current ratio has been optimized w.r.t. width and instantaneous position both the pocket layers. The much improved current ratio and low power consumption makes the proposed device suitable for low-power and high speed application. The simulation work of DP-CGT is done using 3D Sentaurus TCAD device simulator from Synopsys.

CALUTRON STRUCTURE

DOEpatents

Price, D.

1958-09-01

An improved means is described for removably installing and supporting a collector pocket in a calutron. The salient feature of the invention is the support of the collector pocket by means of suspension bolts engaging the pocket at a point intermediate the top and bottom of the pocket, and having nuts so arranged that by turing the desired predetermined position.

Choosing the 'best' plan in a health insurance exchange: actuarial value tells only part of the story.

PubMed

Lore, Ryan; Gabel, Jon R; McDevitt, Roland; Slover, Michael

2012-08-01

In the health insurance exchanges that will come online in 2014, consumers will be able to compare health plans with respect to actuarial value, or the percentage of health care costs that a plan would pay for a standard population. This analysis illustrates the out-of-pocket costs that might result from plans with various plan designs and actuarial values. We find that average out-of-pocket expense declines as actuarial values rise, but two plans with similar actuarial values can produce very different outcomes for a given person. The overall affordability of a plan also will be influenced by age rating, income-related premium subsidies, and out-of-pocket subsidies. Actuarial value is a useful starting point for selecting a plan, but it does not pinpoint which plan will produce the best overall value for a particular person.

Development of purely structure-based pharmacophores for the topoisomerase I-DNA-ligand binding pocket

NASA Astrophysics Data System (ADS)

Drwal, Malgorzata N.; Agama, Keli; Pommier, Yves; Griffith, Renate

2013-12-01

Purely structure-based pharmacophores (SBPs) are an alternative method to ligand-based approaches and have the advantage of describing the entire interaction capability of a binding pocket. Here, we present the development of SBPs for topoisomerase I, an anticancer target with an unusual ligand binding pocket consisting of protein and DNA atoms. Different approaches to cluster and select pharmacophore features are investigated, including hierarchical clustering and energy calculations. In addition, the performance of SBPs is evaluated retrospectively and compared to the performance of ligand- and complex-based pharmacophores. SBPs emerge as a valid method in virtual screening and a complementary approach to ligand-focussed methods. The study further reveals that the choice of pharmacophore feature clustering and selection methods has a large impact on the virtual screening hit lists. A prospective application of the SBPs in virtual screening reveals that they can be used successfully to identify novel topoisomerase inhibitors.

Exploitation of pocket gophers and their food caches by grizzly bears

USGS Publications Warehouse

Mattson, D.J.

2004-01-01

I investigated the exploitation of pocket gophers (Thomomys talpoides) by grizzly bears (Ursus arctos horribilis) in the Yellowstone region of the United States with the use of data collected during a study of radiomarked bears in 1977-1992. My analysis focused on the importance of pocket gophers as a source of energy and nutrients, effects of weather and site features, and importance of pocket gophers to grizzly bears in the western contiguous United States prior to historical extirpations. Pocket gophers and their food caches were infrequent in grizzly bear feces, although foraging for pocket gophers accounted for about 20-25% of all grizzly bear feeding activity during April and May. Compared with roots individually excavated by bears, pocket gopher food caches were less digestible but more easily dug out. Exploitation of gopher food caches by grizzly bears was highly sensitive to site and weather conditions and peaked during and shortly after snowmelt. This peak coincided with maximum success by bears in finding pocket gopher food caches. Exploitation was most frequent and extensive on gently sloping nonforested sites with abundant spring beauty (Claytonia lanceolata) and yampah (Perdieridia gairdneri). Pocket gophers are rare in forests, and spring beauty and yampah roots are known to be important foods of both grizzly bears and burrowing rodents. Although grizzly bears commonly exploit pocket gophers only in the Yellowstone region, this behavior was probably widespread in mountainous areas of the western contiguous United States prior to extirpations of grizzly bears within the last 150 years.

Proton pump inhibitors reduce the size and acidity of the acid pocket in the stomach.

PubMed

Rohof, Wout O; Bennink, Roelof J; Boeckxstaens, Guy E

2014-07-01

The gastric acid pocket is believed to be the reservoir from which acid reflux events originate. Little is known about how changes in position, size, and acidity of the acid pocket contribute to the therapeutic effect of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD). Thirty-six patients with GERD (18 not taking PPIs, 18 taking PPIs; 19 men; age, 55 ± 2.1 y) were analyzed by concurrent high-resolution manometry and pH-impedance monitoring after a standardized meal. The acid pocket was visualized using scintigraphy after intravenous administration of (99m)technetium-pertechnetate. The size of the acid pocket was measured and its position was determined, relative to the diaphragm, using radionuclide markers on a high-resolution manometry catheter. At the end of the study, the acid pocket was aspirated, and its pH level was measured. The number of reflux episodes was comparable between patients on and off PPIs, but the number of acid reflux episodes was reduced significantly in patients on PPIs. In patients on PPIs, the acid pocket was smaller and more frequently located below the diaphragm. The mean pH of the acid pocket was significantly lower in patients not taking PPIs (n = 6) than in those who were (n = 16) (0.9; range, 0.7-1.2 vs 4.0; range, 1.6-5.9; P < .001). The pH of acid pockets correlated significantly with the lowest pH values measured for refluxate (r = 0.72; P < .01). Based on analyses of acid pockets in patients with GERD, the acid pocket appears to be a reservoir from which reflux occurs when patients are receiving PPIs. PPIs might affect the size, acidity, or position of the acid pocket, which contributes to the efficacy in patients with GERD. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Should new health technology be available only for patients able and willing to pay?

PubMed Central

Calcoen, Piet; Boer, Albert; van de Ven, Wynand P.M.M.

2017-01-01

ABSTRACT New health technology comes on the market at a rapid pace and – sometimes – at a huge cost. Providing access to new health technology is a serious challenge for many countries with mandatory health insurance. This article analyses access to new health technology in Belgium and the Netherlands, using eight concrete examples as a starting point for comparing the two – neighbouring – countries. Contrary to the Netherlands, out-of-pocket payments for new health technology are widely accepted and practiced in Belgium. This difference is largely the result of different regulatory environments. A major difference is the way that entitlements to care are described: closed and explicit in Belgium versus open and non-explicit in the Netherlands. The characteristics of in-kind policies versus reimbursement policies also play a role. Allowing out-of-pocket payments for new health technology has consequences for the patients. It leads to greater access to new health technology (for those who are able and willing to pay), but has a negative effect on equal access to care. Choice and transparency are enhanced by allowing out-of-pocket payments for new health technology. It could be argued that lack of coverage by mandatory health insurance should not render private access to new health technology impossible. PMID:28740619

Fiber-type dosimeter with improved illuminator

DOEpatents

Fox, Richard J.

1987-01-01

A single-piece, molded plastic, Cassigrainian-type condenser arrangement is incorporated in a tubular-shaped personal pocket dosimeter of the type which combines an ionization chamber with an optically-read fiber electrometer to provide improved illumination of the electrometer fiber. The condenser routes incoming light from one end of the dosimeter tubular housing around a central axis charging pin assembly and focuses the light at low angles to the axis so that it falls within the acceptance angle of the electrometer fiber objective lens viewed through an eyepiece lens disposed in the opposite end of the dosimeter. This results in improved fiber illumination and fiber image contrast.

A pocket of variability in Pinus rigida

Treesearch

F. Thomas Ledig; John H. Fryer

1971-01-01

Steady state gene frequencies around a pocket of differential fitness have been formulated by Hanson (1966) in a generalization of the work of Haldane (1948). A pocket of differential fitness would result in a pocket-of-variability, assuming that the radius of the area of contrasting fitness was large in relation to the vagility of the organism. Conversely, the absence...

The 2.1Å Crystal Structure of an Acyl-CoA Synthetase from Methanosarcina acetivorans reveals an alternate acyl binding pocket for small branched acyl substrates†,‡

PubMed Central

Shah, Manish B.; Ingram-Smith, Cheryl; Cooper, Leroy L.; Qu, Jun; Meng, Yu; Smith, Kerry S.; Gulick, Andrew M.

2009-01-01

The acyl-AMP forming family of adenylating enzymes catalyze two-step reactions to activate a carboxylate with the chemical energy derived from ATP hydrolysis. X-ray crystal structures have been determined for multiple members of this family and, together with biochemical studies, provide insights into the active site and catalytic mechanisms used by these enzymes. These studies have shown that the enzymes use a domain rotation of 140° to reconfigure a single active site to catalyze the two partial reactions. We present here the crystal structure of a new medium chain acyl-CoA synthetase from Methanosarcina acetivorans. The binding pocket for the three substrates is analyzed, with many conserved residues present in the AMP binding pocket. The CoA binding pocket is compared to the pockets of both acetyl-CoA synthetase and 4-chlorobenzoate:CoA ligase. Most interestingly, the acyl binding pocket of the new structure is compared with other acyl- and aryl-CoA synthetases. A comparison of the acyl-binding pocket of the acyl-CoA synthetase from M. acetivorans with other structures identifies a shallow pocket that is used to bind the medium chain carboxylates. These insights emphasize the high sequence and structural diversity among this family in the area of the acyl binding pocket. PMID:19544569

The impact of health insurance programs on out-of-pocket expenditures in Indonesia: an increase or a decrease?

PubMed

Aji, Budi; De Allegri, Manuela; Souares, Aurelia; Sauerborn, Rainer

2013-07-18

We used panel data from the Indonesian Family Life Survey to investigate the impact of health insurance programs on reducing out-of-pocket expenditures. We employed three linear panel data models, two of which accounted for endogeneity: pooled ordinary least squares (OLS), pooled two-stage least squares (2SLS) for instrumental variable (IV), and fixed effects (FE). The study revealed that two health insurance programs had a significantly negative impact on out-of-pocket expenditures by using IV estimates. In the IV model, Askeskin decreased out-of-pocket expenditures by 34% and Askes by 55% compared with non-Askeskin and non-Askes, respectively, while Jamsostek was found to bear a nonsignificant effect on out-of-pocket expenditures. In the FE model, only Askeskin had a significant negative effect with an 11% reduction on out-of-pocket expenditures. This study showed that two large existing health insurance programs in Indonesia, Askeskin and Askes, effectively reduced household out-of-pocket expenditures. The ability of programs to offer financial protection by reducing out-of-pocket expenditures is likely to be a direct function of their benefits package and co-payment policies.

The acid pocket: a target for treatment in reflux disease?

PubMed

Kahrilas, Peter J; McColl, Kenneth; Fox, Mark; O'Rourke, Lisa; Sifrim, Daniel; Smout, Andre J P M; Boeckxstaens, Guy

2013-07-01

The nadir esophageal pH of reflux observed during pH monitoring in the postprandial period is often more acidic than the concomitant intragastric pH. This paradox prompted the discovery of the "acid pocket", an area of unbuffered gastric acid that accumulates in the proximal stomach after meals and serves as the reservoir for acid reflux in healthy individuals and gastroesophageal reflux disease (GERD) patients. However, there are differentiating features between these populations in the size and position of the acid pocket, with GERD patients predisposed to upward migration of the proximal margin onto the esophageal mucosa, particularly when supine. This upward migration of acid, sometimes referred to as an "acid film", likely contributes to mucosal pathology in the region of the squamocolumnar junction. Furthermore, movement of the acid pocket itself to a supradiaphragmatic location with hiatus hernia increases the propensity for acid reflux by all conventional mechanisms. Consequently, the acid pocket is an attractive target for GERD therapy. It may be targeted in a global way with proton pump inhibitors that attenuate acid pocket development, or with alginate/antacid combinations that colocalize with the acid pocket and displace it distally, thereby demonstrating the potential for selective targeting of the acid pocket in GERD.

The Impact of Health Insurance Programs on Out-of-Pocket Expenditures in Indonesia: An Increase or a Decrease?

PubMed Central

Aji, Budi; De Allegri, Manuela; Souares, Aurelia; Sauerborn, Rainer

2013-01-01

We used panel data from the Indonesian Family Life Survey to investigate the impact of health insurance programs on reducing out-of-pocket expenditures. We employed three linear panel data models, two of which accounted for endogeneity: pooled ordinary least squares (OLS), pooled two-stage least squares (2SLS) for instrumental variable (IV), and fixed effects (FE). The study revealed that two health insurance programs had a significantly negative impact on out-of-pocket expenditures by using IV estimates. In the IV model, Askeskin decreased out-of-pocket expenditures by 34% and Askes by 55% compared with non-Askeskin and non-Askes, respectively, while Jamsostek was found to bear a nonsignificant effect on out-of-pocket expenditures. In the FE model, only Askeskin had a significant negative effect with an 11% reduction on out-of-pocket expenditures. This study showed that two large existing health insurance programs in Indonesia, Askeskin and Askes, effectively reduced household out-of-pocket expenditures. The ability of programs to offer financial protection by reducing out-of-pocket expenditures is likely to be a direct function of their benefits package and co-payment policies. PMID:23873263

Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania

NASA Astrophysics Data System (ADS)

Zuccotto, Fabio; Martin, Andrew C. R.; Laskowski, Roman A.; Thornton, Janet M.; Gilbert, Ian H.

1998-05-01

Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

Health benefits of reduced patient cost sharing in Japan.

PubMed

Nishi, Akihiro; McWilliams, J Michael; Noguchi, Haruko; Hashimoto, Hideki; Tamiya, Nanako; Kawachi, Ichiro

2012-06-01

To assess the effect on out-of-pocket medical spending and physical and mental health of Japan's reduction in health-care cost sharing from 30% to 10% when people turn 70 years of age. Study data came from a 2007 nationally-representative cross-sectional survey of 10 293 adults aged 64 to 75 years. Physical health was assessed using a 16-point scale based on self-reported data on general health, mobility, self-care, activities of daily living and pain. Mental health was assessed using a 24-point scale based on the Kessler-6 instrument for nonspecific psychological distress. The effect of reduced cost sharing was estimated using a regression discontinuity design. For adults aged 70 to 75 years whose income made them ineligible for reduced cost sharing, neither out-of-pocket spending nor health outcomes differed from the values expected on the basis of the trend observed in 64- to 69-year-olds. However, for eligible adults aged 70 to 75 years, out-of-pocket spending was significantly lower (P < 0.001) and mental health was significantly better (P < 0.001) than expected. These differences emerged abruptly at the age of 70 years. Moreover, the mental health benefits were similar in individuals who were and were not using health-care services (P = 0.502 for interaction). The improvement in physical health after the age of 70 years in adults eligible for reduced cost-sharing tended to be greater than in non-eligible adults (P = 0.084). Reduced cost sharing was associated with lower out-of-pocket medical spending and improved mental health in older Japanese adults.

Out-of-Pocket Expenses and Treatment Choice for Men with Prostate Cancer

PubMed Central

Jung, Olivia S.; Guzzo, Thomas; Lee, David; Mehler, Michael; Christodouleas, John; Deville, Curtiland; Hollis, Genny; Shah, Anand; Vapiwala, Neha; Wein, Alan; Pauly, Mark; Bekelman, Justin E.

2012-01-01

Objective To describe prostate cancer patients’ knowledge of and attitudes toward out-of-pocket expenses (OOPE) associated with prostate cancer treatment or the influence of OOPE on treatment choices. Material and Methods We undertook a qualitative research study in which we recruited patients with clinically localized prostate cancer. Patients answered a series of open-ended questions during a semi-structured interview and completed a questionnaire about the physician’s role in discussing OOPE, the burden of OOPE, the effect of OOPE on treatment decisions, and prior knowledge of OOPE. Results Forty-one (26 white, 15 black) eligible patients were enrolled from the urology and radiation oncology practices of the University of Pennsylvania. Qualitative assessment revealed five major themes: (1) “My insurance takes care of it” (2) “Health is more important than cost” (3) “I didn’t look into it” (4) “I can’t afford it but would have chosen the same treatment” (5) “It’s not my doctor’s business.” Most patients (38/41, 93%) reported that they would not have chosen a different treatment even if they had known the actual OOPE of their treatment. Patients who reported feeling burdened by out-of-pocket costs were socioeconomically heterogeneous and their treatment choices remained unaffected. Only two patients said they knew “a lot” about the likely out-of-pocket costs for different prostate cancer treatments before choosing treatment. Conclusions Among insured prostate cancer patients treated at a large academic medical center, few had knowledge of OOPE prior to making treatment choices. PMID:23102446

Identification of Small Molecules against Botulinum Neurotoxin B Binding to Neuronal Cells at Ganglioside GT1b Binding Site with Low to Moderate Affinity

DTIC Science & Technology

2014-10-01

BoNT serotype B (BoNT/B) for the trisaccharide GT1b were identified from the x-ray crystal structure of the BoNT/B/trisaccharide (GT1b) complex ( PDB ...trisaccharide and all the water from the structure and identified four potential binding pockets (Pocket-1, Pocket-2, and Pocket-4) as shown in...four potential binding sites or pockets on BoNT serotype B (BoNT/B) for the trisaccharide GT1b were identified from the x-ray crystal structure of the

BOLA-DRB3 gene polymorphisms influence bovine leukaemia virus infection levels in Holstein and Holstein × Jersey crossbreed dairy cattle.

PubMed

Carignano, H A; Beribe, M J; Caffaro, M E; Amadio, A; Nani, J P; Gutierrez, G; Alvarez, I; Trono, K; Miretti, M M; Poli, M A

2017-08-01

Bovine leukemia virus (BLV) infections, causing persistent lymphocytosis and lethal lymphosarcoma in cattle, have reached high endemicity on dairy farms. We observed extensive inter-individual variation in the level of infection (LI) by assessing differences in proviral load in peripheral blood. This phenotypic variation appears to be determined by host genetics variants, especially those located in the BoLA-DRB3 MHCII molecule. We performed an association study using sequencing-based typed BOLA-DRB3 alleles from over 800 Holstein and Holstein × Jersey cows considering LI in vivo and accounting for filial relationships. The DBR3*0902 allele was associated with a low level of infection (LLI) (<1% of circulating infected B-cells), whereas the DRB3*1001 and DRB3*1201 alleles were related to a high level of infection (HLI). We found evidence that 13 polymorphic positions located in the pockets of the peptide-binding cleft of the BOLA-DRB3 alleles were associated with LI. DRB3*0902 had unique haplotypes for each of the pockets: Ser 13 -Glu 70 -Arg 71 -Glu 74 (pocket 4), Ser 11 -Ser 30 (pocket 6), Glu 28 -Trp 61 -Arg 71 (pocket 7) and Asn 37 -Asp 57 (pocket 9), and all of them were significantly associated with LLI. Conversely, Lys 13 -Arg 70 -Ala 71 -Ala 74 and Ser 13 -Arg 70 -Ala 71 -Ala 74 , corresponding to the DRB3*1001 and *1201 alleles respectively, were associated with HLI. We showed that the specific amino acid pattern in the DRB3*0902 peptide-binding cleft may be related to the set point of a very low proviral load level in adult cows. Moreover, we identified two BOLA-DRB3 alleles associated with a HLI, which is compatible with a highly contagious profile. © 2017 Stichting International Foundation for Animal Genetics.

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

Schooneveldt, G.; Kok, H.P.; Bakker, A.

Purpose: Hyperthermia combined with Mitomycin C is used for the treatment of non-muscle invasive bladder cancer (NMIBC), using a phased array system of microwave antennas for bladder heating. Often some air is present in the bladder, which effectively blocks the microwave radiation, potentially preventing proper treatment of that part of the bladder. Air can be a relevant fraction of the bladder content and large air pockets are expected to have a noticeable influence on achieved temperatures. Methods: We analysed 14 NMIBC patients treated at our institute with our AMC-4 hyperthermia device with four 70MHz antennas around the pelvis. A CTmore » scan was made after treatment and a physician delineated the bladder on the CT scan. On the same scan, the amount of air present in the bladder was delineated. Using our in-house developed hyperthermia treatment planning system, we simulated the treatment using the clinically applied device settings. We did this once with the air pocket delineated on the CT scan, and once with the same volume filled with bladder tissue. Results: The patients had on average 4.2ml (range 0.8–10.1ml) air in the bladder. The bladder volume was delineated by the physician, that is including air pocket and bladder wall, was on average 253ml (range 93–452ml). The average volume in which changes exceeded 0.25°C was 22ml (range 0–108 ml), with the bladder being up to 2°C cooler when an air pocket was present. Except for extreme cases, there was no evident relation between the quantity of air and the difference in temperature. Conclusion: The effect of an air pocket in the bladder during bladder hyperthermia treatment varies strongly between patients. Generally, this leads to lower temperatures in the bladder, potentially affecting treatment quality, and suggesting that care need be taken to minimise the size of air pockets during hyperthermia treatments. The KWF Dutch Cancer Society financially supported this work, grant UVA 2012-5539.« less

Estimating Premium and Out-of-Pocket Outlays Under All Child Dental Coverage Options in the Federally Facilitated Marketplace.

PubMed

Vujicic, Marko; Yarbrough, Cassandra

2017-03-01

To estimate premium and out-of-pocket costs for child dental care services under various dental coverage options offered within the federally facilitated marketplace. We estimated premium and out-of-pocket costs for child dental care services for 12 patient profiles, which vary by dental care use and spending. We did this for 1039 medical plans that include child dental coverage, 2703 medical plans that do not include child dental coverage, and 583 stand-alone dental plans for the 2015 plan year. Our analysis is based on plan data from the Center for Consumer Information and Insurance Oversight and Data.HealthCare.Gov. On average, expected total financial outlays for child dental care services were lower when dental coverage was embedded within a medical plan compared with the alternative of a stand-alone dental plan. The difference, however, in average expected out-of-pocket spending varied significantly for our 12 patient profiles. Older children who are very high users of dental care, for example, have lower expected out-of-pocket costs under a stand-alone dental plan. For the vast majority of other age groups and dental care use profiles, the reverse holds. Our results show that embedding dental coverage within medical plans, on average, results in lower total financial outlays for child beneficiaries. Although our results are specific to the federally facilitated marketplace, they hold lessons for both state-based marketplaces and the general private health insurance and dental benefits market, as well. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Pulp temperature increase during photo-activated disinfection (PAD) of periodontal pockets: an in vitro study.

PubMed

El Yazami, H; Zeinoun, Toni; Bou Saba, S; Lamard, L; Peremans, A; Limme, M; Geerts, S; Lamy, M; Nammour, S

2010-09-01

The capacity of photo-sensitizers, used in combination with laser light to kill micro-organisms has been demonstrated in different studies. Photo-activated disinfection (PAD) has been introduced in periodontology as an aid for disinfection of periodontal pockets. The aim of this study is to verify the harm for dental vitality of the use of PAD in periodontal pockets. Root canals of 24 freshly extracted human teeth where prepared using profiles up to a size of ISO #50 and filled with thermo-conductor paste. A silicon-based false gum was made in which a periodontal pocket was created and filled with photo-sensitizer phenothiazine chloride (phenothiazine-5-ium, 3.7-bis (dimethylamino)-, chloride). The external root surface was irradiated during 60 s with a 660-nm diode laser (output power: 20 mW; power density: 0.090 W/cm(2); Energy density: 5.46 J/cm(2)) using a periodontal tip with a diameter of 1 mm and a length of 7 mm. Temperatures were recorded inside the root canal using a thermocouple. Measurements were recorded every second, starting at 10 s before lasering, during the irradiation and were continued for 150 s after the end of irradiation, and six measurements were done per tooth. An average temperature increase of 0.48 +/- 0.11 degrees C was recorded. Our results demonstrated that pulp temperature increase was lower than 3 degrees C, which is considered to be harmless for pulp injury. Regarding pulp temperature increase, the use of PAD for disinfection of periodontal pockets can be considered as a safe procedure for dental vitality.

Disparity in Dental Out-of-Pocket Payments Among Older Adult Populations: A Comparative Analysis Across Selected European Countries and the United States

PubMed Central

Manski, Richard; Moeller, John; Chen, Haiyan; Widström, Eeva; Listl, Stefan

2017-01-01

Background The current study addresses the extent to which diversity exists in dental out-of-pocket payments across population subgroups within and between the United States and selected European countries. This represents the final paper in a series in which the previous 2 papers addressed diversity in dental coverage and dental utilization, respectively, using similar data and methods. Method We use 2006/2007 HRS and 2004-2006 SHARE data for respondents aged 51 years and older. We estimated the impacts of dental care coverage and demographic, socioeconomic, and health status on the likelihood and amount of dental out of pocket payments. Results Our findings show that older persons with the least education, lowest income, and worst health are most likely to pay nothing out of pocket (OOP) for their dental care and for persons with a payment OOP increase with income and education and are greater for persons who are uninsured, and in fair or poor health. These results were found in the USA but were not consistently found in the 10 European countries we studied. Conclusions European countries classified by social welfare state or presence of social health insurance (SHI) had no effect on the likelihood of making payments out of pocket for dental care nor, when OOP payments were made, on the amounts paid. Variation in generosity of coverage and procedures reimbursed by insurance, even within SHI countries, as well as differing needs, tastes and access to care across countries, contribute to this finding. PMID:28213893

Clinical effectiveness of diode laser therapy as an adjunct to non-surgical periodontal treatment: a randomized clinical study.

PubMed

Dukić, Walter; Bago, Ivona; Aurer, Andrej; Roguljić, Marija

2013-08-01

The aim of this randomized clinical study is to evaluate the effect of a 980-nm diode laser as an adjunct to scaling and root planing (SRP) treatment. Thirty-five patients with chronic periodontitis were selected for the split-mouth clinical study. SRP was performed using a sonic device and hand instruments. Quadrants were equally divided between the right and left sides. Teeth were treated with SRP in two control quadrants (control groups [CG]), and the diode laser was used adjunctively with SRP in contralateral quadrants (laser groups [LG]). Diode laser therapy was applied to periodontal pockets on days 1, 3, and 7 after SRP. Baseline data, including approximal plaque index (API), bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL), were recorded before the treatment and 6 and 18 weeks after treatment. Changes in PD and CAL were analyzed separately for initially moderate (4 to 6 mm) and deep (7 to 10 mm) pockets. The results were similar for both groups in terms of API, BOP, PD in deep pockets, and CAL. The laser group showed only significant PD gain in moderate pockets during the baseline to 18-week (P <0.05) and 6- to 18- week (P <0.05) periods, whereas no difference was found between LG and CG in the remaining clinical parameters (P >0.05). The present study indicates that, compared to SRP alone, multiple adjunctive applications of a 980-nm diode laser with SRP showed PD improvements only in moderate periodontal pockets (4 to 6 mm).

Molecular and thermodynamic mechanisms of the chloride-dependent human angiotensin-I-converting enzyme (ACE).

PubMed

Yates, Christopher J; Masuyer, Geoffrey; Schwager, Sylva L U; Akif, Mohd; Sturrock, Edward D; Acharya, K Ravi

2014-01-17

Somatic angiotensin-converting enzyme (sACE), a key regulator of blood pressure and electrolyte fluid homeostasis, cleaves the vasoactive angiotensin-I, bradykinin, and a number of other physiologically relevant peptides. sACE consists of two homologous and catalytically active N- and C-domains, which display marked differences in substrate specificities and chloride activation. A series of single substitution mutants were generated and evaluated under varying chloride concentrations using isothermal titration calorimetry. The x-ray crystal structures of the mutants provided details on the chloride-dependent interactions with ACE. Chloride binding in the chloride 1 pocket of C-domain ACE was found to affect positioning of residues from the active site. Analysis of the chloride 2 pocket R522Q and R522K mutations revealed the key interactions with the catalytic site that are stabilized via chloride coordination of Arg(522). Substrate interactions in the S2 subsite were shown to affect chloride affinity in the chloride 2 pocket. The Glu(403)-Lys(118) salt bridge in C-domain ACE was shown to stabilize the hinge-bending region and reduce chloride affinity by constraining the chloride 2 pocket. This work demonstrated that substrate composition to the C-terminal side of the scissile bond as well as interactions of larger substrates in the S2 subsite moderate chloride affinity in the chloride 2 pocket of the ACE C-domain, providing a rationale for the substrate-selective nature of chloride dependence in ACE and how this varies between the N- and C-domains.

Molecular and Thermodynamic Mechanisms of the Chloride-dependent Human Angiotensin-I-converting Enzyme (ACE)*

PubMed Central

Yates, Christopher J.; Masuyer, Geoffrey; Schwager, Sylva L. U.; Akif, Mohd; Sturrock, Edward D.; Acharya, K. Ravi

2014-01-01

Somatic angiotensin-converting enzyme (sACE), a key regulator of blood pressure and electrolyte fluid homeostasis, cleaves the vasoactive angiotensin-I, bradykinin, and a number of other physiologically relevant peptides. sACE consists of two homologous and catalytically active N- and C-domains, which display marked differences in substrate specificities and chloride activation. A series of single substitution mutants were generated and evaluated under varying chloride concentrations using isothermal titration calorimetry. The x-ray crystal structures of the mutants provided details on the chloride-dependent interactions with ACE. Chloride binding in the chloride 1 pocket of C-domain ACE was found to affect positioning of residues from the active site. Analysis of the chloride 2 pocket R522Q and R522K mutations revealed the key interactions with the catalytic site that are stabilized via chloride coordination of Arg522. Substrate interactions in the S2 subsite were shown to affect chloride affinity in the chloride 2 pocket. The Glu403-Lys118 salt bridge in C-domain ACE was shown to stabilize the hinge-bending region and reduce chloride affinity by constraining the chloride 2 pocket. This work demonstrated that substrate composition to the C-terminal side of the scissile bond as well as interactions of larger substrates in the S2 subsite moderate chloride affinity in the chloride 2 pocket of the ACE C-domain, providing a rationale for the substrate-selective nature of chloride dependence in ACE and how this varies between the N- and C-domains. PMID:24297181

Individual responsibility for healthcare financing: application of an analytical framework exploring the suitability of private financing of assistive devices.

PubMed

Tinghög, Gustav; Carlsson, Per

2012-12-01

To operationalise and apply a conceptual framework for exploring when health services contain characteristics that facilitate individuals' ability to take individual responsibility for health care through out-of-pocket payment. In addition, we investigate if the levels of out-of-pocket payment for assistive devices (ADs) in Sweden are in line with the proposed framework. Focus groups were used to operationalise the core concepts of sufficient knowledge, individual autonomy, positive externalities, sufficient demand, affordability, and lifestyle enhancement into a measurable and replicable rationing tool. A selection of 28 ADs were graded separately as having high, medium, or low suitability for private financing according to the measurement scale provided through the operationalised framework. To investigate the actual level of private financing, a questionnaire about the level of out-of-pocket payment for the specific ADs was administered to county councils in Sweden. Concepts were operationalised into three levels indicating possible suitability for private financing. Responses to the questionnaire indicate that financing of ADs in Sweden varies across county councils as regards co-payment, full payment, discretionary payment for certain healthcare consumer groups, and full reimbursement. According to the framework, ADs commonly funded privately were generally considered to be more suitable for private financing. Sufficient knowledge, individual autonomy, and sufficient demand did not appear to influence why certain ADs were financed out-of-pocket. The level of positive externalities, affordability, and lifestyle enhancement appeared to be somewhat higher for ADs that were financed out-of-pocket, but the differences were small. Affordability seemed to be the most influential concept.

Implementation in Indonesia of the WHO Pocket Book of Hospital Care for Children.

PubMed

Li, Michelle Y; Puspita, Ratih; Duke, Trevor; Agung, Fransisca H; Hegar, Badriul; Pritasari, Kirana; Weber, Martin W

2014-05-01

Effective implementation of evidence-based practice guidelines has the potential to improve quality of hospital care for children. To achieve this in Indonesia, a locally adapted version of the WHO Pocket Book of Hospital Care for Children was published in 2009. To document implementation of the Pocket Book in Indonesia and to compare uptake in health facilities in which there has been a quality-improvement approach involving audit and feedback with uptake in settings in which there has been only passive dissemination. Indonesian district health offices, district hospitals, health centres with beds, and medical schools were surveyed by telephone, and an online and telephone survey of paediatricians was conducted. Health facilities in four provinces were visited, and key stakeholders were interviewed. Health facilities were assessed on availability of the guidelines, use by staff, and their incorporation into hospital procedures and activities. There was evidence of use of the Pocket Book across Indonesia, despite limited funding for implementation. Its distribution had reached all provinces; 61% (33/54) of health facilities surveyed had a copy of the guidelines. Hospitals involved in a related quality audit were more likely to report use of the guidelines than hospitals exposed to passive dissemination, although this difference was not significant. Of 150 paediatricians sampled, 109 (73%) reported referring to the guidelines in their clinical practice. The guidelines have been incorporated into the postgraduate paediatric curriculum in four of 13 universities sampled. There was encouraging evidence of uptake of the Pocket Book in Indonesia following local adaptation, nationwide mailing distribution and small-scale local implementation activities.

Invariance of wearing location of Omron-BI pedometers: a validation study.

PubMed

Zhu, Weimo; Lee, Miyoung

2010-11-01

The purpose of this study was to investigate the validity and reliability evidences of the Omron BI pedometer, which could count steps taken even when worn at different locations on the body. Forty (20 males and 20 females) adults were recruited to walk wearing 5 sets, 1 set at a time, of 10 BI pedometers during testing, 1 each at 10 different locations. For comparison, they also wore 2 Yamax Digi-Walker SW-200 pedometers and a Dynastream AMP 331 activity monitor. The subjects walked in 3 free-living conditions: a flat sidewalk, stairs, and mixed conditions. Except for a slight decrease in accuracy in the pant pocket locations, Omron BI pedometers counted steps accurately across other locations when subjects walked on the flat sidewalk, and the performance was consistent across devices and trials. When the subjects climbed up stairs, however, the absolute error % of the pant pocket locations increased significantly (P < .05) and similar or higher error rates were found in the AMP 331 and SW-200s. The Omron BI pedometer can accurately count steps when worn at various locations on the body in free-living conditions except for front pant pocket locations, especially when climbing stairs.

The Effect of Medicaid Physician Fee Increases on Health Care Access, Utilization, and Expenditures.

PubMed

Callison, Kevin; Nguyen, Binh T

2018-04-01

To evaluate the effect of Medicaid fee changes on health care access, utilization, and spending for Medicaid beneficiaries. We use the 2008 and 2012 waves of the Medical Expenditure Panel Survey linked to state-level Medicaid-to-Medicare primary care reimbursement ratios obtained through surveys conducted by the Urban Institute. We also incorporate data from the Current Population Survey and the Area Resource Files. Using a control group made up of the low-income privately insured, we conduct a difference-in-differences analysis to assess the relationship between Medicaid fee changes and access to care, utilization of health care services, and out-of-pocket medical expenditures for Medicaid enrollees. We find that an increase in the Medicaid-to-Medicare payment ratio for primary care services results in an increase in outpatient physician visits, emergency department utilization, and prescription fills, but only minor improvements in access to care. In addition, we report an increase in total annual out-of-pocket expenditures and spending on prescription medications. Compared to the low-income privately insured, increased primary care reimbursement for Medicaid beneficiaries leads to higher utilization and out-of-pocket spending for Medicaid enrollees. © Health Research and Educational Trust.

Economic and social impact of out-of-pocket expenditure on households of patients attending public hospitals.

PubMed

Bajpai, Vikas; Singh, Namrata; Sardana, Hardik; Kumari, Sanjana; Vettiyil, Beth; Saraya, Anoop

2017-01-01

We aimed to generate evidence on the social and economic impact of out-of-pocket expenses incurred by households on illness. We did a hospital-based cross-sectional study including a convenience sample of 374 inpatients and outpatients. The median illness expenditure was the same (₹62 500) for inpatients and outpatients. Of all respondents, 51.3% among the rural and 65.5% among the urban patients were employed before illness, but after illness only 24.4% among the rural and 23.4% among the urban patients remained in employment. The proportion of rural households of different socioeconomic categories that experienced decrease in expenditure on food, education and health, and those who had to sell land or cattle, and the education of whose children suffered was statistically significant. The proportion of indebted families in different socioeconomic classes was also statistically significant among both rural and urban patients. The lowest socioeconomic strata depended mostly upon the financial support of their friends to tide over the financial crisis of an illness. Our study shows that out-of-pocket expenses on healthcare are a burden not only for the poor but also the middle classes.

The effects of rotation on the surface composition and yields of low mass AGB stars.

NASA Astrophysics Data System (ADS)

Cristallo, S.; Piersanti, L.; Straniero, O.

Over the past 20 years, stellar evolutionary models have been strongly improved in order to reproduce with reasonable accuracy both photometric and spectroscopic observations. Notwithstanding, the majority of these models do not take into account macroscopic phenomena, like rotation and/or magnetic fields. Their explicit treatment could modify stellar physical and chemical properties. One of the most interesting problems related to stellar nucleosynthesis is the behavior of the s-process spectroscopic indexes ([hs/ls] and [Pb/hs]) in Asymptotic Giant Branch (AGB) stars. In this contribution we show that, for a fixed metallicity, rotation can lead to a spread in the [hs/ls] and [Pb/hs] in low-mass AGB stars. In particular, we demonstrate that the Eddington-Sweet and the Goldreich-Schubert-Fricke instabilities may have enough time to smear the 13C-pocket (the major neutron source) and the 14N-pocket (the major neutron poison). In fact, a different overlap between these pockets leads to a different neutrons-to-seeds ratio, with important consequences on the corresponding s-process distributions. Possible consequences on the chemical evolution of Galactic globular clusters are discussed.

State health insurance and out-of-pocket health expenditures in Andhra Pradesh, India.

PubMed

Fan, Victoria Y; Karan, Anup; Mahal, Ajay

2012-09-01

In 2007 the state of Andhra Pradesh in southern India began rolling out Aarogyasri health insurance to reduce catastrophic health expenditures in households 'below the poverty line'. We exploit variation in program roll-out over time and districts to evaluate the impacts of the scheme using difference-in-differences. Our results suggest that within the first nine months of implementation Phase I of Aarogyasri significantly reduced out-of-pocket inpatient expenditures and, to a lesser extent, outpatient expenditures. These results are robust to checks using quantile regression and matching methods. No clear effects on catastrophic health expenditures or medical impoverishment are seen. Aarogyasri is not benefiting scheduled caste and scheduled tribe households as much as the rest of the population.

E-mail on the Move

NASA Technical Reports Server (NTRS)

1999-01-01

PocketScience, Inc. was a member of the NASA Ames Technology Commercialization Center. Their PocketMail product is an email service that brings email capabilities to new hand-held devices. The PocketMail service uses technology originally developed at JPL. Through its involvement with the ATCC, PocketScience, Inc. was able to use this space probe communications technology and adapt it for advanced signal processing on Earth.

Improved cardiovascular diagnostic accuracy by pocket size imaging device in non-cardiologic outpatients: the NaUSiCa (Naples Ultrasound Stethoscope in Cardiology) study

PubMed Central

2010-01-01

Miniaturization has evolved in the creation of a pocket-size imaging device which can be utilized as an ultrasound stethoscope. This study assessed the additional diagnostic power of pocket size device by both experts operators and trainees in comparison with physical examination and its appropriateness of use in comparison with standard echo machine in a non-cardiologic population. Three hundred four consecutive non cardiologic outpatients underwent a sequential assessment including physical examination, pocket size imaging device and standard Doppler-echo exam. Pocket size device was used by both expert operators and trainees (who received specific training before the beginning of the study). All the operators were requested to give only visual, qualitative insights on specific issues. All standard Doppler-echo exams were performed by expert operators. One hundred two pocket size device exams were performed by experts and two hundred two by trainees. The time duration of the pocket size device exam was 304 ± 117 sec. Diagnosis of cardiac abnormalities was made in 38.2% of cases by physical examination and in 69.7% of cases by physical examination + pocket size device (additional diagnostic power = 31.5%, p < 0.0001). The overall K between pocket size device and standard Doppler-echo was 0.67 in the pooled population (0.84 by experts and 0.58 by trainees). K was suboptimal for trainees in the eyeball evaluation of ejection fraction, left atrial dilation and right ventricular dilation. Overall sensitivity was 91% and specificity 76%. Sensitivity and specificity were lower in trainees than in experts. In conclusion, pocket size device showed a relevant additional diagnostic value in comparison with physical examination. Sensitivity and specificity were good in experts and suboptimal in trainees. Specificity was particularly influenced by the level of experience. Training programs are needed for pocket size device users. PMID:21110840

Plasticity of the Binding Site of Renin: Optimized Selection of Protein Structures for Ensemble Docking.

PubMed

Strecker, Claas; Meyer, Bernd

2018-05-29

Protein flexibility poses a major challenge to docking of potential ligands in that the binding site can adopt different shapes. Docking algorithms usually keep the protein rigid and only allow the ligand to be treated as flexible. However, a wrong assessment of the shape of the binding pocket can prevent a ligand from adapting a correct pose. Ensemble docking is a simple yet promising method to solve this problem: Ligands are docked into multiple structures, and the results are subsequently merged. Selection of protein structures is a significant factor for this approach. In this work we perform a comprehensive and comparative study evaluating the impact of structure selection on ensemble docking. We perform ensemble docking with several crystal structures and with structures derived from molecular dynamics simulations of renin, an attractive target for antihypertensive drugs. Here, 500 ns of MD simulations revealed binding site shapes not found in any available crystal structure. We evaluate the importance of structure selection for ensemble docking by comparing binding pose prediction, ability to rank actives above nonactives (screening utility), and scoring accuracy. As a result, for ensemble definition k-means clustering appears to be better suited than hierarchical clustering with average linkage. The best performing ensemble consists of four crystal structures and is able to reproduce the native ligand poses better than any individual crystal structure. Moreover this ensemble outperforms 88% of all individual crystal structures in terms of screening utility as well as scoring accuracy. Similarly, ensembles of MD-derived structures perform on average better than 75% of any individual crystal structure in terms of scoring accuracy at all inspected ensembles sizes.

pocketZebra: a web-server for automated selection and classification of subfamily-specific binding sites by bioinformatic analysis of diverse protein families

PubMed Central

Suplatov, Dmitry; Kirilin, Eugeny; Arbatsky, Mikhail; Takhaveev, Vakil; Švedas, Vytas

2014-01-01

The new web-server pocketZebra implements the power of bioinformatics and geometry-based structural approaches to identify and rank subfamily-specific binding sites in proteins by functional significance, and select particular positions in the structure that determine selective accommodation of ligands. A new scoring function has been developed to annotate binding sites by the presence of the subfamily-specific positions in diverse protein families. pocketZebra web-server has multiple input modes to meet the needs of users with different experience in bioinformatics. The server provides on-site visualization of the results as well as off-line version of the output in annotated text format and as PyMol sessions ready for structural analysis. pocketZebra can be used to study structure–function relationship and regulation in large protein superfamilies, classify functionally important binding sites and annotate proteins with unknown function. The server can be used to engineer ligand-binding sites and allosteric regulation of enzymes, or implemented in a drug discovery process to search for potential molecular targets and novel selective inhibitors/effectors. The server, documentation and examples are freely available at http://biokinet.belozersky.msu.ru/pocketzebra and there are no login requirements. PMID:24852248

Association between blood cholesterol level with periodontal status of coronary heart disease patients

NASA Astrophysics Data System (ADS)

Valensia, Rosy; Masulili, Sri Lelyati C.; Lessang, Robert; Radi, Basuni

2017-02-01

Coronary heart disease (CHD) is an abnormal narrowing of heart arteries associated with local accumulation of lipids, in the form of cholesterol and triglycerides. Periodontal disease is a chronic inflammatory that suggests link to the development of CHD. In periodontitis have been reported changes in lipid profile, include increased of cholesterol levels of blood. Objective: to analyse correlation between blood cholesterol level with periodontal status of CHD and non CHD subjects. Methods: Periodontal status and blood cholesterol level of 60 CHD and 40 non CHD subjects was measured. Result: Blood cholesterol level in CHD subjects differs from non CHD subjects (p=0.032). Blood cholesterol level correlates with pocket depth (p=0.003) and clinical attachment loss (CAL) (p=0.000) in CHD subjects. Blood cholesterol level correlates with pocket depth (p=0.010) in non CHD subjects. There is no significant correlation between blood cholesterol level and bleeding on probing (BOP) in CHD subjects. There is no significant correlation between blood cholesterol level with BOP and CAL in non CHD subjects. Conclusion: Blood cholesterol level in control group is higher than CHD patients. Blood cholesterol level positively associated with pocket depth (r=0.375) and CAL (r=0.450) in CHD patients. Blood cholesterol level is positively associated with pocket depth (r=0.404) in control group.

Lead isotope ratios in tree bark pockets: an indicator of past air pollution in the Czech Republic.

PubMed

Conkova, M; Kubiznakova, J

2008-10-15

Tree bark pockets were collected at four sites in the Czech Republic with differing levels of lead (Pb) pollution. The samples, spanning 1923-2005, were separated from beech (Fagus sylvatica) and spruce (Picea abies). Elevated Pb content (0.1-42.4 microg g(-1)) reflected air pollution in the city of Prague. The lowest Pb content (0.3-2.6 microg g(-1)) was found at the Kosetice EMEP "background pollution" site. Changes in (206)Pb/(207)Pb and (208)Pb/(206)Pb isotope ratios were in agreement with operation times of the Czech main anthropogenic Pb sources. Shortly after the Second World War, the (206)Pb/(207)Pb isotope ratio in bark pockets decreased from 1.17 to 1.14 and the (208)Pb/(206)Pb isotope ratio increased from 2.12 to 2.16. Two dominant emission sources responsible for these changes, lignite and leaded petrol combustion, contributed to the shifts in Pb isotope ratios. Low-radiogenic petrol Pb ((206)Pb/(207)Pb of 1.11) lead to lower (206)Pb/(207)Pb in bark pockets over time. High-radiogenic lignite-derived Pb ((206)Pb/(207)Pb of 1.18 to 1.19) was detected in areas affected by coal combustion rather than by traffic.

Bacterial analysis of combined periodontal-endodontic lesions by polymerase chain reaction-denaturing gradient gel electrophoresis.

PubMed

Xia, Minghui; Qi, Qingguo

2013-01-01

We used denaturing gradient gel electrophoresis (DGGE) to compare bacterial profiles in periodontium and root canals of teeth with combined periodontal-endodontic lesions. Samples of dental plaque and necrotic pulp were collected from thirteen extracted teeth with advanced periodontitis. Genomic DNA was extracted for polymerase chain reaction (PCR) analysis using universal bacterial primers. The PCR products were then loaded onto DGGE gels to obtain fractionated bands. Characteristic DGGE bands were excised and DNA was cloned and sequenced. The number of bands, which indicates the number of bacterial species, was compared between dental plaques and necrotic pulp tissues from the same tooth. Although the difference was statistically significant (P < 0.01), there was no positive correlation; similarity (Dice coefficient) was 13.1% to 62.5%. Some bacteria species were present in both the periodontal pockets and root canals of the same tooth; however, periodontal bacteria did not always invade the root canals, and some bacteria in root canals were not present in periodontal pockets of the same tooth. In some teeth, unique bacteria in root canals had not passed from periodontal pockets. A basic local alignment search tool (BLAST) sequence search in Genbank indicated that new bacteria species were present in periodontal pockets and root canals. Their characteristics must thus be further analyzed.

Epitympanum volume and tympanic isthmus area in temporal bones with retraction pockets.

PubMed

Monsanto, Rafael da Costa; Pauna, Henrique Furlan; Kaya, Serdar; Hızlı, Ömer; Kwon, Geeyoun; Paparella, Michael M; Cureoglu, Sebahattin

2016-11-01

To compare the volume of the epitympanic space, as well as the area of the tympanic isthmus, in human temporal bones with retraction pockets to those with chronic otitis media without retraction pockets and to those with neither condition. Comparative human temporal bone study. We generated a three-dimensional model of the bony epitympanum and measured the epitympanic space. We also compared the area of the tympanic isthmus. The mean total volume of the epitympanum was 40.55 ± 7.14 mm 3 in the retraction pocket group, 50.03 ± 8.49 mm 3 in the chronic otitis media group, and 48.03 ± 9.16 mm 3 in the neither condition group. The mean volume of the anterior, lateral, and medial compartments in temporal bones in the retraction pocket group was significantly smaller than in the two control groups (P < 0.05). Total epitympanic volume was also significantly smaller in the retraction pocket group than in both control groups (P < 0.05). The mean area of the tympanic isthmus was significantly smaller in the retraction pocket group (8.11 ± 2.44 mm 2 ) than in the chronic otitis media group (9.82 ± 2.06 mm 2 ) or the neither condition group (10.66 ± 1.78 mm 2 ) (P < 0.05). Our data indicate that temporal bones with retraction pockets have a smaller volume bony epitympanum and a smaller tympanic isthmus area as compared with temporal bones from both control groups. The smaller volume tympanic isthmus in the retraction pocket group may suggest that a blockage in the aeration pathways to the epitympanum could create dysventilation, resulting in negative pressure and ultimately in retraction pockets and cholesteatomas. NA Laryngoscope, 126:E369-E374, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Histological analysis of retraction pocket pars tensa of tympanic membrane in children.

PubMed

Urík, M; Hurník, P; Žiak, D; Machač, J; Šlapák, I; Motyka, O; Vaculová, J; Dvořáčková, J

2016-07-01

Histological and histochemical analysis of retraction pocket of pars tensa of tympanic membrane in children. Identification of morphological abnormalities in comparison with a healthy tympanic membrane as it is described in standard textbook. Identification of signs typical for cholesteatoma and support for a retraction theory of cholesteatoma formation. A prospective study analysing 31 samples of retraction pockets taken during surgery. University Hospital, Children's Medical Centre Samples of retraction pockets were processed by a standard process for light microscopy, stained by haematoxylin-eosin. Van Gieson's stain was used for differential staining of collagen, Verhoeff's stain for elastic fibre tissues, Alcian blue for acidic polysaccharides and PAS (Periodic Acid Schiff) method for basement membrane polysaccharides. The following findings were observed in the samples of retraction pockets: hyperkeratosis (100%), hypervascularisations (100%), subepithelial fragmented elastic fibres (96%), myxoid changes (87%), subepithelial inflammatory infiltration (84%), rete pegs (71%), papilomatosis (71%), intraepithelial inflammatory cellularizations, (48%), intraepithelial spongiosis (16%) and parakeratosis (3%). No basement membrane continuity interruptions were observed. Thickness of retraction pocket, thickness of epidermis, occurrence of rete pegs and frequency of fragmented elastic fibres was higher in a Grade III stage RP than Grade II stage RP (according to Charachon). Morphological abnormalities in the structure of retraction pockets in comparison with a healthy tympanic membrane were described. The changes are typical for a structure of cholesteatoma (these changes are common in matrix and perimatrix), supporting retraction theory of its origin. Our observations show that it is inflammation that probably plays a key role in the pathogenesis of retraction pocket. The frequency of some of the changes increases with the stage of retraction pocket (II-III according to Charachon). Basement membrane continuity interruptions are not typical for retraction pockets. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Alzheimer Disease and Related Disorders and Out-of-Pocket Health Care Spending and Burden Among Elderly Medicare Beneficiaries.

PubMed

Dwibedi, Nilanjana; Findley, Patricia A; Wiener R, Constance; Shen, Chan; Sambamoorthi, Usha

2018-03-01

To estimate the excess burden of out-of-pocket health care spending associated with Alzheimer disease and related disorders (ADRD) among older individuals (age 65 y and older). We adopted a retrospective, cross-sectional study design with data from 2012 Medicare Current Beneficiary Survey. The study sample comprised of elderly community-dwelling individuals who had positive total health care expenditures, and enrolled in Medicare throughout the calendar year (462 with ADRD, and 7160 without ADRD). We estimated the per-capita total annual out-of-pocket spending on health care and out-of-pocket spending by service type: inpatient, outpatient, home health, prescription drugs, and other services. We measured out-of-pocket spending burden by calculating the percentage of income spent on health care and defined high out-of-pocket spending burden as having this percentage above 10%. Multivariable analyses included ordinary least squares regressions and logistic regressions and these analyses adjusted for predisposing, enabling, need, personal health care practices and external environment characteristics. The average annual per-capita out-of-pocket health care spending was greater among individuals with ADRD compared with those without ADRD ($3285 vs. $1895); home health and prescription drugs accounted for 52% of total out-of-pocket spending among individuals with ADRD and 34% among individuals without ADRD. Elderly individuals with ADRD were more likely to have high out-of-pocket spending burden (adjusted odds ratio, 1.49; 95% confidence interval, 1.13-1.97) compared with those without ADRD. ADRD is associated with excess out-of-pocket health care spending, primarily driven by prescription drugs and home health care use.

3. DOWNHILL SIDE AND END ELEVATION OF COAL POCKETS, WITH ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. DOWNHILL SIDE AND END ELEVATION OF COAL POCKETS, WITH RETAINING WALL IN BACKGROUND. VIEW LOOKING NORTHEAST. - Honesdale Coal Pockets, Main & Commercial Streets, between 700 & 800 blocks, Honesdale, Wayne County, PA

Planview Geometry and morphological characteristics of pocket beaches on the Catalan coast (Spain)

NASA Astrophysics Data System (ADS)

Bowman, D.; Guillén, J.; López, L.; Pellegrino, V.

2009-07-01

Coastal planform studies are a relevant initial stage before launching detailed dynamic field experiments. The aim of this study is to define the planform characteristics of 72 Catalan pocket beaches, natural and man-made, and to determine their sheltering effect, embaymentization and their status of equilibrium. Planform measurements were performed on SIGPAC, 1:5000 orthophoto sets and wave climate was provided by Puertos del Estado (Wana model). Planform parameters were applied and coastal planview indexes were determined. The study shows that the Catalan pocket beaches display a wide range of indentation, suggesting that no single structural, tectonic or morphological control dominates their planform. The man-made pocket beaches typically display indentations which are smaller than those shown by natural pocket beaches. Headland spacing and beach area are positively correlated. The more indented bays are, the shorter their beaches become. Low-indented pocket beaches are the widest and the longest ones. Deep indentation contributes towards beach protection and energy dissipation which counteracts rip efficiency and inhibits the formation of mega-rips. Pocket beaches often show gradual and moderate alongshore changes in texture and beach morphology. One third of the Catalan pocket beaches are "sediment starved", i.e., 60% and more of their embayed shorelines are deprived of beach sediments. Examination of the status of equilibrium demonstrates that most of the Catalan pocket beaches are in an unstable mode, with indentation ratios that are unrelated to the wave obliquity.

CONTROL SYSTEM FOR ISOTOPE SEPARATING APPARATUS

DOEpatents

Barnes, S.W.

1960-01-26

A method is described for controlling the position of the ion beams in a calutron used for isotope separation. The U/sup 238/ beams is centered over the U/sup 235/ receiving pocket, the operator monitoring the beam until a maximum reading is achieved on the meter connected to that pocket. Then both beams are simultaneously shifted by a preselected amount to move the U/sup 235/ beam over the U/sup 235/ pocket. A slotted door is placed over the entrance to that pocket during the U/sup 238/ beam centering to reduce the contamination to the pocket, while allowing enough beam to pass for monitoring purposes.

Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery.

PubMed

Pérot, Stéphanie; Sperandio, Olivier; Miteva, Maria A; Camproux, Anne-Claude; Villoutreix, Bruno O

2010-08-01

Detection, comparison and analyses of binding pockets are pivotal to structure-based drug design endeavors, from hit identification, screening of exosites and de-orphanization of protein functions to the anticipation of specific and non-specific binding to off- and anti-targets. Here, we analyze protein-ligand complexes and discuss methods that assist binding site identification, prediction of druggability and binding site comparison. The full potential of pockets is yet to be harnessed, and we envision that better understanding of the pocket space will have far-reaching implications in the field of drug discovery, such as the design of pocket-specific compound libraries and scoring functions.

Generic Penetration of the SSRI Market.

PubMed

Cascade, Elisa F; Kalali, Amir H

2008-04-01

In this article, we investigate the penetration of generic selective serotonin reuptake inhibitors (SSRIs) in the US market and the implications for patient out-of-pocket expense. The data suggest that generic penetration into the SSRI market has grown from approximately nine percent in 2000, the year that the patent for Prozac((R)) expired, to 72 percent in 2007. For December, 2007, the difference in patient out-of-pocket expense for branded vs. generic agents was, on average, $55.42 for patients paying by cash (i.e., they had no prescription drug insurance) and $22.39 for patients with insurance coverage.

Generic Penetration of the SSRI Market

PubMed Central

2008-01-01

In this article, we investigate the penetration of generic selective serotonin reuptake inhibitors (SSRIs) in the US market and the implications for patient out-of-pocket expense. The data suggest that generic penetration into the SSRI market has grown from approximately nine percent in 2000, the year that the patent for Prozac® expired, to 72 percent in 2007. For December, 2007, the difference in patient out-of-pocket expense for branded vs. generic agents was, on average, $55.42 for patients paying by cash (i.e., they had no prescription drug insurance) and $22.39 for patients with insurance coverage. PMID:19727306

Analysis of the antigen recognition sites of anti-methamphetamine monoclonal antibodies (II): unique feature of MA-3 antibody.

PubMed

Ishimaru, M; Morikawa, K; Hifumi, E; Itoh, T; Uda, T

2000-01-01

A monoclonal antibody against methamphetamine (MA-3 mAb) was found to be strongly bound to ephedrine. This feature was quite different from that of other fourteen mAbs against MA. Analyses of cDNA sequence and steric conformation by molecular modeling revealed that one hydrophilic pocket was generated in the heavy chain of MA-3 mAb involving CDRH-1 and CDRH-2. Asn33, Asn35, Asn50 and Asp52 were the main components of the unique pocket capable of binding to the hydroxyl group of ephedrine.

Origin of the extremely large magnetoresistance in the semimetal YSb

DOE PAGES

Xu, J.; Ghimire, N. J.; Jiang, J. S.; ...

2017-08-29

Extremely large magnetoresistance (XMR) was recently discovered in YSb but its origin, along with that of many other XMR materials, is an active subject of debate. Here we demonstrate that YSb, with a cubic crystalline lattice and anisotropic bulk electron Fermi pockets, can be an excellent candidate for revealing the origin of XMR. We carried out angle dependent Shubnikov – de Haas quantum oscillation measurements to determine the volume and shape of the Fermi pockets. In addition, by investigating both Hall and longitudinal magnetoresistivities, we reveal that the origin of XMR in YSb lies in its carrier high mobility withmore » a diminishing Hall factor that is obtained from the ratio of the Hall and longitudinal magentoresistivities. The high mobility leads to a strong magnetic field dependence of the longitudinal magnetoconductivity while a diminishing Hall factor reveals the latent XMR hidden in the longitudinal magnetoconductivity whose inverse has a nearly quadratic magnetic-field dependence. The Hall factor highlights the deviation of the measured magnetoresistivity from its full potential value and provides a general formulation to reveal the origin of XMR behavior in high mobility materials and of nonsaturating MR behavior as a whole. Our approach can be readily applied to other XMR materials.« less

Spatial Analysis and Quantification of the Thermodynamic Driving Forces in Protein-Ligand Binding: Binding Site Variability

PubMed Central

Raman, E. Prabhu; MacKerell, Alexander D.

2015-01-01

The thermodynamic driving forces behind small molecule-protein binding are still not well understood, including the variability of those forces associated with different types of ligands in different binding pockets. To better understand these phenomena we calculate spatially resolved thermodynamic contributions of the different molecular degrees of freedom for the binding of propane and methanol to multiple pockets on the proteins Factor Xa and p38 MAP kinase. Binding thermodynamics are computed using a statistical thermodynamics based end-point method applied on a canonical ensemble comprising the protein-ligand complexes and the corresponding free states in an explicit solvent environment. Energetic and entropic contributions of water and ligand degrees of freedom computed from the configurational ensemble provides an unprecedented level of detail into the mechanisms of binding. Direct protein-ligand interaction energies play a significant role in both non-polar and polar binding, which is comparable to water reorganization energy. Loss of interactions with water upon binding strongly compensates these contributions leading to relatively small binding enthalpies. For both solutes, the entropy of water reorganization is found to favor binding in agreement with the classical view of the “hydrophobic effect”. Depending on the specifics of the binding pocket, both energy-entropy compensation and reinforcement mechanisms are observed. Notable is the ability to visualize the spatial distribution of the thermodynamic contributions to binding at atomic resolution showing significant differences in the thermodynamic contributions of water to the binding of propane versus methanol. PMID:25625202

Visualizing Earth's Core-Mantle Interactions using Nanoscale X-ray Tomography

NASA Astrophysics Data System (ADS)

Mao, W. L.; Wang, J.; Yang, W.; Hayter, J.; Pianetta, P.; Zhang, L.; Fei, Y.; Mao, H.; Hustoft, J. W.; Kohlstedt, D. L.

2010-12-01

Early-stage, core-mantle differentiation and core formation represent a pivotal geological event which defined the major geochemical signatures. However current hypotheses of the potential mechanism for core-mantle separation and interaction need more experimental input which has been awaiting technological breakthroughs. Nanoscale x-ray computed tomography (nanoXCT) within a laser-heated diamond anvil cell has exciting potential as a powerful 3D petrographic probe for non-destructive, nanoscale (<40nm) resolution of multiple minerals and amorphous phases (including melts) which are synthesized under the high pressure-temperature conditions found deep within the Earth and planetary interiors. Results from high pressure-temperature experiments which illustrate the potential for this technique will be presented. By extending measurements of the texture, shape, porosity, tortuosity, dihedral angle, and other characteristics of molten Fe-rich alloys in relation to silicates and oxides, along with the fracture systems of rocks under deformation by high pressure-temperature conditions, potential mechanisms of core formation can be tested. NanoXCT can also be used to investigate grain shape, intergrowth, orientation, and foliation -- as well as mineral chemistry and crystallography at core-mantle boundary conditions -- to understand whether shape-preferred orientation is a primary source of the observed seismic anisotropy in Earth’s D” layer and to determine the textures and shapes of the melt pockets and channels which would form putative partial melt which may exist in ultralow velocity zones.

1. Photocopy of photograph. ORIGINAL CANAL COAL POCKETS Source: Delaware ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. Photocopy of photograph. ORIGINAL CANAL COAL POCKETS Source: Delaware and Hudson Railroad and Canal, by Wayne County Historical Society. - Honesdale Coal Pockets, Main & Commercial Streets, between 700 & 800 blocks, Honesdale, Wayne County, PA

Pocket Guide to Transportation 2017

DOT National Transportation Integrated Search

2017-05-01

The BTS Pocket Guide to Transportation is a quick reference guide to significant transportation statistics. All the previous seven sections plus a new Major Trends section are included. This year marks the 20th anniversary of the Pocket Guide, which ...

What regulates the catalytic activities in AGE catalysis? An answer from quantum mechanics/molecular mechanics simulations.

PubMed

Zhang, Yulai; Zhang, Hongxing; Zheng, Qingchuan

2017-12-06

The AGE superfamily (AGEs) is made up of kinds of isomerase which are very important both physiologically and industrially. One of the most intriguing aspects of AGEs has to do with the mechanism that regulates their activities in single conserved active pocket. In order to clarify the relationship among single conserved active pocket and two activities in AGEs, results for the epimerization activity catalyzed by RaCE and the isomerization activity catalyzed by SeYihS were obtained by using QM/MM umbrella sampling simulations and 2D-FES calculations. Our results show that both of them have similar enzyme-substrate combination mode for inner pyranose ring in single conserved active pocket even though they have different substrate specificity. This means that the pathways of ring opening catalyzed by them are similar. However, one non-conserved residue (Leu183 in RaCE, Met175 in SeYihS) in the active site, which has different steric hindrance, causes a small but effective change in the direction of ring opening in stage 1. And then this change will induce a fundamentally different catalytic activity for RaCE and SeYihS in stage 2. Our results give a novel viewpoint about the regulatory mechanism between CE and YihS in AGEs, and may be helpful for further experiments of rational enzyme design based on the (α/α) 6 -barrel basic scaffold.

Enhanced fluorescence norfloxacin substituted naphthalimide derivatives: Molecular docking and antibacterial activity

NASA Astrophysics Data System (ADS)

Kumar, Santosh; Kumar, Gaurav; Tripathi, Amit Kumar; Seena, Sahadevan; Koh, Joonseok

2018-04-01

Hybrid derivatives are a fascinating and challenging process in the area of drug discovery. Naphthalimide derivatives with modified norfloxacin moiety were designed and synthesized. Docking simulations were done to assess the interactions of the derivatives with the E. coli type II topoisomerases Gyrase B and ParE ATP-binding pocket by taking novobiocin as a standard molecule. Results suggested that the norfloxacin substituted naphthalimide derivatives indicate red-shift emission maxima when compared to 4-bromo 1,8-naphthalic anhydride. The molecular docking simulation study revealed that the derivatives have similar interaction but a different mode of binding with the gyrase B ATP-binding pocket as compare to novobiocin. However, they bound to ParE ATP-binding pocket similarly to novobiocin. The antibacterial property was confirmed with disc diffusion method. Our study indicated that the norfloxacin substituted naphthalimide novel derivatives have pronounced fluorescence, anti-topoisomerase activity, and antibacterial properties; therefore, they could be developed into new drug candidates.

Therapy Caps and Variation in Cost of Outpatient Occupational Therapy by Provider, Insurance Status, and Geographic Region.

PubMed

Pergolotti, Mackenzi; Lavery, Jessica; Reeve, Bryce B; Dusetzina, Stacie B

This article describes the cost of occupational therapy by provider, insurance status, and geographic region and the number of visits allowed and out-of-pocket costs under proposed therapy caps. This retrospective, population-based study used Medicare Provider Utilization and Payment Data for occupational therapists billing in 2012 and 2013 (Ns = 3,662 and 3,820, respectively). We examined variations in outpatient occupational therapy services with descriptive statistics and the impact of therapy caps on occupational therapy visits and patient out-of-pocket costs. Differences in cost between occupational and physical therapists were minimal. The most frequently billed service was therapeutic exercises. Wisconsin had the most inflated outpatient costs in both years. Under the proposed therapy cap, patients could receive an evaluation plus 12-14 visits. . Wide variation exists in potential patient out-of-pocket costs for occupational therapy services on the basis of insurance coverage and state. Patients without insurance pay a premium. Copyright © 2018 by the American Occupational Therapy Association, Inc.

Therapy Caps and Variation in Cost of Outpatient Occupational Therapy by Provider, Insurance Status, and Geographic Region

PubMed Central

Pergolotti, Mackenzi; Lavery, Jessica; Reeve, Bryce B.; Dusetzina, Stacie B.

2018-01-01

OBJECTIVE. This article describes the cost of occupational therapy by provider, insurance status, and geographic region and the number of visits allowed and out-of-pocket costs under proposed therapy caps. METHOD. This retrospective, population-based study used Medicare Provider Utilization and Payment Data for occupational therapists billing in 2012 and 2013 (Ns = 3,662 and 3,820, respectively). We examined variations in outpatient occupational therapy services with descriptive statistics and the impact of therapy caps on occupational therapy visits and patient out-of-pocket costs. RESULTS. Differences in cost between occupational and physical therapists were minimal. The most frequently billed service was therapeutic exercises. Wisconsin had the most inflated outpatient costs in both years. Under the proposed therapy cap, patients could receive an evaluation plus 12–14 visits. DISCUSSION. Wide variation exists in potential patient out-of-pocket costs for occupational therapy services on the basis of insurance coverage and state. Patients without insurance pay a premium. PMID:29426383

Photoinduced transport in an H64Q neuroglobin antidote for carbon monoxide poisoning

NASA Astrophysics Data System (ADS)

Rydzewski, J.; Nowak, W.

2018-03-01

Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, without available antidotal therapy. Recently, a potential treatment for CO poisoning was introduced, based on binding of CO by neuroglobin (Ngb) with a mutated distal histidine (H64Q). Here, we present an atomistic mechanism of CO trapping by H64Q Ngb revealed by nonadiabatic molecular dynamics. We focused on CO photodissociation and recombination of CO to wild type (WT) and H64Q Ngb. Our results demonstrate that the distribution of CO within the proteins differs substantially due to rearrangement of amino acids surrounding the distal heme pocket. This leads to the decrease of the distal pocket volume in H64Q Ngb in comparison to WT Ngb, trapping migrating CO molecules in the distal pocket. We show that the mutation implicates the shortening of the time scale of CO geminate recombination, making H64Q Ngb 2.7 times more frequent binder than WT Ngb.

Photoinduced transport in an H64Q neuroglobin antidote for carbon monoxide poisoning.

PubMed

Rydzewski, J; Nowak, W

2018-03-21

Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, without available antidotal therapy. Recently, a potential treatment for CO poisoning was introduced, based on binding of CO by neuroglobin (Ngb) with a mutated distal histidine (H64Q). Here, we present an atomistic mechanism of CO trapping by H64Q Ngb revealed by nonadiabatic molecular dynamics. We focused on CO photodissociation and recombination of CO to wild type (WT) and H64Q Ngb. Our results demonstrate that the distribution of CO within the proteins differs substantially due to rearrangement of amino acids surrounding the distal heme pocket. This leads to the decrease of the distal pocket volume in H64Q Ngb in comparison to WT Ngb, trapping migrating CO molecules in the distal pocket. We show that the mutation implicates the shortening of the time scale of CO geminate recombination, making H64Q Ngb 2.7 times more frequent binder than WT Ngb.

Riboswitches: emerging themes in RNA structure and function.

PubMed

Montange, Rebecca K; Batey, Robert T

2008-01-01

Riboswitches are RNAs capable of binding cellular metabolites using a diverse array of secondary and tertiary structures to modulate gene expression. The recent determination of the three-dimensional structures of parts of six different riboswitches illuminates common features that allow riboswitches to be grouped into one of two types. Type I riboswitches, as exemplified by the purine riboswitch, are characterized by a single, localized binding pocket supported by a largely pre-established global fold. This arrangement limits ligand-induced conformational changes in the RNA to a small region. In contrast, Type II riboswitches, such as the thiamine pyrophosphate riboswitch, contain binding pockets split into at least two spatially distinct sites. As a result, binding induces both local changes to the binding pocket and global architecture. Similar organizational themes are found in other noncoding RNAs, making it possible to begin to build a hierarchical classification of RNA structure based on the spatial organization of their active sites and associated secondary structural elements.

Structural insights into μ-opioid receptor activation

PubMed Central

Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, A. J.; Laeremans, Toon; Feinberg, Evan N.; Sanborn, Adrian L.; Kato, Hideaki E.; Livingston, Kathryn E.; Thorsen, Thor S.; Kling, Ralf; Granier, Sébastien; Gmeiner, Peter; Husbands, Stephen M.; Traynor, John R.; Weis, William I.; Steyaert, Jan; Dror, Ron O.; Kobilka, Brian K.

2015-01-01

Summary Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To understand the structural basis for μOR activation, we obtained a 2.1 Å X-ray crystal structure of the μOR bound to the morphinan agonist BU72 and stabilized by a G protein-mimetic camelid-antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2 adrenergic receptor (β2AR) and the M2 muscarinic receptor (M2R). Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three GPCRs. PMID:26245379

Assembly-directed antivirals differentially bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure.

PubMed

Katen, Sarah P; Tan, Zhenning; Chirapu, Srinivas Reddy; Finn, M G; Zlotnick, Adam

2013-08-06

Hepatitis B virus (HBV) is a major cause of liver disease. Assembly of the HBV capsid is a critical step in virus production and an attractive target for new antiviral therapies. We determined the structure of HBV capsid in complex with AT-130, a member of the phenylpropenamide family of assembly effectors. AT-130 causes tertiary and quaternary structural changes but does not disrupt capsid structure. AT-130 binds a hydrophobic pocket that also accommodates the previously characterized heteroaryldihydropyrimidine compounds but favors a unique quasiequivalent location on the capsid surface. Thus, this pocket is a promiscuous drug-binding site and a likely target for different assembly effectors with a broad range of mechanisms of activity. That AT-130 successfully decreases virus production by increasing capsid assembly rate without disrupting capsid structure delineates a paradigm in antiviral design, that disrupting reaction timing is a viable strategy for assembly effectors of HBV and other viruses. Copyright © 2013 Elsevier Ltd. All rights reserved.

Separation of charge-order and magnetic QCPs in heavy fermions and high Tc cuprates

NASA Astrophysics Data System (ADS)

Harrison, Neil

2010-03-01

The Fermi surface topology of high temperature superconductors inferred from magnetic quantum oscillation measurements provides clues for the origin of unconventional pairing thus previously not accessed by other spectroscopy techniques. While the overdoped regime of the high Tc phase diagram has a large Fermi surface consistent with bandstructure calculations, the underdoped regime of YBa2Cu2O6+x is found to be composed of small pockets. There is considerable debate as to whether the small observed ``pocket'' is hole-like or electron-like- whether the Fermi surface is best described by a t-J model or a conventional band folding picture- whether or not a Fermi liquid description applies- or- whether bilayer coupling splits the degeneracy of the observed pockets. We (myself and collaborators) have now collected an extensive body of experimental data that brings this debate to rest, but raises new questions about the nature of itinerant magnetism in underdoped high Tc cuprates. Quantum oscillation measurements are performed on multiple samples in magnetic fields extending to 85 T, temperatures between 30 mK (dilution fridge in dc fields to 45 T) and 18 K, over a range of hole dopings and with samples rotated in-situ about multiple axes with respect to the magnetic field. We perform a topographical map of the Fermi surface, enabling the in-plane shape of one of the pockets to be determined- imposing stringent constraints on the origin of the Fermi surface. While quantum oscillations measurements are consistent with a topological Fermi surface change associated with magnetism near optimal doping, they also point to a secondary instability deep within the underdoped regime beneath a high Tc superconducting sub-dome. An steep upturn in the quasiparticle effective mass is observed on underdoping, suggestive of a quantum critical point near x= 0.46 separating the metallic regime (composed of small pockets) from a more underdoped insulating charge-ordered regime (earlier reported in neutron scattering measurements). Our findings suggest the importance of two critical instabilities affecting the Fermi surface beneath the high Tc superconducting dome(s). While one of these has been proposed to provide the likely origin of unconventional pairing in the cuprates, the other can be an important factor in boosting transition temperatures. [4pt] This work is supported by the DoE BES grant ``Science in 100 T''. The author would like to thank collaborators S. E. Sebastian, C. H. Mielke, P. A. Goddard, M. M. Altarawneh, R. Liang, D. A. Bonn, W. N. Hardy and G. G. Lonzarich, and supporting staff at the National High Magnetic Field Laboratory (NHMFL). Quantum oscillation experiments are performed at the NHMFL, which is funded by the NSF with support from the DoE and State of Florida.

Superconductivity in SnO: a nonmagnetic analog to Fe-based superconductors?

PubMed

Forthaus, M K; Sengupta, K; Heyer, O; Christensen, N E; Svane, A; Syassen, K; Khomskii, D I; Lorenz, T; Abd-Elmeguid, M M

2010-10-08

We discovered that under pressure SnO with α-PbO structure, the same structure as in many Fe-based superconductors, e.g., β-FeSe, undergoes a transition to a superconducting state for p≳6 GPa with a maximum Tc of 1.4 K at p=9.3 GPa. The pressure dependence of Tc reveals a domelike shape and superconductivity disappears for p≳16 GPa. It is further shown from band structure calculations that SnO under pressure exhibits a Fermi surface topology similar to that reported for some Fe-based superconductors and that the nesting between the hole and electron pockets correlates with the change of Tc as a function of pressure.

Enzymatic reduction of acetophenone derivatives with a benzil reductase from Pichia glucozyma (KRED1-Pglu): electronic and steric effects on activity and enantioselectivity.

PubMed

Contente, Martina L; Serra, Immacolata; Palazzolo, Luca; Parravicini, Chiara; Gianazza, Elisabetta; Eberini, Ivano; Pinto, Andrea; Guidi, Benedetta; Molinari, Francesco; Romano, Diego

2016-04-07

A recombinant ketoreductase from Pichia glucozyma (KRED1-Pglu) was used for the enantioselective reduction of various mono-substituted acetophenones. Reaction rates of meta- and para-derivatives were consistent with the electronic effects described by σ-Hammett coefficients; on the other hand, enantioselectivity was determined by an opposite orientation of the substrate in the binding pocket. Reduction of ortho-derivatives occurred only with substrates bearing substituents with low steric impact (i.e., F and CN). Reactivity was controlled by stereoelectronic features (C[double bond, length as m-dash]O length and charge, shape of LUMO frontier molecular orbitals), which can be theoretically calculated.

Polymorphisms in the F Pocket of HLA-B27 Subtypes Strongly Affect Assembly, Chaperone Interactions, and Heavy-Chain Misfolding.

PubMed

Guiliano, David B; North, Helen; Panayoitou, Eleni; Campbell, Elaine C; McHugh, Kirsty; Cooke, Fiona G M; Silvestre, Marine; Bowness, Paul; Powis, Simon J; Antoniou, Antony N

2017-03-01

HLA-B27 is associated with the inflammatory spondyloarthritides (SpA), although subtypes HLA-B*27:06 and HLA-B*27:09 are not. These subtypes differ from the HLA-B*27:05 disease-associated allele primarily at residues 114 and 116 of the heavy chain, part of the F pocket of the antigen-binding groove. Dimerization of HLA-B27 during assembly has been implicated in disease onset. The purpose of this study was to investigate the factors that influence differences in dimerization between disease-associated and non-disease-associated HLA-B27 alleles. HLA-B*27:05 and mutants resembling the HLA-B*27:06 and 09 subtypes were expressed in the rat C58 T cell line, the human CEM T cell line and its calnexin-deficient variant CEM.NKR. Immunoprecipitation, pulse-chase experiments, flow cytometry, and immunoblotting were performed to study the assembly kinetics, heavy-chain dimerization, and chaperone associations. By expressing HLA-B*27:05, 06-like, and 09 alleles on a restrictive rat transporter associated with antigen processing background, we demonstrate that a tyrosine expressed at p116, either alone or together with an aspartic acid residue at p114, inhibited HLA-B27 dimerization and increased the assembly rate. F-pocket residues altered the associations with chaperones of the early major histocompatibility complex class I folding pathway. Calnexin was demonstrated to participate in endoplasmic reticulum (ER) stress-mediated degradation of dimers, whereas the oxidoreductase ERp57 does not appear to influence dimerization. Residues within the F pocket of the peptide-binding groove, which differ between disease-associated and non-disease-associated HLA-B27 subtypes, can influence the assembly process and heavy-chain dimerization, events which have been linked to the initiation of disease pathogenesis. © 2016, American College of Rheumatology.

Validity of the Omron HJ-112 pedometer during treadmill walking.

PubMed

Hasson, Rebecca E; Haller, Jeannie; Pober, David M; Staudenmayer, John; Freedson, Patty S

2009-04-01

The purpose of this investigation was to examine the validity of step counts measured with the Omron HJ-112 pedometer and to assess the effect of pedometer placement. Ninety-two subjects (44 males and 48 females; 71 with body mass index [BMI] <30 kg.m and 21 with BMI >or=30 kg.m) completed three, 12-min bouts of treadmill walking at speeds of 1.12, 1.34, and 1.56 mxs. A subset (21 males and 23 females; 38 BMI <30 kg.m and 6 BMI >or=30 kg.m) completed a variable walking condition. For all conditions, participants wore an Omron HJ-112 pedometer on the hip, in the pants pocket, in the chest shirt pocket, and around the neck. Hip pedometer placement was alternated between right and left sides with the Yamax Digiwalker SW-701. During each walk, an investigator recorded actual steps with a manual hand counter. There was no substantial bias with the Omron in any speed condition (-0.1% to 0.5%). Bias was larger with the Yamax (-3.6% to 2.0%). The largest random error for the Omron was 3.7% in the variable-speed condition for the BMI <30 kg.m group, whereas random errors for the Yamax were larger and up to 20%. None of the Omron placement positions produced statistically significant bias. Hip mounting produced the smallest random error (1.2%), followed by shirt pocket (1.7%), neck (2.2%), and pants pocket (5.8%). The Omron HJ-112 pedometer validly assesses steps in different BMI groups during constant- and variable-speed walking; other than that in the pants pocket, placement of the pedometer has little effect on validity.

Who pays for healthcare in Bangladesh? An analysis of progressivity in health systems financing.

PubMed

Molla, Azaher Ali; Chi, Chunhuei

2017-09-06

The relationship between payments towards healthcare and ability to pay is a measure of financial fairness. Analysis of progressivity is important from an equity perspective as well as for macroeconomic and political analysis of healthcare systems. Bangladesh health systems financing is characterized by high out-of-pocket payments (63.3%), which is increasing. Hence, we aimed to see who pays what part of this high out-of-pocket expenditure. To our knowledge, this was the first progressivity analysis of health systems financing in Bangladesh. We used data from Bangladesh Household Income and Expenditure Survey, 2010. This was a cross sectional and nationally representative sample of 12,240 households consisting of 55,580 individuals. For quantification of progressivity, we adopted the 'ability-to-pay' principle developed by O'Donnell, van Doorslaer, Wagstaff, and Lindelow (2008). We used the Kakwani index to measure the magnitude of progressivity. Health systems financing in Bangladesh is regressive. Inequality increases due to healthcare payments. The differences between the Gini coefficient and the Kakwani index for all sources of finance are negative, which indicates regressivity, and that financing is more concentrated among the poor. Income inequality increases due to high out-of-pocket payments. The increase in income inequality caused by out-of-pocket payments is 89% due to negative vertical effect and 11% due to horizontal inequity. Our findings add substantial evidence of health systems financing impact on inequitable financial burden of healthcare and income. The heavy reliance on out-of-pocket payments may affect household living standards. If the government and people of Bangladesh are concerned about equitable financing burden, our study suggests that Bangladesh needs to reform the health systems financing scheme.

Common Anesthetic-binding Site for Inhibition of Pentameric Ligand-gated Ion Channels.

PubMed

Kinde, Monica N; Bu, Weiming; Chen, Qiang; Xu, Yan; Eckenhoff, Roderic G; Tang, Pei

2016-03-01

Identifying functionally relevant anesthetic-binding sites in pentameric ligand-gated ion channels (pLGICs) is an important step toward understanding the molecular mechanisms underlying anesthetic action. The anesthetic propofol is known to inhibit cation-conducting pLGICs, including a prokaryotic pLGIC from Erwinia chrysanthemi (ELIC), but the sites responsible for functional inhibition remain undetermined. We photolabeled ELIC with a light-activated derivative of propofol (AziPm) and performed fluorine-19 nuclear magnetic resonance experiments to support propofol binding to a transmembrane domain (TMD) intrasubunit pocket. To differentiate sites responsible for propofol inhibition from those that are functionally irrelevant, we made an ELIC-γ-aminobutyric acid receptor (GABAAR) chimera that replaced the ELIC-TMD with the α1β3GABAAR-TMD and compared functional responses of ELIC-GABAAR and ELIC with propofol modulations. Photolabeling showed multiple AziPm-binding sites in the extracellular domain (ECD) but only one site in the TMD with labeled residues M265 and F308 in the resting state of ELIC. Notably, this TMD site is an intrasubunit pocket that overlaps with binding sites for anesthetics, including propofol, found previously in other pLGICs. Fluorine-19 nuclear magnetic resonance experiments supported propofol binding to this TMD intrasubunit pocket only in the absence of agonist. Functional measurements of ELIC-GABAAR showed propofol potentiation of the agonist-elicited current instead of inhibition observed on ELIC. The distinctly different responses of ELIC and ELIC-GABAAR to propofol support the functional relevance of propofol binding to the TMD. Combining the newly identified TMD intrasubunit pocket in ELIC with equivalent TMD anesthetic sites found previously in other cationic pLGICs, we propose this TMD pocket as a common site for anesthetic inhibition of pLGICs.

Triple burden of disease and out of pocket healthcare expenditure of women in India

PubMed Central

Ladusingh, Laishram; Mohanty, Sanjay Kumar

2018-01-01

Aim Women, unlike men, are subjected to triple burden of disease, namely, non-communicable and communicable diseases and reproductive health related diseases. To assess prevalence of triple burden of disease of currently married women and to contrast out of pocket maternal care expenditure of these diseases in India. Subject and methods This study uses nationally representative unit level data from the 71st round (2014) of the National Sample Survey Organisation. Descriptive statistics and bivariate analysis are employed to assess triple burden of diseases by background of currently married women. Mean out of pocket (OOP) expenditure for healthcare care by demographic and household characteristics of women are also compared by type of diseases. Two parts model is adopted for assessment of determents of out of pocket healthcare expenditure of women. Results Overall medical and non-medical expenses of non–communicable disease are much higher than those of other disease and disability, reproductive health related and communicable diseases. OOP expenditure for treatment of non-communicable diseases, reproductive health and related diseases and other disease and disability are significantly higher than the inpatient treatment of communicable diseases and the differences are statistically significant. Conclusion Out of pocket expenditure for treatment of non-communicable diseases is the highest, followed by that of other diseases & disability, then reproductive health related diseases and the least is for communicable diseases. OOP expenditures for maternal healthcare in private health facilities are much higher than in public health facilities regardless of types of disease. Women from households having insurance of any member spent less than that of women from households not having health insurance. There is an urgent need to expand the outreach of the public health system in India to rural areas. PMID:29746506

Cigarette smoking in Chinese adolescents: importance of controlling the amount of pocket money.

PubMed

Ma, J; Zhu, J; Li, N; He, Y; Cai, Y; Qiao, Y; Redmon, P; Wang, Z

2013-07-01

To estimate the proportion of smokers that could potentially have been prevented from smoking by limiting the amount of pocket money received by Chinese adolescents. Cross-sectional study. Current smoking, ever smoking and the amount of pocket money were determined through self-administered questionnaires among 12,708 adolescents (aged 12-18 years) from 21 schools in Shanghai, China. Adjusted odds ratios for current smoking ranged from 2.0 [95% confidence interval (CI) 1.5-2.7] for adolescents receiving 200-399 Reminbin (RMB)/month as pocket money to 6.5 (95% CI 3.3-12.7) for those receiving ≥1000 RMB/month, compared with those receiving <200 RMB/month. The crude population-attributable risk percentage (PAR%) due to higher pocket money (≥200 RMB/month) for current smoking was 50.4% (95% CI 42.2-57.4), and adjusted PAR% was 43.3% (95% CI 30.7-53.1). Approximately half of current smokers may have been prevented from smoking if pocket money was limited to <200 RMB/month among Chinese adolescents. An even larger proportion could have been prevented from smoking if pocket money was reduced further. It is recommended that future intervention programmes should target parents to reduce the amount of pocket money in China. Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Raf Kinase Inhibitory Protein Function Is Regulated via a Flexible Pocket and Novel Phosphorylation-Dependent Mechanism▿ †

PubMed Central

Granovsky, Alexey E.; Clark, Matthew C.; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

2009-01-01

Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics. PMID:19103740

Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism.

PubMed

Granovsky, Alexey E; Clark, Matthew C; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

2009-03-01

Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.

Exploration of the effect of sequence variations located inside the binding pocket of HIV-1 and HIV-2 proteases.

PubMed

Triki, Dhoha; Billot, Telli; Visseaux, Benoit; Descamps, Diane; Flatters, Delphine; Camproux, Anne-Claude; Regad, Leslie

2018-04-10

HIV-2 protease (PR2) is naturally resistant to most FDA (Food and Drug Administration)-approved HIV-1 protease inhibitors (PIs), a major antiretroviral class. In this study, we compared the PR1 and PR2 binding pockets extracted from structures complexed with 12 ligands. The comparison of PR1 and PR2 pocket properties showed that bound PR2 pockets were more hydrophobic with more oxygen atoms and fewer nitrogen atoms than PR1 pockets. The structural comparison of PR1 and PR2 pockets highlighted structural changes induced by their sequence variations and that were consistent with these property changes. Specifically, substitutions at residues 31, 46, and 82 induced structural changes in their main-chain atoms that could affect PI binding in PR2. In addition, the modelling of PR1 mutant structures containing V32I and L76M substitutions revealed a cooperative mechanism leading to structural deformation of flap-residue 45 that could modify PR2 flexibility. Our results suggest that substitutions in the PR1 and PR2 pockets can modify PI binding and flap flexibility, which could underlie PR2 resistance against PIs. These results provide new insights concerning the structural changes induced by PR1 and PR2 pocket variation changes, improving the understanding of the atomic mechanism of PR2 resistance to PIs.

Relationship between quantitative measurement of Porphyromonas gingivalis on dental plaque with periodontal status of patients with coronary heart disease

NASA Astrophysics Data System (ADS)

Dwiyanti, Stephani; Soeroso, Yuniarti; Sunarto, Hari; Radi, Basuni

2017-02-01

Coronary heart disease is a narrowing of coronary artery due to plaque build-up. [1] Chronic periodontitis increases risk of cardiovascular disease. P.gingivalis is linked to both diseases. Objective: to analyse quantitative difference of P.gingivalis on dental plaque and its relationship with periodontal status of CHD patient and control. Methods: Periodontal status of 66 CHD patient and 40 control was checked. Subgingival plaque was isolated and P.gingivalis was measured using real-time PCR. Result: P.gingivalis of CHD patient differs from control. P.gingivalis is linked to pocket depth of CHD patient. Conclusion: P.gingivalis count of CHD patient is higher than control. P.gingivalis count is not linked to any periodontal status, except for pocket depth of CHD patient.

The Effect of Pharmacy Benefit Design on Patient-Physician Communication About Costs

PubMed Central

Shrank, William H; Fox, Sarah A; Kirk, Adele; Ettner, Susan L; Cantrell, Clairessa H; Glassman, Peter; Asch, Steven M

2006-01-01

BACKGROUND Incentive-based formularies have been widely instituted to control the rising costs of prescription drugs. To work properly, such formularies depend on patients to be aware of financial incentives and communicate their cost preferences with prescribing physicians. The impact of financial incentives on patient awareness of and communication about those costs is unknown. OBJECTIVE To evaluate the relationship between enrollment in incentive-based pharmacy benefit plans and awareness of out-of-pocket costs and rates of communication about out-of-pocket costs. DESIGN A matched telephone survey of patients and their primary care physicians. SETTING Los Angeles County. PARTICIPANTS One thousand nine hundred and seventeen patients aged 53 to 82 (73% response rate). MEASUREMENTS Patient-reported pharmacy benefit design, knowledge of out-of-pocket costs, and discussion of out-of-pocket costs with physicians. RESULTS Sixty-two percent of patients who had prescription drug coverage and were aware of their pharmacy benefit design reported being enrolled in incentive-based plans. The majority of these (54%) were “never” or only “sometimes” aware of their out-of-pocket cost requirements at the time of the physician visit. After controlling for numerous physician and patient level variables, we found that patients enrolled in pharmacy benefit designs requiring no copayments were more likely to report they “never” discuss out-of-pocket costs with physicians compared with patients enrolled in incentive-based pharmacy benefit designs (81% vs 67%, P =.001) and patients with no prescription druginsurance (57%, P <.001). CONCLUSIONS Incentive-based pharmacy benefit plans and lack of insurance are associated with increased rates of discussions about out-of-pocket costs. Nonetheless, most incentive-based enrollees are unaware of out-of-pocket costswhen prescriptions are written and never discuss out-of-pocket costs with their physicians, likely mitigating the effectiveness of financial incentives to guide decision making. Considering that out-of-pocket costs are associated with adherence to medical therapy, interventions to improve patient access to out-of-pocket cost information and the frequency of patient-physician discussions about costs are needed. PMID:16686808

Elimination of the Out-of-Pocket Charge for Children's Primary Care Visits: An Application of Value-Based Insurance Design.

PubMed

Sepúlveda, Martín-J; Roebuck, M Christopher; Fronstin, Paul; Vidales-Calderon, Pablo; Parikh, Ashish; Rhee, Kyu

2016-08-01

To evaluate the impact of a value-based insurance design for primary care among children. A retrospective analysis of health care claims data on 25 950 children (<18 years of age) was conducted. Individuals were enrolled in a large employer's health plans when zero out-of-pocket cost for primary care physician visits was implemented. A rigorous propensity score matching process was used to generate a control group of equal size from a database of other employer-sponsored insurees. Multivariate difference-in-differences models estimated the effect of zero out-of-pocket cost on 21 health services and cost outcomes 24 months after intervention. Zero out-of-pocket cost for primary care was associated with significant increases (P < .01) in primary care physician visits (+32 per 100 children), as well as decreases in emergency department (-5 per 100 children) and specialist physician visits (-12 per 100 children). The number of prescription drug fills also declined (-20 per 100 children), yet medication adherence for 3 chronic conditions was unaffected. The receipt of well child visits and 4 recommended vaccinations were all significantly (P < .05) greater under the new plan design feature. Employer costs for primary care increased significantly (P < .01) in association with greater utilization ($29 per child), but specialist visit costs declined (-$12 per child) and total health care costs per child did not exhibit a statistically significant increase. This novel application of value-based insurance design warrants broader deployment and assessment of its longer term outcomes. As with recommended preventive services, policymakers should consider exempting primary care from health insurance cost-sharing. Copyright © 2016 Elsevier Inc. All rights reserved.

Reference Pricing, Consumer Cost-Sharing, and Insurer Spending for Advanced Imaging Tests.

PubMed

Robinson, James C; Whaley, Christopher; Brown, Timothy T

2016-12-01

Fees charged for similar imaging tests often vary dramatically within the same market, leading to wide variation in insurer spending and consumer cost-sharing. Reference pricing is an insurance design that offers good coverage to patients up to a defined contribution limit but requires the patients who select high-priced facilities to pay the remainder out of pocket. To measure the association between implementation of reference pricing and patient choice of facility, test prices, out-of-pocket spending, and insurer spending for advanced imaging (CT and MRI) procedures. Difference-in-differences multivariable analysis of insurance claims data. Study included 4751 employees of a national grocery chain (treatment group) and 23,428 enrollees in the nation's largest private insurance plan (comparison group) that used CT or MRI tests between 2010 and 2013. Patient choice of facility, price paid per test, patient out-of-pocket cost-sharing, and employer spending. Compared with trends in prices paid by insurance enrollees not subject to reference pricing, and after adjusting for characteristics of tests and patients, implementation of reference pricing was associated with a 12.5% (95% CI, -25.0%, 2.1%) reduction in average price paid per test by the end of the second full year of the program for CT scans and a 10.5% (95% CI, -16.9%, 3.6%) for MRIs. Out-of-pocket cost-sharing by patients declined by $71,508 (13.8%). The savings accruing to employees amounted to 45.5% of total savings from reference pricing, with the remainder accruing to the employer. Implementation of reference pricing led to reductions in payments by both employer and employees.

Subperiosteal and intraosseous connective tissue grafts for pocket reduction: a 9- to 13-year retrospective case series report.

PubMed

Nelson, S W

2001-10-01

Recent histological evidence has documented that grafted palatal connective tissue is capable of forming a new attachment to previously exposed roots in the treatment of gingival recession. No clinical studies have tested the ability of connective tissue that has been implanted beneath the periosteum into periodontal osseous defects to reduce probing depth and increase clinical attachment levels. This study reports the long-term clinical effect of subperiosteal and intraosseous connective tissue grafts on deep periodontal pockets. Connective tissue (CT) grafts were placed in 32 periodontal pockets on 27 patients. Grafts were classified into 3 groups. Type I grafts had 50% or more vascular surface contact and were < or = 2.5 mm thick. Type II grafts had 50% or more contact but were > 2.5 mm thick, and Type III grafts had less than 50% vascular contact regardless of thickness. Twelve of 14 Type I sites, 9 of 15 Type II sites, and 3 of 3 Type III sites were analyzed 9 to 13 years following treatment. Clinical attachment level change differed significantly between the graft types on survivor teeth (P < 0.05): Type III had 2 mm loss (95% confidence interval [CI]: 0.4 to 3.6), while Type II and Type I grafts had a 2.7 mm gain (95% CI: 2.0 to 3.4) and 4.3 mm gain (95% CI: 3.3 to 5.2), respectively. Similar substantial differences were presented for changes in probing depth and recession. This long-term (9 to 13 years) retrospective case-series analysis suggests substantial improvements in periodontal clinical measures for Type I CT grafts in deep periodontal pockets. Randomized trials are required to evaluate this promising procedure.

The Effect of Medicare Part D on Prescription Drug Spending and Health Care Use: 6 Years of Follow-up, 2007-2012.

PubMed

Park, Taehwan; Jung, Jeah

2017-01-01

Previous studies have shown that Medicare Part D was associated with a reduction in out-of-pocket expenditures for Medicare beneficiaries during the early years of its implementation (2006 and 2007). However, a question remains regarding the effect of Part D on out-of-pocket expenditures in the longer term. To evaluate the effects of Part D on prescription drug expenditures and certain health care use for a longer time period using a large, nationally representative sample of Medicare beneficiaries. Using Medical Expenditure Panel Survey (MEPS) data from 2000 through 2005 (pre-Part D period) and from 2007 through 2012 (Part D era), this study identified a cohort of elderly Medicare beneficiaries (treatment group) and a near-elderly non-Medicare population (control group). A difference-in-differences analysis was conducted to estimate the effect of Part D on prescription medication use and expenditures and outpatient visits. Propensity score weights and sampling weights were applied to obtain unbiased effect estimates accounting for complex survey designs. A total of 26,585 elderly Medicare beneficiaries and 20,688 near-elderly non-Medicare beneficiaries were identified. The introduction of Part D was associated with an adjusted average reduction of $105 in annual out-of-pocket spending on prescription drugs during the post-Part D period (2007 through 2012). The reduction in annual out-of-pocket spending ranged from $49 to $152 during the post-Part D period. No significant increase was found in total prescription expenditures or prescription medication use following the introduction of Part D nor were there significant changes in outpatient visits. A continued reduction of Part D out-of-pocket drug expenditures was found each year from 2007 to 2012. No funding has been received to conduct this study or prepare this manuscript. The authors have no conflicts of interest to declare. Study concept and design were primarily contributed by Park with assistance from Jung. Both authors contributed equally to data analysis and interpretation. The manuscript was written primarily by Park, with assistance from Jung, and revised primarily by Jung.

Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: total energy of complexation as a predictor of drug placement and activity.

PubMed Central

Kroeger Smith, M. B.; Rouzer, C. A.; Taneyhill, L. A.; Smith, N. A.; Hughes, S. H.; Boyer, P. L.; Janssen, P. A.; Moereels, H.; Koymans, L.; Arnold, E.

1995-01-01

Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), using crystal coordinate data from a subset of the protein surrounding the binding pocket region. Results from the minimizations of solvated complexes of 2-cyclopropyl-4-methyl-5,11-dihydro-5H-dipyrido[3,2-b :2',3'-e][1,4] diazepin-6-one (nevirapine), alpha-anilino-2, 6-dibromophenylacetamide (alpha-APA), and 8-chloro-tetrahydro-imidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-thi one (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as pi-electron donors to aromatic side-chain residues surrounding the pocket. However, side-chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these binding energies correlate with EC50 values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. Interactions of the inhibitors with individual residues correlate with crystallographic and site-specific mutational data. pi-Stacking interactions are important in binding and correlate with drug HOMO RHF/6-31G* energies. Modeling results are discussed with respect to the mechanism of complex formation and the design of nonnucleoside inhibitors that will be more effective against mutants of HIV-1 RT that are resistant to the currently available drugs. PMID:8535257

Ultrasonic Abrasive Removal Of EDM Recast

NASA Technical Reports Server (NTRS)

Mandel, Johnny L.; Jacobson, Marlowe S.

1990-01-01

Ultrasonic abrasive process removes layer of recast material generated during electrical-discharge machining (EDM) of damper pocket on turbine blade. Form-fitted tool vibrated ultrasonically in damper pocket from which material removed. Vibrations activate abrasive in pocket. Amount of material removed controlled precisely.

Adaptive self-assembly and induced-fit transformations of anion-binding metal-organic macrocycles

NASA Astrophysics Data System (ADS)

Zhang, Ting; Zhou, Li-Peng; Guo, Xiao-Qing; Cai, Li-Xuan; Sun, Qing-Fu

2017-06-01

Container-molecules are attractive to chemists due to their unique structural characteristics comparable to enzymes and receptors in nature. We report here a family of artificial self-assembled macrocyclic containers that feature induced-fit transformations in response to different anionic guests. Five metal-organic macrocycles with empirical formula of MnL2n (M=Metal L=Ligand n=3, 4, 5, 6, 7) are selectively obtained starting from one simple benzimidazole-based ligand and square-planar palladium(II) ions, either by direct anion-adaptive self-assembly or induced-fit transformations. Hydrogen-bonding interactions between the inner surface of the macrocycles and the anionic guests dictate the shape and size of the product. A comprehensive induced-fit transformation map across all the MnL2n species is drawn, with a representative reconstitution process from Pd7L14 to Pd3L6 traced in detail, revealing a gradual ring-shrinking mechanism. We envisage that these macrocyclic molecules with adjustable well-defined hydrogen-bonding pockets will find wide applications in molecular sensing or catalysis.

Frequency of "Pocket" Hematoma in Patients Receiving Vitamin K Antagonist and Antiplatelet Therapy at the Time of Pacemaker or Cardioverter Defibrillator Implantation (from the POCKET Study).

PubMed

Malagù, Michele; Trevisan, Filippo; Scalone, Antonella; Marcantoni, Lina; Sammarco, Giuseppe; Bertini, Matteo

2017-04-01

In patients undergoing cardiac device implantation, anticoagulant and antiplatelet therapy are associated with an increased risk of pocket hematoma. In case of vitamin K antagonist therapy, a strategy of continued warfarin with no heparin bridge showed a reduction of pocket hematoma. Evidence regarding antiplatelet therapy management is limited. This is a single-center observational study which reflects our systematic approach to the problem. In 2012, we proposed an improved management protocol for anticoagulant and antiplatelet therapy (no-bridge protocol) based on individual thromboembolic risk stratification, noninterruption of oral anticoagulation, no bridge with heparin and elastic adherence compression bandage. The primary end point was the incidence of clinically significant pocket hematoma in the first 30 days after implantation. A total of 1,035 patients were enrolled, of whom 522 received the standard management and 513 the new protocol. The primary end point occurred in 34 patients of the standard management group and 8 patients of the no-bridge protocol group (6.5% vs 1.6%, p <0.001). Patients in the standard management group had a higher incidence of pocket infections (2.3% vs 0.6%, p = 0.02), lead dislodgements (4.8% vs 2.1%, p = 0.02), and thromboembolic events (1.3% vs 0.0%, p <0.01). On a multivariate analysis, heparin and coronary artery disease were independent predictors of pocket hematoma (relative risk [RR] 3.48, 95% confidence interval [CI] 1.55 to 7.83 and RR 2.43, 95% CI 1.25 to 4.76, respectively), whereas the no-bridge protocol was associated with a reduction of pocket hematoma (RR 0.33, 95% CI 0.14 to 0.76). New anticoagulant and antiplatelet therapy management protocol was associated with a reduced incidence of clinically significant pocket hematomas, thromboembolic events, pocket infections, and lead dislodgements. Copyright © 2017 Elsevier Inc. All rights reserved.

An alginate-antacid formulation localizes to the acid pocket to reduce acid reflux in patients with gastroesophageal reflux disease.

PubMed

Rohof, Wout O; Bennink, Roel J; Smout, Andre J P M; Thomas, Edward; Boeckxstaens, Guy E

2013-12-01

Alginate rafts (polysaccharide polymers that precipitate into a low-density viscous gel when they contact gastric acid) have been reported to form at the acid pocket, an unbuffered pool of acid that floats on top of ingested food and causes postprandial acid reflux. We studied the location of an alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket positioning in patients with gastroesophageal reflux disease (GERD). We randomly assigned patients with symptomatic GERD and large hiatal hernias to groups who were given either (111)In-labeled alginate-antacid (n = 8, Gaviscon Double Action Liquid) or antacid (n = 8, Antagel) after a standard meal. The relative positions of labeled alginate and acid pocket were analyzed for 2 hours by using scintigraphy; reflux episodes were detected by using high-resolution manometry and pH-impedance monitoring. The alginate-antacid label localized to the acid pocket. The number of acid reflux episodes was significantly reduced in patients receiving alginate-antacid (3.5; range, 0-6.5; P = .03) compared with those receiving antacid (15; range, 5-20), whereas time to acid reflux was significantly increased in patients receiving alginate-antacid (63 minutes; range, 23-92) vs those receiving antacid (14 minutes; range, 9-23; P = .01). The acid pocket was located below the diaphragm in 71% of patients given alginate-antacid vs 21% of those given antacid (P = .08). There was an inverse correlation between a subdiaphragm position of the acid pocket and acid reflux (r = -0.76, P < .001). In a study of 16 patients with GERD, we observed that the alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux. These findings indicate the importance of the acid pocket in GERD pathogenesis and establish alginate-antacid as an appropriate therapy for postprandial acid reflux. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA

PubMed Central

2016-01-01

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results. PMID:27983843

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA.

PubMed

Hayatshahi, Hamed S; Roe, Daniel R; Galindo-Murillo, Rodrigo; Hall, Kathleen B; Cheatham, Thomas E

2017-01-26

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results.

Differential recognition of syk-binding sites by each of the two phosphotyrosine-binding pockets of the Vav SH2 domain.

PubMed

Chen, Chih-Hong; Piraner, Dan; Gorenstein, Nina M; Geahlen, Robert L; Beth Post, Carol

2013-11-01

The association of spleen tyrosine kinase (Syk), a central tyrosine kinase in B cell signaling, with Vav SH2 domain is controlled by phosphorylation of two closely spaced tyrosines in Syk linker B: Y342 and Y346. Previous studies established both singly phosphorylated and doubly phosphorylated forms play a role in signaling. The structure of the doubly phosphorylated form identified a new recognition of phosphotyrosine whereby two phosphotyrosines bind simultaneously to the Vav SH2 domain, one in the canonical pTyr pocket and one in the specificity pocket on the opposite side of the central β-sheet. It is unknown if the specificity pocket can bind phosphotyrosine independent of phosphotyrosine binding the pTyr pocket. To address this gap in knowledge, we determined the structure of the complex between Vav1 SH2 and a peptide (SykLB-YpY) modeling the singly phosphorylated-Y346 form of Syk with unphosphorylated Y342. The nuclear magnetic resonance (NMR) data conclusively establish that recognition of phosphotyrosine is swapped between the two pockets; phosphorylated pY346 binds the specificity pocket of Vav1 SH2, and unphosphorylated Y342 occupies what is normally the pTyr binding pocket. Nearly identical changes in chemical shifts occurred upon binding all three forms of singly and doubly phosphorylated peptides; however, somewhat smaller shift perturbations for SykLB-YpY from residues in regions of high internal mobility suggest that internal motions are coupled to binding affinity. The differential recognition that includes this swapped binding of phosphotyrosine to the specificity pocket of Vav SH2 increases the repertoire of possible phosphotyrosine binding by SH2 domains in regulating protein-protein interactions in cellular signaling. Copyright © 2013 Wiley Periodicals, Inc.

pocketZebra: a web-server for automated selection and classification of subfamily-specific binding sites by bioinformatic analysis of diverse protein families.

PubMed

Suplatov, Dmitry; Kirilin, Eugeny; Arbatsky, Mikhail; Takhaveev, Vakil; Svedas, Vytas

2014-07-01

The new web-server pocketZebra implements the power of bioinformatics and geometry-based structural approaches to identify and rank subfamily-specific binding sites in proteins by functional significance, and select particular positions in the structure that determine selective accommodation of ligands. A new scoring function has been developed to annotate binding sites by the presence of the subfamily-specific positions in diverse protein families. pocketZebra web-server has multiple input modes to meet the needs of users with different experience in bioinformatics. The server provides on-site visualization of the results as well as off-line version of the output in annotated text format and as PyMol sessions ready for structural analysis. pocketZebra can be used to study structure-function relationship and regulation in large protein superfamilies, classify functionally important binding sites and annotate proteins with unknown function. The server can be used to engineer ligand-binding sites and allosteric regulation of enzymes, or implemented in a drug discovery process to search for potential molecular targets and novel selective inhibitors/effectors. The server, documentation and examples are freely available at http://biokinet.belozersky.msu.ru/pocketzebra and there are no login requirements. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Protein-protein interface analysis and hot spots identification for chemical ligand design.

PubMed

Chen, Jing; Ma, Xiaomin; Yuan, Yaxia; Pei, Jianfeng; Lai, Luhua

2014-01-01

Rational design for chemical compounds targeting protein-protein interactions has grown from a dream to reality after a decade of efforts. There are an increasing number of successful examples, though major challenges remain in the field. In this paper, we will first give a brief review of the available methods that can be used to analyze protein-protein interface and predict hot spots for chemical ligand design. New developments of binding sites detection, ligandability and hot spots prediction from the author's group will also be described. Pocket V.3 is an improved program for identifying hot spots in protein-protein interface using only an apo protein structure. It has been developed based on Pocket V.2 that can derive receptor-based pharmacophore model for ligand binding cavity. Given similarities and differences between the essence of pharmacophore and hot spots for guiding design of chemical compounds, not only energetic but also spatial properties of protein-protein interface are used in Pocket V.3 for dealing with protein-protein interface. In order to illustrate the capability of Pocket V.3, two datasets have been used. One is taken from ASEdb and BID having experimental alanine scanning results for testing hot spots prediction. The other is taken from the 2P2I database containing complex structures of protein-ligand binding at the original protein-protein interface for testing hot spots application in ligand design.

Out-of-pocket costs, primary care frequent attendance and sample selection: Estimates from a longitudinal cohort design.

PubMed

Pymont, Carly; McNamee, Paul; Butterworth, Peter

2018-03-20

This paper examines the effect of out-of-pocket costs on subsequent frequent attendance in primary care using data from the Personality and Total Health (PATH) Through Life Project, a representative community cohort study from Canberra, Australia. The analysis sample comprised 1197 respondents with two or more GP consultations, and uses survey data linked to administrative health service use (Medicare) data which provides data on the number of consultations and out-of-pocket costs. Respondents identified in the highest decile of GP use in a year were defined as Frequent Attenders (FAs). Logistic regression models that did not account for potential selection effects showed that out-of-pocket costs incurred during respondents' prior two consultations were significantly associated with subsequent FA status. Respondents who incurred higher costs ($15-$35; or >$35) were less likely to become FAs than those who incurred no or low (

Hydration structure of the α-chymotrypsin substrate binding pocket: the impact of constrained geometry

NASA Astrophysics Data System (ADS)

Carey, Christina; Cheng, Yuen-Kit; Rossky, Peter J.

2000-08-01

The concave substrate binding pocket of α-chymotrypsin binds specifically hydrophobic side chains. In order to understand the hydration structure present in the absence of substrate, and elucidate the character of the solvent displaced on binding, molecular dynamics computer simulation of the solvent in a fully hydrated protein has been carried out and analyzed. The pocket is found to be characterized in terms of a mixed polar and apolar macromolecular surface. It is shown that the simulated solvent structure within it is spatially consistent with that seen via crystallography. The solvent structure is energetically characterized by large losses in hydrogen bonding among solvent molecules except at the mouth of the pocket where exposure to bulk-like solvent is possible. The loss in hydrogen bonding is attributed to the highly constrained geometry available to the solvent, preventing formation of a hydrogen bonding network, with only partial compensation by interactions with the macromolecular surface. The solvent displacement concomitant with substrate binding will therefore be associated with a large enthalpic driving force. This result is at the extreme of a continuum of variable cases of "hydrophobic" hydration, which differ most basically in surface curvature. These range from convex solute surfaces, inducing clathrate-like structures, with negligible hydrogen bond loss, to flat surfaces with significant interfacial loss, to the present concave case with hydrogen bonding losses exceeding 50%.

[Impact of volatile sulphur compounds in periodontal pockets on initial periodontal therapy].

PubMed

Li, Xiao-Jun; Dong, Ling-Ling; Kong, Jing-Jia

2008-07-01

To investigate the relationship of volatile sulphur compounds((VSC)levels in periodontal pockets with severity of periodontitis, and the impact of VSC on the result of initial periodontal therapy. Twenty-five patients with chronic periodontitis(CP)(13 males and 12 females with average age of 35) were included in this study. Clinical periodontal parameters, plaque index, probing depth(PD), attachment loss(AL), and bleeding on probing(BOP) were recorded before and 3 months after the initial therapy. VSC levels were measured with a portable monitor in a digital score ranging from 0.0 to 5.0. All of 5 054 sites for 840 teeth were included in this study. Before treatment the percentage of VSC-positive sites was 17.1%, 52.3% and 86.0% for shallow (PD<3 mm), moderate(PD 4-6 mm) and deep (PD>7 mm) pocket, respectively (P<0.001). In most VSC-positive sites the VSC levels were<1.0. Percentage of sites with a high VSC levels was significantly different among three groups (P<0.01). All clinical parameters in VSC-negative sites were reduced significantly following the initial therapy. The reduction of PD and AL in VSC-positive sites by treatment was less marked than that in VSC-negative sites. VSC in periodontal pockets may be a potential indicator for detecting severity of CP and a useful predictor for therapeutic success.

16 CFR 1210.5 - Findings.

Code of Federal Regulations, 2010 CFR

2010-01-01

... percent of all lighters sold are pocket-sized disposable butane models; of the remaining 5 percent, most are pocket refillable butane models. A small proportion of refillables is comprised of pocket liquid-fuel models; still smaller proportions are represented by table lighters and by “novelty” lighters...

Unique Approach to Hydraulic Characterization at an Underground Lab

NASA Astrophysics Data System (ADS)

Jones, T. L.; Wang, J. S.

2009-12-01

The Sanford Underground Laboratory is the interim lab for the future federally funded DUSEL (Deep Underground Science and Engineering Lab). The Sanford Lab took over the abandoned Homestake mine in Lead, SD. Over three hundred miles of drift, extending 8,000 feet below the surface, are now being used to house experiments in disciplines including physics, geology, and biology. The lab is situated in Precambrian metamorphic rocks intersected by Tertiary dike swarms. Three relevant geologic units are defined within the Precambrian rock system; all of which are interpreted to be metamorphosed igneous and sedimentary deposits. The Sanford Lab provides a unique environment to study several aspects of hydrogeology and hydrology; including geochemistry, hydraulic systems in fractured aquifers, and fluvial activity within mine workings. Aquifer characteristics housing the mine workings’ is important to define for future and present research at the underground lab. Outlined here is a unique approach to defining the matrix porosity within the fractured aquifer system. The Homestake mine was abandoned and the pump system keeping the mine dry was turned off in 2003. Over the course of the next five years the water level rose 3470 feet. Oxidation of iron from the water left a red staining on the submerged rocks. Hydrological observations are conducted on different levels throughout the Homestake facility as the water levels are lowered. Isolated air pockets and long stretches of unstained areas along the roof of drifts have been observed, together with less frequent occurrences of seepages. These observations are documented to supplement hydrological monitoring and testing with sensors. The sizes and widths of the trapped air pockets are indications of low permeability values and can be used to estimate the degree of heterogeneity along drifts. It is noted that sections of long stretches of trapped air have more delayed drainages, consistent with low effective permeability values for the metamorphic rocks. The air pockets reveal a distinctive difference in size between the geologic units; the average size of the air pockets associated with different geologic units differs by an order of magnitude. The infrequent seepage observations are also consistent with the hydrological setting of this facility with low inflow rates.

Enzyme specificity under dynamic control

NASA Astrophysics Data System (ADS)

Ota, Nobuyuki; Agard, David A.

2002-03-01

The contributions of conformational dynamics to substrate specificity have been examined by the application of principal component analysis to molecular dynamics trajectories of alpha-lytic protease. The wild-type alpha-lytic protease is highly specific for substrates with small hydrophobic side chains at the specificity pocket, while the Met190Ala binding pocket mutant has a much broader specificity, actively hydrolyzing substrates ranging from Ala to Phe. We performed a principal component analysis using 1-nanosecond molecular dynamics simulations using solvent boundary condition. We found that the walls of the wild-type substrate binding pocket move in tandem with one another, causing the pocket size to remain fixed so that only small substrates are recognized. In contrast, the M190A mutant shows uncoupled movement of the binding pocket walls, allowing the pocket to sample both smaller and larger sizes, which appears to be the cause of the observed broad specificity. The results suggest that the protein dynamics of alpha-lytic protease may play a significant role in defining the patterns of substrate specificity.

Study Of Physician And Patient Communication Identifies Missed Opportunities To Help Reduce Patients’ Out-Of-Pocket Spending

PubMed Central

Ubel, Peter A.; Zhang, Cecilia J.; Hesson, Ashley; Davis, J. Kelly; Kirby, Christine; Barnett, Jamison; Hunter, Wynn G.

2018-01-01

Some experts contend that requiring patients to pay out of pocket for a portion of their care will bring consumer discipline to health care markets. But are physicians prepared to help patients factor out-of-pocket expenses into medical decisions? In this qualitative study of audiorecorded clinical encounters, we identified physician behaviors that stand in the way of helping patients navigate out-of-pocket spending. Some behaviors reflected a failure to fully engage with patients’ financial concerns, from never acknowledging such concerns to dismissing them too quickly. Other behaviors reflected a failure to resolve uncertainty about out-of-pocket expenses or reliance on temporary solutions without making long-term plans to reduce spending. Many of these failures resulted from systemic barriers to health care spending conversations, such as a lack of price transparency. For consumer health care markets to work as intended, physicians need to be prepared to help patients navigate out-of-pocket expenses when financial concerns arise during clinical encounters. PMID:27044966

Molecular Docking Studies to Explore Potential Binding Pockets and Inhibitors for Chikungunya Virus Envelope Glycoproteins.

PubMed

Nguyen, Phuong T V; Yu, Haibo; Keller, Paul A

2017-03-11

The chikungunya virus (CHIKV) envelope glycoproteins are considered important potential targets for anti-CHIKV drug discovery due to their crucial roles in virus attachment and virus entry. In this study, using two available crystal structures of the immature and mature forms of envelope glycoproteins, virtual screenings based on blind dockings and focused dockings were carried out to identify potential binding pockets and hit compounds for the virus. The chemical library database of compounds, NCI Diversity Set II, was used in these docking studies. In addition to reproducing previously reported examples, new binding pockets were identified, e.g., Pocket 2 in the 3N40, and Pocket 2 and Pocket 3 in the 3N42. Convergences in conformational sampling in docking using AutoDock Vina were evaluated. An analysis of docking results was carried out to understand interactions of the envelope glycoproteins complexes. Some key residues for interactions, for example Gly91 and His230, are identified as possessing important roles in the fusion process.

Growth, the Mediterranean diet and the buying power of adolescents in Greece.

PubMed

Grammatikopoulou, Maria G; Gkiouras, Konstantinos; Daskalou, Efstratia; Apostolidou, Eirini; Theodoridis, Xenophon; Stylianou, Charilaos; Galli-Tsinopoulou, Assimina; Tsigga, Maria; Dardavessis, Theodore; Chourdakis, Michael

2018-06-01

The aim of the present cross-sectional study was to evaluate associations between pocket money, Mediterranean diet (MD) adherence and growth among Greek adolescents. A total of 319 (157 boys and 162 girls) Greek adolescents, aged 10-18 years participated in the study. Pocket money was recorded, MD adherence was assessed with the KIDMED score and growth was evaluated using the World Health Organization (WHO) growth charts. Participants receiving pocket money exceeding 6.0€ daily demonstrated increased fast-food consumption and breakfast skipping. Overall, a negative relationship was revealed between pocket money and obesity. However, lower allowance receivers were less likely to be obese, consume fruit per day and more likely to consume breakfast and sweets, compared to average pocket money receivers. Increased MD adherence was associated with a lower risk of overweight and as expected, unhealthy eating habits were observed among obese adolescents. Interrelationships tend to exist between MD adherence, pocket money and growth among adolescents.

Evidence for a small hole pocket in the Fermi surface of underdoped YBa2Cu3Oy

PubMed Central

Doiron-Leyraud, N.; Badoux, S.; René de Cotret, S.; Lepault, S.; LeBoeuf, D.; Laliberté, F.; Hassinger, E.; Ramshaw, B. J.; Bonn, D. A.; Hardy, W. N.; Liang, R.; Park, J.-H..; Vignolles, D.; Vignolle, B.; Taillefer, L.; Proust, C.

2015-01-01

In underdoped cuprate superconductors, the Fermi surface undergoes a reconstruction that produces a small electron pocket, but whether there is another, as yet, undetected portion to the Fermi surface is unknown. Establishing the complete topology of the Fermi surface is key to identifying the mechanism responsible for its reconstruction. Here we report evidence for a second Fermi pocket in underdoped YBa2Cu3Oy, detected as a small quantum oscillation frequency in the thermoelectric response and in the c-axis resistance. The field-angle dependence of the frequency shows that it is a distinct Fermi surface, and the normal-state thermopower requires it to be a hole pocket. A Fermi surface consisting of one electron pocket and two hole pockets with the measured areas and masses is consistent with a Fermi-surface reconstruction by the charge–density–wave order observed in YBa2Cu3Oy, provided other parts of the reconstructed Fermi surface are removed by a separate mechanism, possibly the pseudogap. PMID:25616011

Intraoral fiber-optic-based diagnostic for periodontal disease

NASA Astrophysics Data System (ADS)

Colston, Bill W., Jr.; Gutierrez, Dora M.; Everett, Matthew J.; Brown, Steve B.; Langry, Kevin C.; Cox, Weldon R.; Johnson, Paul W.; Roe, Jeffrey N.

2000-05-01

The purpose of this initial study was to begin development of a new, objective diagnostic instrument that will allow simultaneous quantitation of multiple proteases within a single periodontal pocket using a chemical fiber optic senor. This approach could potentially be adapted to use specific antibodies and chemiluminescence to detect and quantitate virtually any compound and compare concentrations of different compounds within the same periodontal pocket. The device could also be used to assay secretions in salivary ducts or from a variety of wounds. The applicability is, therefore, not solely limited to dentistry and the device would be important both for clinical diagnostics and as a research too.

NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.

PubMed

Güttler, Thomas; Madl, Tobias; Neumann, Piotr; Deichsel, Danilo; Corsini, Lorenzo; Monecke, Thomas; Ficner, Ralf; Sattler, Michael; Görlich, Dirk

2010-11-01

Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Φ) residues, yet CRM1 recognizes them with the same rigid set of five Φ pockets. The different Φ spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an α-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Φ pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly.

Does the financial protection of health insurance vary across providers? Vietnam's experience.

PubMed

Sepehri, Ardeshir; Sarma, Sisira; Oguzoglu, Umut

2011-08-01

Using household panel data from Vietnam, this paper compares out-of-pocket health expenditures on outpatient care at a health facility between insured and uninsured patients as well as across various providers. In the random effects model, the estimated coefficient of the insurance status variable suggests that insurance reduces out-of-pocket spending by 24% for those with the compulsory and voluntary coverage and by about 15% for those with the health insurance for the poor coverage. However, the modest financial protection of the compulsory and voluntary schemes disappears once we control for time-invariant unobserved individual effects using the fixed effects model. Additional analysis of the interaction terms involving the type of insurance and health facility suggests that the overall insignificant reduction in out-of-pocket expenditures as a result of the insurance schemes masks wide variations in the reduction in out-of-pocket sending across various providers. Insurance reduces out-of-pocket expenditures more for those enrollees using district and higher level public health facilities than those using commune health centers. Compared to the uninsured patients using district hospitals, compulsory and voluntary insurance schemes reduce out-of-pocket expenditures by 40 and 32%, respectively. However, for contacts at the commune health centers, both the compulsory health scheme and the voluntary health insurance scheme schemes have little influence on out-of-pocket spending while the health insurance scheme for the poor reduces out-of-pocket spending by about 15%. Copyright © 2011 Elsevier Ltd. All rights reserved.

ESMO International Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe.

PubMed

Cherny, N I; Sullivan, R; Torode, J; Saar, M; Eniu, A

2017-11-01

The availability and affordability of safe, effective, high-quality, affordable anticancer therapies are a core requirement for effective national cancer control plans. Online survey based on a previously validated approach. The aims of the study were to evaluate (i) the availability on national formulary of licensed antineoplastic medicines across the globe, (ii) patient out-of-pocket costs for the medications, (iii) the actual availability of the medication for a patient with a valid prescription, (iv) information relating to possible factors adversely impacting the availability of antineoplastic agents and (v) the impact of the country's level of economic development on these parameters. A total of 304 field reporters from 97 countries were invited to participate. The preliminary set of data was posted on the ESMO website for open peer review and amendments have been incorporated into the final report. Surveys were submitted by 135 reporters from 63 countries and additional peer-review data were submitted by 54 reporters from 19 countries. There are substantial differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines. The most substantial issues are in lower-middle- and low-income countries. Even among medications on the WHO Model List of Essential Medicines (EML) the discrepancies are profound and these relate to high out-of-pocket costs (in low-middle-income countries 32.0% of EML medicines are available only at full cost and 5.2% are not available at all, and for low-income countries, the corresponding figures are even worse at 57.7% and 8.3%, respectively). There is wide global variation in formulary availability, out-of-pocket expenditures and actual availability for most licensed anticancer medicines. Low- and low-middle-income countries have significant lack of availability and high out-of-pocket expenditures for cancer medicines on the WHO EML, with much less availability of new, more expensive targeted agents compared with high-income countries. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

ESMO International Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe

PubMed Central

Cherny, N I; Sullivan, R; Torode, J; Saar, M; Eniu, A

2017-01-01

Abstract Background The availability and affordability of safe, effective, high-quality, affordable anticancer therapies are a core requirement for effective national cancer control plans. Method Online survey based on a previously validated approach. The aims of the study were to evaluate (i) the availability on national formulary of licensed antineoplastic medicines across the globe, (ii) patient out-of-pocket costs for the medications, (iii) the actual availability of the medication for a patient with a valid prescription, (iv) information relating to possible factors adversely impacting the availability of antineoplastic agents and (v) the impact of the country’s level of economic development on these parameters. A total of 304 field reporters from 97 countries were invited to participate. The preliminary set of data was posted on the ESMO website for open peer review and amendments have been incorporated into the final report. Results Surveys were submitted by 135 reporters from 63 countries and additional peer-review data were submitted by 54 reporters from 19 countries. There are substantial differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines. The most substantial issues are in lower-middle- and low-income countries. Even among medications on the WHO Model List of Essential Medicines (EML) the discrepancies are profound and these relate to high out-of-pocket costs (in low-middle-income countries 32.0% of EML medicines are available only at full cost and 5.2% are not available at all, and for low-income countries, the corresponding figures are even worse at 57.7% and 8.3%, respectively). Conclusions There is wide global variation in formulary availability, out-of-pocket expenditures and actual availability for most licensed anticancer medicines. Low- and low-middle-income countries have significant lack of availability and high out-of-pocket expenditures for cancer medicines on the WHO EML, with much less availability of new, more expensive targeted agents compared with high-income countries. PMID:28950323

Pockets, conduits, channels, and plumes: links to volcanism and orogeny in the rollback dominated western Mediterranean

NASA Astrophysics Data System (ADS)

Miller, Meghan S.; Sun, Daoyuan; O'Driscoll, Leland; Becker, Thorsten W.; Holt, Adam; Diaz, Jordi; Thomas, Christine

2015-04-01

Detailed mantle and lithospheric structure from the Canary Islands to Iberia have been imaged with data from recent temporary deployments and select permanent stations from over 300 broadband seismometers. The stations extended across Morocco and Spain as part of the PICASSO, IberArray, and Morocco-Münster experiments. We present results from S receiver functions (SRF), shear wave splitting, waveform modeling, and geodynamic models that help constrain the tectonic evolution of the westernmost Mediterranean, including orogenesis of the Atlas Mountains and occurrence of localized alkaline volcanism. Our receiver function images, in agreement with previous geophysical modeling, show that the lithosphere is thin (~65 km) beneath the Atlas, but thickens (~100 km) over a very short length scale at the flanks of the mountains. We find that these dramatic changes in lithospheric thickness also correspond to dramatic decreases in delay times inferred from S and SKS splitting observations of seismic anisotropy. Pockets and conduits of low seismic velocity material below the lithosphere extend along much of the Atlas to Southern Spain and correlate with the locations of Pliocene-Quaternary magmatism. Waveform analysis from the USC linear seismic array across the Atlas Mountains constrains the position, shape, and physical characteristics of one localized, low velocity conduit that extends from the uppermost mantle (~200 km depth) up to the volcanoes in the Middle Atlas. The shape, position and temperature of these seismically imaged low velocity anomalies, topography of the base of the lithosphere, morphology of the subducted slab beneath the Alboran Sea, position of the West African Craton and correlation with mantle flow inferred from shear wave splitting suggest that the unusually high topography of the Atlas Mountains and isolated recent volcanics are due to active mantle support that may be from material channeled from the Canary Island plume.

Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors

PubMed Central

Di Pietro, Ornella; Laughton, Charles A.

2017-01-01

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer’s disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challenging. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments—huprine and rhein—that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8–14, 154–169 and 307–318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable “floppy” pocket would enable the binding of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligomethylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications introduced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors. PMID:28505196

Equity in health care financing: The case of Malaysia

PubMed Central

Yu, Chai Ping; Whynes, David K; Sach, Tracey H

2008-01-01

Background Equitable financing is a key objective of health care systems. Its importance is evidenced in policy documents, policy statements, the work of health economists and policy analysts. The conventional categorisations of finance sources for health care are taxation, social health insurance, private health insurance and out-of-pocket payments. There are nonetheless increasing variations in the finance sources used to fund health care. An understanding of the equity implications would help policy makers in achieving equitable financing. Objective The primary purpose of this paper was to comprehensively assess the equity of health care financing in Malaysia, which represents a new country context for the quantitative techniques used. The paper evaluated each of the five financing sources (direct taxes, indirect taxes, contributions to Employee Provident Fund and Social Security Organization, private insurance and out-of-pocket payments) independently, and subsequently by combined the financing sources to evaluate the whole financing system. Methods Cross-sectional analyses were performed on the Household Expenditure Survey Malaysia 1998/99, using Stata statistical software package. In order to assess inequality, progressivity of each finance sources and the whole financing system was measured by Kakwani's progressivity index. Results Results showed that Malaysia's predominantly tax-financed system was slightly progressive with a Kakwani's progressivity index of 0.186. The net progressive effect was produced by four progressive finance sources (in the decreasing order of direct taxes, private insurance premiums, out-of-pocket payments, contributions to EPF and SOCSO) and a regressive finance source (indirect taxes). Conclusion Malaysia's two tier health system, of a heavily subsidised public sector and a user charged private sector, has produced a progressive health financing system. The case of Malaysia exemplifies that policy makers can gain an in depth understanding of the equity impact, in order to help shape health financing strategies for the nation. PMID:18541025

Deconnable self-reading pocket dosimeter containment with self-contained light

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

Stevens, R.L.; Arnold, G.N.; McBride, R.G.

1996-10-22

A container for a self-reading pocket dosimeter includes a transparent tube for receiving the self-reading pocket dosimeter, a light source mounted at one end of the transparent tube, and an eyepiece mounted on an opposite end of the transparent tube for viewing a read-out of the self-reading pocket dosimeter. The container may further include an activation device for selectively supplying power to the light source. The container both protects the dosimeter from being contaminated and provides a light source for viewing the dosimeter. 4 figs.

Deconnable self-reading pocket dosimeter containment with self-contained light

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

Stevens, R.L.; Arnold, G.N.; McBride, R.G.

1995-12-31

A container for a self-reading pocket dosimeter includes a transparent tube for receiving the self-reading pocket dosimeter, a light source mounted at one end of the transparent tube, and an eyepiece mounted on an opposite end of the transparent tube for viewing a read-out of the self-reading pocket dosimeter. The container may further include an activation device for selectively supplying power to the light source. The container both protects the dosimeter from being contaminated and provides a light source for viewing the dosimeter.

Deconnable self-reading pocket dosimeter containment with self-contained light

DOEpatents

Stevens, Robyn L.; Arnold, Greg N.; McBride, Ryan G.

1996-01-01

A container for a self-reading pocket dosimeter includes a transparent tube for receiving the self-reading pocket dosimeter, a light source mounted at one end of the transparent tube, and an eyepiece mounted on an opposite end of the transparent tube for viewing a read-out of the self-reading pocket dosimeter. The container may further include an activation device for selectively supplying power to the light source. The container both protects the dosimeter from being contaminated and provides a light source for viewing the dosimeter.

Out-of-pocket health care expenditures, by insurance status, 2007-10.

PubMed

Catlin, Mary K; Poisal, John A; Cowan, Cathy A

2015-01-01

Out-of-pocket health care spending in the United States totaled $306.2 billion in 2010 and represented 11.8 percent of total national health expenditures, according to the Centers for Medicare and Medicaid Services' National Health Expenditure Accounts. Spending by people with employer-sponsored health insurance and those covered by Medicare accounted for over 80 percent of total out-of-pocket spending. People without comprehensive medical coverage accounted for less than 8 percent of all out-of-pocket expenditures in 2010. Between 2007 and 2010 per person out-of-pocket spending grew most rapidly for people primarily covered by employer-sponsored insurance and declined for people primarily covered by Medicare and those without coverage. Project HOPE—The People-to-People Health Foundation, Inc.

Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface.

PubMed

Johnson, David K; Karanicolas, John

2013-01-01

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically "druggable" by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that "druggability" is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.

Subgingival air-polishing with erythritol during periodontal maintenance

PubMed Central

Müller, Nada; Moëne, Raphaël; Cancela, José A; Mombelli, Andrea

2014-01-01

Objectives To evaluate repeated subgingival air-polishing in residual pockets with a new erythritol powder containing 0.3% chlorhexidine. Material and Methods Single-centre, examiner masked, randomized clinical trial of 12 months with a two-arm, within-subject parallel design. Fifty patients in periodontal maintenance were monitored in 3-month intervals. At months 0, 3, 6 and 9, all sites presenting with a probing depth (PD) >4 mm were subject to subgingival air-polishing (test side) or ultrasonic debridement (control side). The primary endpoint was presence/absence of PD >4 mm after 12 months. Results Totally 6918 sites were monitored at baseline, 457 of them had a PD >4 mm (range 5–9 mm). The number of pockets >4 mm per subject, PD and bleeding on probing were significantly lower at month 12. Differences between test and control were not significant. There was a significant difference in favour of air-polishing for the perception of pain/discomfort. Differences of frequencies at >1000 and >100,000 cells/ml of six microorganisms between baseline and month 12 were not significant. At month 12, test sites were less frequently positive for Aggregatibacter actinomycetemcomitans at >1000 cells/ml than controls, and counts never exceeded 100,000 cells/ml. Conclusions Repeated subgingival air-polishing reduced the number of pockets >4 mm similar to ultrasonic debridement. It was safe and induced less pain. PMID:25041441

Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol

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

Suino-Powell, Kelly; Xu, Yong; Zhang, Chenghai

A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GRmore » LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 {angstrom}{sup 3}, effectively doubling the size of the GR dexamethasone-binding pocket of 540 {angstrom}{sup 3} and yet leaving the structure of the coactivator binding site intact. DAC occupies only {approx}50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.« less

Effects of fine sediment on fish populations

Treesearch

Russ Thurow; Jack King

1991-01-01

To describe conditions in natural redds of steelhead trout (Oncorhynchus mykiss), we evaluated the particle size distribution of egg pockets, redd pits and tailspills, artificially constructed redds, and undisturbed substrate outside redds. Egg pockets were located in upper strata an average of 14.9 cm below the substrate surface. Egg pockets contained fewer fines (...

Patients' annual income adequacy, insurance premiums and out-of-pocket expenses related to heart failure care.

PubMed

Piamjariyakul, Ubolrat; Yadrich, Donna Macan; Russell, Christy; Myer, Jane; Prinyarux, Chanawee; Vacek, James L; Ellerbeck, Edward F; Smith, Carol E

2014-01-01

To (1) identify the amount patients spend for insurance premiums, co-payments, deductibles, and other out-of-pocket costs related to HF and chronic health care services and estimate their annual non-reimbursed and out-of-pocket costs; and (2) identify patients' concerns about nonreimbursed and out-of-pocket expenses. HF is one of the most expensive illnesses for our society with multiple health services and financial burdens for families. Mixed methods with quantitative questionnaires and qualitative interviews. Patients (N = 149) reported annual averages for non-reimbursed health services co-payments and out-of-pocket costs ranging from $3913 to $5829 depending on insurance coverage. Thirty one patients (21%) reported inadequate health coverage related to their non-reimbursed costs. Non-reimbursed costs related to HF care are substantial and vary depending on their insurance, health services use, and out-of-pocket costs. Patient referral to social services to assist with expenses could provide some relief from the burden of high HF-related costs. Copyright © 2014 Elsevier Inc. All rights reserved.

[Disposable nursing applicator-pocket of indwelling central venous catheter].

PubMed

Wei, Congli; Ma, Chunyuan

2017-11-01

Catheter related infection is the most common complication of central venous catheter, which pathogen mainly originate from the pipe joint and the skin around puncture site. How to prevent catheter infection is an important issue in clinical nursing. The utility model disclosed a "disposable nursing applicator-pocket of indwelling central venous catheter", which is mainly used for the fixation and the protection. The main structure consists of two parts, one is medical applicator to protect the skin around puncture site, and the other is gauze pocket to protect the catheter external connector. When in use, the catheter connector is fitted into the pocket, and then the applicator is applied to cover the puncture point of the skin. Integrated design of medical applicator and gauze pocket was designed to realize double functions of fixation and protection. The disposable nursing applicator-pocket is made of medical absorbent gauze (outer layer) and non-woven fabric (inner layer), which has the characteristics of comfortable, breathable, dust filtered, bacteria filtered, waterproof, antiperspirant and anti-pollution. The utility model has the advantages of simple structure, low cost, simple operation, effective protection, easy realization and popularization.

Method of underground mining by pillar extraction

DOEpatents

Bowen, Ray J.; Bowen, William R.

1980-08-12

A method of sublevel caving and pillar and top coal extraction for mining thick coal seams includes the advance mining of rooms and crosscuts along the bottom of a seam to a height of about eight feet, and the retreat mining of the top coal from the rooms, crosscuts and portions of the pillars remaining from formation of the rooms and cross-cuts. In the retreat mining, a pocket is formed in a pillar, the top coal above the pocket is drilled, charged and shot, and then the fallen coal is loaded by a continuous miner so that the operator remains under a roof which has not been shot. The top coal from that portion of the room adjacent the pocket is then mined, and another pocket is formed in the pillar. The top coal above the second pocket is mined followed by the mining of the top coal of that portion of the room adjacent the second pocket, all by use of a continuous miner which allows the operator to remain under a roof portion which has not been shot.

Structural Insights into Central Hypertension Regulation by Human Aminopeptidase A*

PubMed Central

Yang, Yang; Liu, Chang; Lin, Yi-Lun; Li, Fang

2013-01-01

Hypertension is regulated through both the central and systemic renin-angiotensin systems. In the central renin-angiotensin system, zinc-dependent aminopeptidase A (APA) up-regulates blood pressure by specifically cleaving the N-terminal aspartate, but not the adjacent arginine, from angiotensin II, a process facilitated by calcium. Here, we determined the crystal structures of human APA and its complexes with different ligands and identified a calcium-binding site in the S1 pocket of APA. Without calcium, the S1 pocket can bind both acidic and basic residues through formation of salt bridges with the charged side chains. In the presence of calcium, the binding of acidic residues is enhanced as they ligate the cation, whereas the binding of basic residues is no longer favorable due to charge repulsion. Of the peptidomimetic inhibitors of APA, amastatin has higher potency than bestatin by fitting better in the S1 pocket and interacting additionally with the S3′ subsite. These results explain the calcium-modulated substrate specificity of APA in central hypertension regulation and can guide the design and development of brain-targeting antihypertensive APA inhibitors. PMID:23888046

Factors associated with tobacco use among adolescents in India: results from the Global Youth Tobacco Survey, India (2000-2003).

PubMed

Oswal, Kunal C

2015-03-01

To differentiate between the different types of tobacco users and analyze the association between types of tobacco users and factors like pocket money and peer and parental influence across most of the state in India using the data obtained from Global Youth Tobacco Survey (GYTS) between 2000 and 2004. The GYTS data encompassed a representative 2-stage probability sample of students aged 13 to 15 years across 24 states and 2 union territories in India. These students were interviewed using an anonymous, self-administered questionnaire. A very strong association between users and pocket money was found in most of the states, with northeastern states having a very strong association-Sikkim, odds ratio (OR) = 8.43 (confidence interval [CI] = 6.08-11.69), and Manipur, OR = 5.58 (CI = 3.60-8.65)-after adjusting for close friend being smoker, close friend being smokeless tobacco user, parental influence, age, and gender. This study found a strong association between tobacco use by adolescents and having pocket money and close friends being tobacco users. © 2012 APJPH.

ACA dependent coverage provision reduced high out-of-pocket health care spending for young adults.

PubMed

Busch, Susan H; Golberstein, Ezra; Meara, Ellen

2014-08-01

Since September 2010 the Affordable Care Act (ACA) has required that insurers allow children to remain as dependents on their parents' private insurance plans until age twenty-six. Studies have shown that this provision increased coverage rates among young adults. In this article we analyze whether the provision also protected young adults from large and uncertain out-of-pocket expenses. We found that the policy was associated with a statistically significant reduction in the share of young adults facing annual out-of-pocket expenditures greater than $1,500 (decreasing from 4.2 percent to 2.9 percent), compared to an increase in the proportion of their slightly older peers facing such expenditures (increasing from 4.4 percent to 5.4 percent), a net difference of -2.4 percentage points, or 57 percent. We conclude that the dependent coverage provision in the ACA provides financial protection for young adults at a time when they often face high debt burden but low wages. Project HOPE—The People-to-People Health Foundation, Inc.

Structural insights into central hypertension regulation by human aminopeptidase A.

PubMed

Yang, Yang; Liu, Chang; Lin, Yi-Lun; Li, Fang

2013-08-30

Hypertension is regulated through both the central and systemic renin-angiotensin systems. In the central renin-angiotensin system, zinc-dependent aminopeptidase A (APA) up-regulates blood pressure by specifically cleaving the N-terminal aspartate, but not the adjacent arginine, from angiotensin II, a process facilitated by calcium. Here, we determined the crystal structures of human APA and its complexes with different ligands and identified a calcium-binding site in the S1 pocket of APA. Without calcium, the S1 pocket can bind both acidic and basic residues through formation of salt bridges with the charged side chains. In the presence of calcium, the binding of acidic residues is enhanced as they ligate the cation, whereas the binding of basic residues is no longer favorable due to charge repulsion. Of the peptidomimetic inhibitors of APA, amastatin has higher potency than bestatin by fitting better in the S1 pocket and interacting additionally with the S3' subsite. These results explain the calcium-modulated substrate specificity of APA in central hypertension regulation and can guide the design and development of brain-targeting antihypertensive APA inhibitors.

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

Xu Wei; Leal, Walter S.

Pheromone-binding proteins (PBPs) are involved in the uptake of pheromones from pores on the antennae, transport through an aqueous environment surrounding the olfactory receptor neurons, and fast delivery to pheromone receptors. We tested the hypothesis that a C-terminal segment and a flexible loop are involved in the release of pheromones to membrane-bound receptors. We expressed in Escherichia coli 11 mutants of the PBP from the silkworm moth, BmorPBP, taking into consideration structural differences between the forms with high and low binding affinity. The N-terminus was truncated and His-69, His-70 and His-95 at the base of a flexible loop, and amore » cluster of acidic residues at the C-terminus were mutated. Binding assays and circular dichroism analyses support a mechanism involving protonation of acidic residues Asp-132 and Glu-141 at the C-terminus and histidines, His-70 and His-95, in the base of a loop covering the binding pocket. The former leads to the formation of a new {alpha}-helix, which competes with pheromone for the binding pocket, whereas positive charge repulsion of the histidines opens the opposite side of the binding pocket.« less

Histology of periapical lesions obtained during apical surgery.

PubMed

Schulz, Malte; von Arx, Thomas; Altermatt, Hans Jörg; Bosshardt, Dieter

2009-05-01

The aim of this was to evaluate the histology of periapical lesions in teeth treated with periapical surgery. After root-end resection, the root tip was removed together with the periapical pathological tissue. Histologic sectioning was performed on calcified specimens embedded in methylmethacrylate (MMA) and on demineralized specimens embedded in LR White (Fluka, Buchs, Switzerland). The samples were evaluated with light and transmission electron microscopy (TEM). The histologic findings were classified into periapical abscesses, granulomas, or cystic lesions (true or pocket cysts). The final material comprised 70% granulomas, 23% cysts and 5% abscesses, 1% scar tissues, and 1% keratocysts. Six of 125 samples could not be used. The cystic lesions could not be subdivided into pocket or true cysts. All cysts had an epithelium-lined cavity, two of them with cilia-lined epithelium. These results show the high incidence of periapical granulomas among periapical lesions obtained during apical surgery. Periapical abscesses were a rare occasion. The histologic findings from samples obtained during apical surgery may differ from findings obtained by teeth extractions. A determination between pocket and true apical cysts is hardly possible when collecting samples by apical surgery.

Double gate graphene nanoribbon field effect transistor with single halo pocket in channel region

NASA Astrophysics Data System (ADS)

Naderi, Ali

2016-01-01

A new structure for graphene nanoribbon field-effect transistors (GNRFETs) is proposed and investigated using quantum simulation with a nonequilibrium Green's function (NEGF) method. Tunneling leakage current and ambipolar conduction are known effects for MOSFET-like GNRFETs. To minimize these issues a novel structure with a simple change of the GNRFETs by using single halo pocket in the intrinsic channel region, "Single Halo GNRFET (SH-GNRFET)", is proposed. An appropriate halo pocket at source side of channel is used to modify potential distribution of the gate region and weaken band to band tunneling (BTBT). In devices with materials like Si in channel region, doping type of halo and source/drain regions are different. But, here, due to the smaller bandgap of graphene, the mentioned doping types should be the same to reduce BTBT. Simulations have shown that in comparison with conventional GNRFET (C-GNRFET), an SH-GNRFET with appropriately halo doping results in a larger ON current (Ion), smaller OFF current (Ioff), a larger ON-OFF current ratio (Ion/Ioff), superior ambipolar characteristics, a reduced power-delay product and lower delay time.

A combination of 19F NMR and surface plasmon resonance for site-specific hit selection and validation of fragment molecules that bind to the ATP-binding site of a kinase.

PubMed

Nagatoishi, Satoru; Yamaguchi, Sou; Katoh, Etsuko; Kajita, Keita; Yokotagawa, Takane; Kanai, Satoru; Furuya, Toshio; Tsumoto, Kouhei

2018-05-01

19 F NMR has recently emerged as an efficient, sensitive tool for analyzing protein binding to small molecules, and surface plasmon resonance (SPR) is also a popular tool for this purpose. Herein a combination of 19 F NMR and SPR was used to find novel binders to the ATP-binding pocket of MAP kinase extracellular regulated kinase 2 (ERK2) by fragment screening with an original fluorinated-fragment library. The 19 F NMR screening yielded a high primary hit rate of binders to the ERK2 ATP-binding pocket compared with the rate for the SPR screening. Hit compounds were evaluated and categorized according to their ability to bind to different binding sites in the ATP-binding pocket. The binding manner was characterized by using isothermal titration calorimetry and docking simulation. Combining 19 F NMR with other biophysical methods allows the identification of multiple types of hit compounds, thereby increasing opportunities for drug design using preferred fragments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Out-of-pocket expenditures on traditional and Western medicine in Taiwan.

PubMed

Yen, Steven T; Chang, Hung-Hao; Lin, Tsui-Fang

2013-08-01

Coexistence of traditional and modern medicine is common in Asian countries. This paper investigates out-of-pocket expenditures on traditional medicine, traditional medical service, and Western medicine by households in Taiwan. Using a national sample of 13,765 households, the three expenditure equations are estimated with a censored system procedure. Effects of socio-demographic variables are explored by calculating marginal effects on probabilities and levels of medical expenses. Different types of medical expenditures are correlated. Households with higher income and more aging members use more traditional medicine than others, as do households in agricultural sector and in urban areas. In addition, households living in rural areas relative to those in the cities are more likely to use and also spend more on traditional service. Regional disparity of health care utilization is found. Higher income households spend more on traditional medicine, likely due to the fact that patients usually pay out-of-pocket for herbal materials needed in preparation of traditional medicine. To ensure equity in health care utilization, establishment of hospitals and clinics in rural areas should be considered.

Comparison of stromal hydration techniques for clear corneal cataract incisions: conventional hydration versus anterior stromal pocket hydration.

PubMed

Mifflin, Mark D; Kinard, Krista; Neuffer, Marcus C

2012-06-01

Anterior stromal pocket hydration was compared with conventional hydration for preventing wound leak after 2.8 mm uniplanar clear corneal incisions (CCIs) in patients having routine cataract surgery. Conventional hydration involves hydration of the lateral walls of the main incision with visible whitening of the stroma. The anterior stromal pocket hydration technique involves creation of an additional supraincisional stromal pocket overlying the main incision, which is then hydrated instead of the main incision. Sixty-six eyes of 48 patients were included in the data analysis with 33 assigned to each study group. The anterior stromal pocket hydration technique was significantly better than conventional hydration in preventing wound leak due to direct pressure on the posterior lip of the incision. Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

Three critical hydrogen bonds determine the catalytic activity of the Diels–Alderase ribozyme

PubMed Central

Kraut, Stefanie; Bebenroth, Dirk; Nierth, Alexander; Kobitski, Andrei Y.; Nienhaus, G. Ulrich; Jäschke, Andres

2012-01-01

Compared to protein enzymes, our knowledge about how RNA accelerates chemical reactions is rather limited. The crystal structures of a ribozyme that catalyzes Diels–Alder reactions suggest a rich tertiary architecture responsible for catalysis. In this study, we systematically probe the relevance of crystallographically observed ground-state interactions for catalytic function using atomic mutagenesis in combination with various analytical techniques. The largest energetic contribution apparently arises from the precise shape complementarity between transition state and catalytic pocket: A single point mutant that folds correctly into the tertiary structure but lacks one H-bond that normally stabilizes the pocket is completely inactive. In the rate-limiting chemical step, the dienophile is furthermore activated by two weak H-bonds that contribute ∼7–8 kJ/mol to transition state stabilization, as indicated by the 25-fold slower reaction rates of deletion mutants. These H-bonds are also responsible for the tight binding of the Diels–Alder product by the ribozyme that causes product inhibition. For high catalytic activity, the ribozyme requires a fine-tuned balance between rigidity and flexibility that is determined by the combined action of one inter-strand H-bond and one magnesium ion. A sharp 360° turn reminiscent of the T-loop motif observed in tRNA is found to be important for catalytic function. PMID:21976731

Crystal growth of Dirac semimetal ZrSiS with high magnetoresistance and mobility.

PubMed

Sankar, Raman; Peramaiyan, G; Muthuselvam, I Panneer; Butler, Christopher J; Dimitri, Klauss; Neupane, Madhab; Rao, G Narsinga; Lin, M-T; Chou, F C

2017-01-18

High quality single crystal ZrSiS as a theoretically predicted Dirac semimetal has been grown successfully using a vapor phase transport method. The single crystals of tetragonal structure are easy to cleave into perfect square-shaped pieces due to the van der Waals bonding between the sulfur atoms of the quintuple layers. Physical property measurement results including resistivity, Hall coefficient (R H ), and specific heat are reported. The transport and thermodynamic properties suggest a Fermi liquid behavior with two Fermi pockets at low temperatures. At T = 3 K and magnetic field of Hǁc up to 9 Tesla, large magneto-resistance up to 8500% and 7200% for Iǁ (100) and Iǁ (110) were found. Shubnikov de Haas (SdH) oscillations were identified from the resistivity data, revealing the existence of two Fermi pockets at the Fermi level via the fast Fourier transform (FFT) analysis. The Hall coefficient (R H ) showed hole-dominated carriers with a high mobility of 3.05 × 10 4  cm 2 V -1 s -1 at 3 K. ZrSiS has been confirmed to be a Dirac semimetal by the Dirac cone mapping near the X-point via angle resolved photoemission spectroscopy (ARPES) with a Dirac nodal line near the Fermi level identified using scanning tunneling spectroscopy (STS).

Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: binding of phosphonamidate to the S₁'-pocket of thermolysin.

PubMed

Englert, L; Biela, A; Zayed, M; Heine, A; Hangauer, D; Klebe, G

2010-11-01

Prerequisite for the design of tight binding protein inhibitors and prediction of their properties is an in-depth understanding of the structural and thermodynamic details of the binding process. A series of closely related phosphonamidates was studied to elucidate the forces underlying their binding affinity to thermolysin. The investigated inhibitors are identical except for the parts penetrating into the hydrophobic S₁'-pocket. A correlation of structural, kinetic and thermodynamic data was carried out by X-ray crystallography, kinetic inhibition assay and isothermal titration calorimetry. Binding affinity increases with larger ligand hydrophobic P₁'-moieties accommodating the S₁'-pocket. Surprisingly, larger P₁'-side chain modifications are accompanied by an increase in the enthalpic contribution to binding. In agreement with other studies, it is suggested that the release of largely disordered waters from an imperfectly hydrated pocket results in an enthalpically favourable integration of these water molecules into bulk water upon inhibitor binding. This enthalpically favourable process contributes more strongly to the binding energetics than the entropy increase resulting from the release of water molecules from the S₁'-pocket or the formation of apolar interactions between protein and inhibitor. Displacement of highly disordered water molecules from a rather imperfectly hydrated and hydrophobic specificity pocket can reveal an enthalpic signature of inhibitor binding. Copyright © 2010 Elsevier B.V. All rights reserved.

Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface

PubMed Central

Johnson, David K.; Karanicolas, John

2013-01-01

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention. PMID:23505360

The mechanism of T-cell mediated cytotoxicity. VI. T-cell projections and their role in target cell killing.

PubMed Central

Sanderson, C J; Glauert, A M

1979-01-01

Electron micrographs of material fixed during the first 10 min of a T-cell cytotoxic system showed T-cell projections and T-cell burrowing into target cells. These observations were made possible by using a system with a very high rate of killing. The projections vary in shape and size, and can push deeply into the target cell, distorting organelles in their path, including the nucleus. The projections contain fine fibrillar material, to the exclusion of organelles. They push the target cell membrane in front of them to form pockets approximating to the shape of the projection. Areas of close contact occur between the projections and the target cell membrane, particularly at the leading edges. The likelihood that these projections develop as a result of contact with specific antigen, and are involved in the cytotoxic mechanism is discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 PMID:311336

Hole spectral functions in lightly doped quantum antiferromagnets

NASA Astrophysics Data System (ADS)

Kar, Satyaki; Manousakis, Efstratios

2011-11-01

We study the hole and magnon spectral functions as a function of hole doping in the two-dimensional t-J and t-t'-t''-J models working within the limits of spin-wave theory by linearizing the hole-spin-deviation interaction and by adapting the noncrossing approximation. We find that the staggered magnetization decreases rather rapidly with doping and it goes to zero at a few percent of hole concentration in both t-J and t-t'-t''-J models. Furthermore, our results show that the residue of the quasiparticle peak at G⃗=(±π/2,±π/2) decreases very rapidly with doping. We also find pockets centered at G⃗, (i) with an elliptical shape with large eccentricity along the antinodal direction in the case of the t-J model and (ii) with an almost circular shape in the case of the t-t'-t''-J model. Last, we show that the spectral intensity distribution in the doped antiferromagnet has a waterfall-like pattern along the nodal direction of the Brillouin zone, a feature that is also seen in angle-resolved photoemission spectroscopy measurements.

Three-Dimensional Phenomena in Microbubble Acoustic Streaming

NASA Astrophysics Data System (ADS)

Marin, Alvaro; Rossi, Massimiliano; Rallabandi, Bhargav; Wang, Cheng; Hilgenfeldt, Sascha; Kähler, Christian J.

2015-04-01

Ultrasound-driven oscillating microbubbles are used as active actuators in microfluidic devices to perform manifold tasks such as mixing, sorting, and manipulation of microparticles. A common configuration consists of side bubbles created by trapping air pockets in blind channels perpendicular to the main channel direction. This configuration consists of acoustically excited bubbles with a semicylindrical shape that generate significant streaming flow. Because of the geometry of the channels, such flows are generally considered as quasi-two-dimensional. Similar assumptions are often made in many other microfluidic systems based on flat microchannels. However, in this Letter we show that microparticle trajectories actually present a much richer behavior, with particularly strong out-of-plane dynamics in regions close to the microbubble interface. Using astigmatism particle-tracking velocimetry, we reveal that the apparent planar streamlines are actually projections of a stream surface with a pseudotoroidal shape. We, therefore, show that acoustic streaming cannot generally be assumed as a two-dimensional phenomenon in confined systems. The results have crucial consequences for most of the applications involving acoustic streaming such as particle trapping, sorting, and mixing.

Accuracy of piezoelectric pedometer and accelerometer step counts.

PubMed

Cruz, Joana; Brooks, Dina; Marques, Alda

2017-04-01

This study aimed to assess step-count accuracy of a piezoeletric pedometer (Yamax PW/EX-510), when worn at different body parts, and a triaxial accelerometer (GT3X+), and to compare device accuracy; and identify the preferred location(s) to wear a pedometer. Sixty-three healthy adults (45.8±20.6 years old) wore 7 pedometers (neck, lateral right and left of the waist, front right and left of the waist, front pockets of the trousers) and 1 accelerometer (over the right hip), while walking 120 m at slow, self-preferred/normal and fast paces. Steps were recorded. Participants identified their preferred location(s) to wear the pedometer. Absolute percent error (APE) and Bland and Altman (BA) method were used to assess device accuracy (criterion measure: manual counts) and BA method for device comparisons. Pedometer APE was below 3% at normal and fast paces despite wearing location, but higher at slow pace (4.5-9.1%). Pedometers were more accurate at the front waist and inside the pockets. Accelerometer APE was higher than pedometer APE (P<0.05); nevertheless, limits of agreement between devices were relatively small. Preferred wearing locations were inside the front right (N.=25) and left (N.=20) pockets of the trousers. Yamax PW/EX-510 pedometers may be preferable than GT3X+ accelerometers to count steps, as they provide more accurate results. These pedometers should be worn at the front right or left positions of the waist or inside the front pockets of the trousers.

Variation in outpatient consultant physician fees in Australia by specialty and state and territory.

PubMed

Freed, Gary L; Allen, Amy R

2017-03-06

To determine the mean, median and 10th and 90th percentile levels of fees and out-of-pocket costs to the patient for an initial consultation with a consultant physician; to determine any differences in fees and bulk-billing rates between specialties and between states and territories. Analysis of 2015 Medicare claims data for an initial outpatient appointment with a consultant physician (Item 110) in 11 medical specialties representative of common adult non-surgical medical care (cardiology, endocrinology, gastroenterology, geriatric medicine, haematology, immunology/allergy, medical oncology, nephrology, neurology, respiratory medicine and rheumatology). Mean, median, 10th and 90th percentile levels for consultant physician fees and out-of-pocket costs, by medical specialty and state or territory; bulk-billing rate, by medical specialty and state/territory. Bulk-billing rates varied between specialties, with only haematology and medical oncology bulk-billing more than half of initial consultations. Bulk-billing rates also varied between states and territories, with rates in the Northern Territory (76%) nearly double those elsewhere. Most private consultations require a significant out-of-pocket payment by the patient, and these payments varied more than fivefold in some specialties. Without data on quality of care in private outpatient services, the rationale for the marked variations in fees within specialties is unknown. As insurers are prohibited from providing cover for the costs of outpatient care, the impact of out-of-pocket payments on access to private specialist care is unknown.

Catastrophic out-of-pocket payments for health and poverty nexus: evidence from Senegal.

PubMed

Séne, Ligane Massamba; Cissé, Momath

2015-09-01

Out-of-pocket payments are the primary source through which health expenditure is met in Senegal. However, these payments are financial burdens that lead to impoverishment when they become catastrophic. The purpose of this study is to cast light on the determinants of catastrophic household out-of-pocket health expenditures and to assess their implications on poverty. The 2011 poverty monitoring survey is used in this study. This survey aims to draw poverty profiles and to highlight the socio-economic characteristics of different social groups. In line with the concerns raised by the new Supplemental Poverty Measure, poverty statistics are adjusted to take into account household health expenditures and to estimate their impoverishing effects. To identify the determinants of the magnitude of catastrophic health expenditure, we implement a seemingly unrelated equations system of Tobit regressions to take into account censoring through a conditional mixed-process estimator procedure. We identify major causes of catastrophic expenditures, such as the level of overall health spending, the expensiveness of health goods and services, the characteristics of health facilities, the health stock shocks, the lack of insurance, etc. Results show evidence that catastrophic health expenditures jeopardize household welfare for some people that fall into poverty as a result of negative effects on disposable income and disruption of the material living standards of households. Our findings warrant further policy improvements to minimize the financial risks of out-of-pocket health expenditures and increase the efficiency of health care system for more effective poverty reduction strategies.

Intraoral fiber optic-based diagnostic for periodontal disease

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

Johnson, P W; Gutierrez, D M; Everett, M J

2000-01-21

The purpose of this initial study was to begin development of a new, objective diagnostic instrument that will allow simultaneous quantitation of multiple proteases within a single periodontal pocket using a chemical fiber optic sensor. This approach could potentially be adapted to use specific antibodies and chemiluminescence to detect and quantitate virtually any compound and compare concentrations of different compounds within the same periodontal pocket. The device could also be used to assay secretions in salivary ducts or from a variety of wounds. The applicability is, therefore, not solely limited to dentistry and the device would be important both formore » clinical diagnostics and as a research tool.« less

An Exploratory Examination of "Pockets of Success" in Creating Urban High Schools of Opportunity for LSES Students

ERIC Educational Resources Information Center

Gaines, Frank

2013-01-01

The purpose of this exploratory study was to examine "pockets of success" through the voices of participant stakeholders in low socio-economic status urban high schools and communities to identify opportunities and structures that can improve post-secondary outcomes for students. Examining those pockets of success to rise above the…

75 FR 19592 - Endangered and Threatened Wildlife and Plants; 12-Month Finding on a Petition to List the Wyoming...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-15

... size of individual pocket gophers and density of pocket gopher populations (Patton and Brylski 1987, p...-100). Pocket gopher population density is likely to be primarily regulated through intraspecific... the density of wells within that range (Keinath 2009, pp. 12-13). This potential risk is based on...

The Role of Electronic Pocket Dictionaries as an English Learning Tool among Chinese Students

ERIC Educational Resources Information Center

Jian, Hua-Li; Sandnes, Frode Eika; Law, Kris M. Y.; Huang, Yo-Ping; Huang, Yueh-Min

2009-01-01

This study addressed the role of electronic pocket dictionaries as a language learning tool among university students in Hong Kong and Taiwan. The target groups included engineering and humanities students at both undergraduate and graduate level. Speed of reference was found to be the main motivator for using an electronic pocket dictionary.…

Scoring ligand similarity in structure-based virtual screening.

PubMed

Zavodszky, Maria I; Rohatgi, Anjali; Van Voorst, Jeffrey R; Yan, Honggao; Kuhn, Leslie A

2009-01-01

Scoring to identify high-affinity compounds remains a challenge in virtual screening. On one hand, protein-ligand scoring focuses on weighting favorable and unfavorable interactions between the two molecules. Ligand-based scoring, on the other hand, focuses on how well the shape and chemistry of each ligand candidate overlay on a three-dimensional reference ligand. Our hypothesis is that a hybrid approach, using ligand-based scoring to rank dockings selected by protein-ligand scoring, can ensure that high-ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site. Results from applying this approach to screen nearly 70 000 National Cancer Institute (NCI) compounds for thrombin inhibitors tend to support the hypothesis. EON ligand-based ranking of docked molecules yielded the majority (4/5) of newly discovered, low to mid-micromolar inhibitors from a panel of 27 assayed compounds, whereas ranking docked compounds by protein-ligand scoring alone resulted in one new inhibitor. Since the results depend on the choice of scoring function, an analysis of properties was performed on the top-scoring docked compounds according to five different protein-ligand scoring functions, plus EON scoring using three different reference compounds. The results indicate that the choice of scoring function, even among scoring functions measuring the same types of interactions, can have an unexpectedly large effect on which compounds are chosen from screening. Furthermore, there was almost no overlap between the top-scoring compounds from protein-ligand versus ligand-based scoring, indicating the two approaches provide complementary information. Matchprint analysis, a new addition to the SLIDE (Screening Ligands by Induced-fit Docking, Efficiently) screening toolset, facilitated comparison of docked molecules' interactions with those of known inhibitors. The majority of interactions conserved among top-scoring compounds for a given scoring function, and from the different scoring functions, proved to be conserved interactions in known inhibitors. This was particularly true in the S1 pocket, which was occupied by all the docked compounds. (c) 2009 John Wiley & Sons, Ltd.

Out-of-pocket medical costs and third-party healthcare costs for children with Down syndrome.

PubMed

Kageleiry, Andrew; Samuelson, David; Duh, Mei Sheng; Lefebvre, Patrick; Campbell, John; Skotko, Brian G

2017-03-01

Prior analyses have estimated the lifetime total societal costs of a person with Down syndrome (DS); however, no studies capture the expected medical costs that patients with DS can expect to incur during childhood. The study utilized the OptumHealth Reporting and Insights administrative claims database from 1999 to 2013. Children with a diagnosis of DS were identified, and their time was divided into clinically relevant age categories. Patients with DS in each age category were matched to controls without chromosomal conditions. Out-of-pocket medical costs and third-party expenditures were compared between the patient-age cohorts with DS and matched controls. Patients with DS had significantly higher mean annual out-of-pocket costs than their matched controls within each age and cost category. Total annual incremental out-of-pocket costs associated with DS were highest among individuals from birth to age 1 ($1,907, P < 0.001). The main drivers of the incremental out-of-pocket costs associated with DS were inpatient costs in the 1st year of life ($925, P < 0.001) and outpatient costs in later years (ranging $183-$623, all P < 0.001). Overall, patients with DS incurred incremental out-of-pocket medical costs of $18,248 between birth and age 18 years; third-party payers incurred incremental costs of $230,043 during the same period. Across all age categories, mean total out-of-pocket annual costs were greater for individuals with DS than those of matched controls. On average, parents of children with DS pay an additional $84 per month for out-of-pocket medical expenses when costs are amortized over 18 years. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD.

PubMed

Beaumont, Hanneke; Bennink, Roelof J; de Jong, Jan; Boeckxstaens, Guy E

2010-04-01

Gastro-oesophageal reflux occurs twice as much during transient lower oesophageal sphincter relaxations (TLOSRs) in patients with gastro-oesophageal reflux disease (GORD) compared to healthy volunteers (HVs). Our aim was to assess whether the localisation of the postprandial acid pocket and its interaction with a hiatal hernia (HH) play a role in the occurrence of acidic reflux during TLOSRs. Ten HVs and 22 patients with GORD (12 with HH<3 cm (s-HH), 10 with HH > or =3 cm (l-HH)) were studied. The squamocolumnar junction and diaphragmatic impression were marked with a radioactively labelled clip. To visualise the acid pocket, (99m)Tc-pertechnetate was injected intravenously and images were acquired up to 2 h postprandial. Concurrently, combined manometry/impedance and four-channel pH-metry were performed, with pH pull-through at multiple time-points. The rate of TLOSRs and the per cent associated with reflux was comparable between all groups. However, acidic reflux was significantly increased in patients, especially in patients with l-HH. Acid pocket length was significantly enlarged in patients. Moreover, immediately before a TLOSR, the acid pocket was more frequently located within the hiatus or above the diaphragm in patients with GORD (s-HH, 54%; l-HH, 77%) compared to HVs (22% of TLOSRs). Acidic reflux was significantly increased when the acid pocket was located above the diaphragm in all groups compared to a sub-diaphragmatic localisation. The position of the acid pocket is largely determined by the presence of a HH. Entrapment of the pocket above the diaphragm, especially in patients with l-HH, is a major risk factor underlying the increased occurrence of acidic reflux during a TLOSR in patients with GORD.

Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators

PubMed Central

Moeder, Katelyn E.; Ho, Chris M. W.; Zimmerman, Maxwell I.; Frederick, Thomas E.; Bowman, Gregory R.

2017-01-01

Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered “undruggable” and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such “cryptic pockets,” and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity. Experimental tests validate our approach by revealing both an inhibitor and two activators of TEM β-lactamase (TEM). To identify hits, a library of compounds is first virtually screened against either the crystal structure of a known cryptic pocket or an ensemble of structures containing the same cryptic pocket that is extracted from an MSM. Hit compounds are then screened experimentally and characterized kinetically in individual assays. We identify three hits, one inhibitor and two activators, demonstrating that screening for binding to allosteric sites can result in both positive and negative modulation. The hit compounds have modest effects on TEM activity, but all have higher affinities than previously identified inhibitors, which bind the same cryptic pocket but were found, by chance, via a computational screen targeting the active site. Site-directed mutagenesis of key contact residues predicted by the docking models is used to confirm that the compounds bind in the cryptic pocket as intended. Because hit compounds are identified from docking against both the crystal structure and structures from the MSM, this platform should prove suitable for many proteins, particularly targets whose crystal structures lack obvious druggable pockets, and for identifying both inhibitory and activating small-molecule modulators. PMID:28570708

Clinical and microbiological evaluation of biofilm-gingival interface classification in patients with generalized forms of periodontitis.

PubMed

Kowalski, Jan; Górska, Renata

2014-01-01

In 2008 a new division of periodontal diseases based on the concept of biofilm-gingival interface (BGI), was presented. The aim of this study was to assess whether the proposed BGI categories could be useful in diagnosing patients with generalized forms of both aggressive (gAP) and chronic (gCP) periodontitis. DESIGN AND KEY METHODS: The study group consisted of 40 individuals (17 with gAP and 23 with gCP). All patients were divided into three groups according to the BGI scale: 4 patients with P1 (pockets deeper than 4 mms with bleeding index below 10%), 20 individuals with P2 (pockets deeper than 4 mms with bleeding index 10-50%) and 16 individuals with P3 (pockets deeper than 4 mms with bleeding index above 50%). The presence of bacteria in subgingival plaque was analyzed using the polymerase chain reaction method. Statistically significant differences with respect to all parameters measured were found when patients were grouped according to the BGI scale--they were higher in P3 group. In gAP group A. actinomycetemcomitans and C. rectus were found in a higher numbers. No such differences were observed between P2 and P3 groups. The BGI scale seems to be helpful in effective and quick classifying of patients into adequate clinical subgroups.

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

Interfaces and hydrophobic interactions in receptor-ligand systems: A level-set variational implicit solvent approach.

PubMed

Cheng, Li-Tien; Wang, Zhongming; Setny, Piotr; Dzubiella, Joachim; Li, Bo; McCammon, J Andrew

2009-10-14

A model nanometer-sized hydrophobic receptor-ligand system in aqueous solution is studied by the recently developed level-set variational implicit solvent model (VISM). This approach is compared to all-atom computer simulations. The simulations reveal complex hydration effects within the (concave) receptor pocket, sensitive to the distance of the (convex) approaching ligand. The ligand induces and controls an intermittent switching between dry and wet states of the hosting pocket, which determines the range and magnitude of the pocket-ligand attraction. In the level-set VISM, a geometric free-energy functional of all possible solute-solvent interfaces coupled to the local dispersion potential is minimized numerically. This approach captures the distinct metastable states that correspond to topologically different solute-solvent interfaces, and thereby reproduces the bimodal hydration behavior observed in the all-atom simulation. Geometrical singularities formed during the interface relaxation are found to contribute significantly to the energy barrier between different metastable states. While the hydration phenomena can thus be explained by capillary effects, the explicit inclusion of dispersion and curvature corrections seems to be essential for a quantitative description of hydrophobically confined systems on nanoscales. This study may shed more light onto the tight connection between geometric and energetic aspects of biomolecular hydration and may represent a valuable step toward the proper interpretation of experimental receptor-ligand binding rates.

A novel single-step surgical technique for vestibular deepening using laser in conjunction with periodontal flap surgery

PubMed Central

Bhardwaj, Ashu; Sultan, Nishat; Sawai, Madhuri; Jafri, Zeba

2016-01-01

Moderate-to-severe chronic periodontitis results in clinical loss of attachment, reduced width of attached gingiva (AG), periodontal pockets beyond mucogingival junction (MGJ), gingival recession, loss of alveolar bone, and decreased vestibular depth (VD). The encroachment of frenal and muscle attachments on marginal gingiva increases the rate of progression of periodontal pockets, prevents healing, and causes their recurrence after therapy. Loss of VD and AG associated with continuous progression of pocket formation and bone loss requires two-stage surgical procedures. In this article, one-stage surgical procedure is being described for the first time, to treat the periodontal pockets extending beyond the MGJ by periodontal flap surgery along with vestibular deepening with diode laser to increase the AG. One-step surgical technique is illustrated whereby pocket therapy with reconstruction of lost periodontal tissues can be done along with gingival augmentation by vestibular deepening. PMID:29238149

Complex home care: Part 2- family annual income, insurance premium, and out-of-pocket expenses.

PubMed

Piamjariyakul, Ubolrat; Yadrich, Donna Macan; Ross, Vicki M; Smith, Carol E; Clements, Faye; Williams, Arthur R

2010-01-01

Annual costs paid by families for intravenous infusion of home parenteral nutrition (HPN) health insurance premiums, deductibles, co-payments for health services, and the wide range of out-of-pocket home health care expenses are significant. The costs of managing complex chronic care at home cannot be completely understood until all out-of-pocket costs have been defined, described, and tabulated. Non-reimbursed and out-of-pocket costs paid by families over years for complex chronic care negatively impact the financial stability of families. National health care reform must take into account the long-term financial burdens of families caring for those with complex home care. Any changes that may increase the out-of-pocket costs or health insurance costs to these families can also have a negative long-term impact on society when greater numbers of patients declare bankruptcy or qualify for medical disability.

Surgical management of retraction pockets of the pars tensa with cartilage and perichondrial grafts.

PubMed

Spielmann, P; Mills, R

2006-09-01

Stable, self-cleansing retraction pockets of the pars tensa are common incidental findings and require no treatment. In other cases, recurrent discharge occurs and there may also be associated conductive hearing loss. In a minority of cases, cholesteatoma may develop. This paper presents the results of surgery using a graft composed of cartilage and perichondrium for retraction pockets involving the posterior half of the tympanic membrane, as well as early results using a larger graft designed to manage retraction of the entire tympanic membrane. Data on 51 patients with posterior retraction pockets are presented. Forty-two (82 per cent) patients had no aural discharge one year following surgery and the tympanic membrane was not retracted in 43 (84 per cent). The larger 'Mercedes-Benz' graft was used in four patients and the results obtained suggested that it may prove a successful technique for extensive retraction pockets.

The effect of EDTA in attachment gain and root coverage.

PubMed

Kassab, Moawia M; Cohen, Robert E; Andreana, Sebastiano; Dentino, Andrew R

2006-06-01

Root surface biomodification using low pH agents such as citric acid and tetracycline has been proposed to enhance root coverage following connective tissue grafting. The authors hypothesized that root conditioning with neutral pH edetic acid would improve vertical recession depth, root surface coverage, pocket depth, and clinical attachment levels. Twenty teeth in 10 patients with Miller class I and II recession were treated with connective tissue grafting. The experimental sites received 24% edetic acid in sterile distilled water applied to the root surface for 2 minutes before grafting. Controls were pretreated with only sterile distilled water. Measurements were evaluated before surgery and 6 months after surgery. Analysis of variance was used to determine differences between experimental and control groups. We found significant postoperative improvements in vertical recession depth, root surface coverage, and clinical attachment levels in test and control groups, compared to postoperative data. Pocket depth differences were not significant (P<.01).

Proton electron nuclear double resonance from nitrosyl horse heart myoglobin: the role of His-E7 and Val-E11.

PubMed Central

Flores, M; Wajnberg, E; Bemski, G

2000-01-01

Electron nuclear double resonance (ENDOR) spectroscopy has been used to study protons in nitrosyl horse heart myoglobin (MbNO). (1)H ENDOR spectra were recorded for different settings of the magnetic field. Detailed analysis of the ENDOR powder spectra, using computer simulation, based on the "orientation-selection" principle, leads to the identification of the available protons in the heme pocket. We observe hyperfine interactions of the N(HisF8)-Fe(2+)-N(NO) complex with five protons in axial and with eight protons in the rhombic symmetry along different orientations, including those of the principal axes of the g-tensor. Protons from His-E7 and Val-E11 residues are identified in the two symmetries, rhombic and axial, exhibited by MbNO. Our results indicate that both residues are present inside the heme pocket and help to stabilize one particular conformation. PMID:10733988

Older women's health and financial vulnerability: implications of the Medicare benefit structure.

PubMed

Sofaer, S; Abel, E

1990-01-01

Elderly women and men have different patterns of disease and utilize health services differently. This essay examines the extent to which Medicare covers the specific conditions and services associated with women and men. Elderly women experience higher rates of poverty than elderly men; consequently, elderly women are especially likely to be unable to pay high out-of-pocket costs for health care. Using a new method for simulating out-of-pocket costs, the Illness Episode Approach, the essay shows that Medicare provides better coverage for illnesses which predominate among men than for those which predominate among women. In addition, women on Medicare who supplement their basic coverage by purchasing a typical private insurance "Medigap" policy do not receive as much of an advantage from their purchases as do men. The calculations also show that the Medicare Catastrophic Coverage Act would have had little impact on the gender gap in financial vulnerability.

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

Chien, Ellen Y.T.; Liu, Wei; Zhao, Qiang

Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differsmore » between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.« less

GALACTIC CHEMICAL EVOLUTION: THE IMPACT OF THE {sup 13}C-POCKET STRUCTURE ON THE s -PROCESS DISTRIBUTION

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

Bisterzo, S.; Travaglio, C.; Wiescher, M.

2017-01-20

The solar s -process abundances have been analyzed in the framework of a Galactic Chemical Evolution (GCE) model. The aim of this work is to implement the study by Bisterzo et al., who investigated the effect of one of the major uncertainties of asymptotic giant branch (AGB) yields, the internal structure of the {sup 13}C pocket. We present GCE predictions of s -process elements computed with additional tests in the light of suggestions provided in recent publications. The analysis is extended to different metallicities, by comparing GCE results and updated spectroscopic observations of unevolved field stars. We verify that themore » GCE predictions obtained with different tests may represent, on average, the evolution of selected neutron-capture elements in the Galaxy. The impact of an additional weak s -process contribution from fast-rotating massive stars is also explored.« less

Towards Humanlike Social Touch for Prosthetics and Sociable Robotics: Three-Dimensional Finite Element Simulations of Synthetic Finger Phalanges

NASA Astrophysics Data System (ADS)

Cabibihan, John-John; Ge, Shuzhi Sam

Synthetic skins with humanlike characteristic would make it possible to address some of the psychosocial requirements of prosthetic hands as well as the safety and acceptance issues in social robotics. This paper describes the development of three-dimensional finite element models of synthetic finger phalanges. With the aim of duplicating the skin compliance of human finger phalanges, the model was used to investigate the effects of (i) introducing open pockets in the internal structure and (ii) combining different materials as external and internal layers. The results show that having pockets in the internal structure of the design can increase the skin compliance of the synthetic phalanges and make it comparable with the human counterpart. Moreover, having different layers can be used to satisfy skin compliance and other design requirements such as wear and tear.

Household portfolio choices, health status and health care systems: A cross-country analysis based on SHARE.

PubMed

Atella, Vincenzo; Brunetti, Marianna; Maestas, Nicole

2012-05-01

Health risk is increasingly viewed as an important form of background risk that affects household portfolio decisions. However, its role might be mediated by the presence of a protective full-coverage national health service that could reduce households' probability of incurring current and future out-of-pocket medical expenditures. We use SHARE data to study the influence of current health status and future health risk on the decision to hold risky assets, across ten European countries with different health systems, each offering a different degree of protection against out-of-pocket medical expenditures. We find robust empirical evidence that perceived health status matters more than objective health status and, consistent with the theory of background risk, health risk affects portfolio choices only in countries with less protective health care systems. Furthermore, portfolio decisions consistent with background risk models are observed only with respect to middle-aged and highly-educated investors.

Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments

NASA Astrophysics Data System (ADS)

Stornaiuolo, Mariano; Bruno, Agostino; Botta, Lorenzo; Regina, Giuseppe La; Cosconati, Sandro; Silvestri, Romano; Marinelli, Luciana; Novellino, Ettore

2015-10-01

A Cannabinoid Receptor 1 (CB1) binding site for the selective allosteric modulator ORG27569 is here identified through an integrate approach of consensus pocket prediction, mutagenesis studies and Mass Spectrometry. This unprecedented ORG27569 pocket presents the structural features of a Cholesterol Consensus Motif, a cholesterol interacting region already found in other GPCRs. ORG27569 and cholesterol affects oppositely CB1 affinity for orthosteric ligands. Moreover, the rise in cholesterol intracellular level results in CB1 trafficking to the axonal region of neuronal cells, while, on the contrary, ORG27568 binding induces CB1 enrichment at the soma. This control of receptor migration among functionally different membrane regions of the cell further contributes to downstream signalling and adds a previously unknown mechanism underpinning CB1 modulation by ORG27569 , that goes beyond a mere control of receptor affinity for orthosteric ligands.

Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease.

PubMed

Rohof, Wout O; Bennink, Roelof J; de Jonge, Hugo; Boeckxstaens, Guy E

2014-10-01

Approximately 30% of patients with gastroesophageal reflux disease have symptoms resistant to treatment with proton pump inhibitors (PPIs). Several mechanisms such as esophageal hypersensitivity, increased mucosal permeability, and possibly the position of the gastric acid pocket might underlie a partial response to PPIs. To what extent these mechanisms interact and contribute to PPI-resistant symptoms, however, has not been investigated previously. In 18 gastroesophageal reflux disease patients (9 PPI responders and 9 PPI partial responders), esophageal sensitivity, mucosal permeability, and postprandial reflux parameters were determined during PPI use. Esophageal sensitivity for distension was measured by gradual balloon inflation at 5 and 15 cm above the lower esophageal sphincter. The mucosal permeability of 4 esophageal biopsy specimens per patient was determined in Ussing chambers by measuring the transepithelial electrical resistance and transmucosal flux of fluorescein. Postprandial reflux parameters were determined using concurrent high-resolution manometry/pH impedance after a standardized meal. In addition, the acid pocket was visualized using scintigraphy. No difference in the rate of postprandial acid reflux, in the pH of the acid pocket (PPI responders 3.7 ± 0.7 vs PPI partial responders 4.2 ± 0.4; P = .54), or in the position of the acid pocket was observed in PPI partial responders compared with PPI responders. In addition, the permeability of the esophageal mucosa was similar in both groups, as shown by a similar transepithelial electrical resistance and flux of fluorescein. PPI partial responders had more reflux episodes with a higher mean proximal extent, compared with PPI responders, and were more sensitive to balloon distension, both in the upper and lower esophagus. PPI-resistant symptoms most likely are explained by increased proximal reflux in a hypersensitive esophagus and less likely by increased mucosal permeability or the position of the acid pocket. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Apolar Distal Pocket Mutants of Yeast Cytochrome c Peroxidase: Hydrogen Peroxide Reactivity and Cyanide Binding of the TriAla, TriVal, and TriLeu Variants

PubMed Central

Bidwai, Anil K.; Meyen, Cassandra; Kilheeney, Heather; Wroblewski, Damian; Vitello, Lidia B.; Erman, James E.

2012-01-01

Three yeast cytochrome c peroxidase (CcP) variants with apolar distal heme pockets have been constructed. The CcP variants have Arg48, Trp51, and His52 mutated to either all alanines, CcP(triAla), all valines, CcP(triVal), or all leucines, CcP(triLeu). The triple mutants have detectable enzymatic activity at pH 6 but the activity is less than 0.02% that of wild-type CcP. The activity loss is primarily due to the decreased rate of reaction between the triple mutants and H2O2 compared to wild-type CcP. Spectroscopic properties and cyanide binding characteristics of the triple mutants have been investigated over the pH stability region of CcP, pH 4 to 8. The absorption spectra indicate that the CcP triple mutants have hemes that are predominantly five-coordinate, high-spin at pH 5 and six-coordinate, low-spin at pH 8. Cyanide binding to the triple mutants is biphasic indicating that the triple mutants have two slowly-exchanging conformational states with different cyanide affinities. The binding affinity for cyanide is reduced at least two orders of magnitude in the triple mutants compared to wild-type CcP and the rate of cyanide binding is reduced by four to five orders of magnitude. Correlation of the reaction rates of CcP and 12 distal pocket mutants with H2O2 and HCN suggests that both reactions require ionization of the reactants within the distal heme pocket allowing the anion to bind the heme iron. Distal pocket features that promote substrate ionization (basic residues involved in base-catalyzed substrate ionization or polar residues that can stabilize substrate anions) increase the overall rate of reaction with H2O2 and HCN while features that inhibit substrate ionization slow the reactions. PMID:23022490

G protein-coupled receptor transmembrane binding pockets and their applications in GPCR research and drug discovery: a survey.

PubMed

Kratochwil, Nicole A; Gatti-McArthur, Silvia; Hoener, Marius C; Lindemann, Lothar; Christ, Andreas D; Green, Luke G; Guba, Wolfgang; Martin, Rainer E; Malherbe, Pari; Porter, Richard H P; Slack, Jay P; Winnig, Marcel; Dehmlow, Henrietta; Grether, Uwe; Hertel, Cornelia; Narquizian, Robert; Panousis, Constantinos G; Kolczewski, Sabine; Steward, Lucinda

2011-01-01

G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor. © 2011 Bentham Science Publishers

Government health insurance for people below poverty line in India: quasi-experimental evaluation of insurance and health outcomes.

PubMed

Sood, Neeraj; Bendavid, Eran; Mukherji, Arnab; Wagner, Zachary; Nagpal, Somil; Mullen, Patrick

2014-09-11

To evaluate the effects of a government insurance program covering tertiary care for people below the poverty line in Karnataka, India, on out-of-pocket expenditures, hospital use, and mortality. Geographic regression discontinuity study. 572 villages in Karnataka, India. 31,476 households (22,796 below poverty line and 8680 above poverty line) in 300 villages where the scheme was implemented and 28,633 households (21,767 below poverty line and 6866 above poverty line) in 272 neighboring matched villages ineligible for the scheme. A government insurance program (Vajpayee Arogyashree scheme) that provided free tertiary care to households below the poverty line in about half of villages in Karnataka from February 2010 to August 2012. Out-of-pocket expenditures, hospital use, and mortality. Among households below the poverty line, the mortality rate from conditions potentially responsive to services covered by the scheme (mostly cardiac conditions and cancer) was 0.32% in households eligible for the scheme compared with 0.90% among ineligible households just south of the eligibility border (difference of 0.58 percentage points, 95% confidence interval 0.40 to 0.75; P<0.001). We found no difference in mortality rates for households above the poverty line (households above the poverty line were not eligible for the scheme), with a mortality rate from conditions covered by the scheme of 0.56% in eligible villages compared with 0.55% in ineligible villages (difference of 0.01 percentage points, -0.03 to 0.03; P=0.95). Eligible households had significantly reduced out-of-pocket health expenditures for admissions to hospitals with tertiary care facilities likely to be covered by the scheme (64% reduction, 35% to 97%; P<0.001). There was no significant increase in use of covered services, although the point estimate of a 44.2% increase approached significance (-5.1% to 90.5%; P=0.059). Both reductions in out-of-pocket expenditures and potential increases in use might have contributed to the observed reductions in mortality. Insuring poor households for efficacious but costly and underused health services significantly improves population health in India. © Sood et al 2014.

Race/ethnicity and economic differences in cost-related medication underuse among insured adults with diabetes: the Translating Research Into Action for Diabetes Study.

PubMed

Tseng, Chien-Wen; Tierney, Edward F; Gerzoff, Robert B; Dudley, R Adams; Waitzfelder, Beth; Ackermann, Ronald T; Karter, Andrew J; Piette, John; Crosson, Jesse C; Ngo-Metzger, Quyen; Chung, Richard; Mangione, Carol M

2008-02-01

To examine racial/ethnic and economic variation in cost-related medication underuse among insured adults with diabetes. We surveyed 5,086 participants from the multicenter Translating Research Into Action for Diabetes Study. Respondents reported whether they used less medication because of cost in the past 12 months. We examined unadjusted and adjusted rates of cost-related medication underuse, using hierarchical regression, to determine whether race/ethnicity differences still existed after accounting for economic, health, and other demographic variables. Participants were 48% white, 14% African American, 14% Latino, 15% Asian/Pacific Islander, and 8% other. Overall, 14% reported cost-related medication underuse. Unadjusted rates were highest for Latinos (23%) and African Americans (17%) compared with whites (13%), Asian/Pacific Islanders (11%), and others (15%). In multivariate analyses, race/ethnicity significantly predicted cost-related medication underuse (P = 0.048). However, adjusted rates were only slightly higher for Latinos (14%) than whites (10%) (P = 0.026) and were not significantly different for African Americans (11%), Asian/Pacific Islanders (7%), and others (11%). Income and out-of-pocket drug costs showed the greatest differences in adjusted rates of cost-related medication underuse (15 vs. 5% for participants with income $50,000 and 24 vs. 7% for participants with out-of-pocket costs >$150 per month vs.

78 FR 54214 - Endangered and Threatened Wildlife and Plants; Removing Five Subspecies of Mazama Pocket Gopher...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-03

... section 3 of the Act, an endangered species is any species which is in danger of extinction throughout all... populations, do not occur elsewhere. Our Response: The presumption of extinction for the Tacoma pocket gopher... contrast to our presumption of extinction for the Tacoma pocket gopher, which is based on evidence from...

Iranian Households’ Payments on Food and Health Out-of-Pocket Expenditures: Evidence of Inequality

PubMed Central

GHIASVAND, Hesam; NAGHDI, Seyran; ABOLHASSANI, Nazanin; SHAARBAFCHIZADEH, Nasrin; MOGHRI, Javad

2015-01-01

Background: Inequality in households’ payments on food and health expenditures presents the accessibility and utilization patterns between them. This study investigated the Iranian rural and urban households’ inequality in payments on food and Out-of-Pocket health expenditures from 1998 to 2012. Methods: This descriptive study was conducted through the analysis of Iranian Statistics Centre data on Iranian households’ income and expenditures. The Gini Coefficients, Concentration and Kakwani indices have been calculated for Iranian rural and urban households’ Out-of-Pocket health and food expenditures. Results: The means of Iranian rural and urban total consumption expenditures inequality were 0.48 and 0.48, respectively. The means of concentration index of food expenditures for rural and urban regions were 0.35 and 0.34, respectively. The means of Out-of-Pocket payments for health services for rural and urban regions were 0.51 and 0.5, respectively. Finally the means of Kakwani index of Out-of-Pocket health payments in rural and urban households were −0.005 and −0.018, respectively. Conclusion: There are relative high levels of inequality in Iranian households’ payments on food and Out-of-Pocket health expenditures. PMID:26587474

Women Saw Large Decrease In Out-Of-Pocket Spending For Contraceptives After ACA Mandate Removed Cost Sharing.

PubMed

Becker, Nora V; Polsky, Daniel

2015-07-01

The Affordable Care Act mandates that private health insurance plans cover prescription contraceptives with no consumer cost sharing. The positive financial impact of this new provision on consumers who purchase contraceptives could be substantial, but it has not yet been estimated. Using a large administrative claims data set from a national insurer, we estimated out-of-pocket spending before and after the mandate. We found that mean and median per prescription out-of-pocket expenses have decreased for almost all reversible contraceptive methods on the market. The average percentages of out-of-pocket spending for oral contraceptive pill prescriptions and intrauterine device insertions by women using those methods both dropped by 20 percentage points after implementation of the ACA mandate. We estimated average out-of-pocket savings per contraceptive user to be $248 for the intrauterine device and $255 annually for the oral contraceptive pill. Our results suggest that the mandate has led to large reductions in total out-of-pocket spending on contraceptives and that these price changes are likely to be salient for women with private health insurance. Project HOPE—The People-to-People Health Foundation, Inc.

Medicare Advantage Members' Expected Out-Of-Pocket Spending For Inpatient And Skilled Nursing Facility Services.

PubMed

Keohane, Laura M; Grebla, Regina C; Mor, Vincent; Trivedi, Amal N

2015-06-01

Inpatient and skilled nursing facility (SNF) cost sharing in Medicare Advantage (MA) plans may reduce unnecessary use of these services. However, large out-of-pocket expenses potentially limit access to care and encourage beneficiaries at high risk of needing inpatient and postacute care to avoid or leave MA plans. In 2011 new federal regulations restricted inpatient and skilled nursing facility cost sharing and mandated limits on out-of-pocket spending in MA plans. After these regulations, MA members in plans with low premiums averaged $1,758 in expected out-of-pocket spending for an episode of seven hospital days and twenty skilled nursing facility days. Among members with the same low-premium plan in 2010 and 2011, 36 percent of members belonged to plans that added an out-of-pocket spending limit in 2011. However, these members also had a $293 increase in average cost sharing for an inpatient and skilled nursing facility episode, possibly to offset plans' expenses in financing out-of-pocket limits. Some MA beneficiaries may still have difficulty affording acute and postacute care despite greater regulation of cost sharing. Project HOPE—The People-to-People Health Foundation, Inc.

Medicare Advantage Members’ Expected Out-Of-Pocket Spending For Inpatient And Skilled Nursing Facility Services

PubMed Central

Keohane, Laura M.; Grebla, Regina C.; Mor, Vincent; Trivedi, Amal N.

2015-01-01

Inpatient and skilled nursing facility (SNF) cost sharing in Medicare Advantage (MA) plans may reduce unnecessary use of these services. However, large out-of-pocket expenses potentially limit access to care and encourage beneficiaries at high risk of needing inpatient and postacute care to avoid or leave MA plans. In 2011 new federal regulations restricted inpatient and skilled nursing facility cost sharing and mandated limits on out-of-pocket spending in MA plans. After these regulations, MA members in plans with low premiums averaged $1,758 in expected out-of-pocket spending for an episode of seven hospital days and twenty skilled nursing facility days. Among members with the same low-premium plan in 2010 and 2011, 36 percent of members belonged to plans that added an out-of-pocket spending limit in 2011. However, these members also had a $293 increase in average cost sharing for an inpatient and skilled nursing facility episode, possibly to offset plans’ expenses in financing out-of-pocket limits. Some MA beneficiaries may still have difficulty affording acute and postacute care despite greater regulation of cost sharing. PMID:26056208

AlloPred: prediction of allosteric pockets on proteins using normal mode perturbation analysis.

PubMed

Greener, Joe G; Sternberg, Michael J E

2015-10-23

Despite being hugely important in biological processes, allostery is poorly understood and no universal mechanism has been discovered. Allosteric drugs are a largely unexplored prospect with many potential advantages over orthosteric drugs. Computational methods to predict allosteric sites on proteins are needed to aid the discovery of allosteric drugs, as well as to advance our fundamental understanding of allostery. AlloPred, a novel method to predict allosteric pockets on proteins, was developed. AlloPred uses perturbation of normal modes alongside pocket descriptors in a machine learning approach that ranks the pockets on a protein. AlloPred ranked an allosteric pocket top for 23 out of 40 known allosteric proteins, showing comparable and complementary performance to two existing methods. In 28 of 40 cases an allosteric pocket was ranked first or second. The AlloPred web server, freely available at http://www.sbg.bio.ic.ac.uk/allopred/home, allows visualisation and analysis of predictions. The source code and dataset information are also available from this site. Perturbation of normal modes can enhance our ability to predict allosteric sites on proteins. Computational methods such as AlloPred assist drug discovery efforts by suggesting sites on proteins for further experimental study.

Enceladus' near-surface CO2 gas pockets and surface frost deposits

NASA Astrophysics Data System (ADS)

Matson, Dennis L.; Davies, Ashley Gerard; Johnson, Torrence V.; Combe, Jean-Philippe; McCord, Thomas B.; Radebaugh, Jani; Singh, Sandeep

2018-03-01

Solid CO2 surface deposits were reported in Enceladus' South Polar Region by Brown et al. (2006). They noted that such volatile deposits are temporary and posited ongoing replenishment. We present a model for this replenishment by expanding on the Matson et al. (2012) model of subsurface heat and chemical transport in Enceladus. Our model explains the distributions of both CO2 frost and complexed CO2 clathrate hydrate as seen in the Cassini Visual and Infrared Mapping Spectrometer (VIMS) data. We trace the journey of CO2 from a subsurface ocean. The ocean-water circulation model of Matson et al. (2012) brings water up to near the surface where gas exsolves to form bubbles. Some of the CO2 bubbles are trapped and form pockets of gas in recesses at the bottom of the uppermost ice layer. When fissures break open these pockets, the CO2 gas is vented. Gas pocket venting is episodic compared to the more or less continuous eruptive plumes, emanating from the "tiger stripes", that are supported by plume chambers. Two styles of gas pocket venting are considered: (1) seeps, and (2) blowouts. The presence of CO2 frost patches suggests that the pocket gas slowly seeped through fractured, cold ice and when some of the gas reached the surface it was cold enough to condense (i.e., T ∼70 to ∼119 K). If the fissure opening is large, a blowout occurs. The rapid escape of gas and drop in pocket pressure causes water in the pocket to boil and create many small aerosol droplets of seawater. These may be carried along by the erupting gas. Electrically charged droplets can couple to the magnetosphere, and be dragged away from Enceladus. Most of the CO2 blowout gas escapes from Enceladus and the remainder is distributed globally. However, CO2 trapped in a clathrate structure does not escape. It is much heavier and slower moving than the CO2 gas. Its motion is ballistic and has an average range of about 17 km. Thus, it contributes to deposits in the vicinity of the vent. Local heat flow indicates that gas pockets can be located as deep as several tens of meters below the surface. Gas pockets can be reused, and we explore their life cycle.

Out-of-Pocket and Health Care Spending Changes for Patients Using Orally Administered Anticancer Therapy After Adoption of State Parity Laws.

PubMed

Dusetzina, Stacie B; Huskamp, Haiden A; Winn, Aaron N; Basch, Ethan; Keating, Nancy L

2017-11-09

Oral anticancer medications are increasingly important but costly treatment options for patients with cancer. By early 2017, 43 states and Washington, DC, had passed laws to ensure patients with private insurance enrolled in fully insured health plans pay no more for anticancer medications administered by mouth than anticancer medications administered by infusion. Federal legislation regarding this issue is currently pending. Despite their rapid acceptance, the changes associated with state adoption of oral chemotherapy parity laws have not been described. To estimate changes in oral anticancer medication use, out-of-pocket spending, and health plan spending associated with oral chemotherapy parity law adoption. Analysis of administrative health plan claims data from 2008-2012 for 3 large nationwide insurers aggregated by the Health Care Cost Institute. Data analysis was first completed in 2015 and updated in 2017. The study population included 63 780 adults living in 1 of 16 states that passed parity laws during the study period and who received anticancer drug treatment for which orally administered treatment options were available. Study analysis used a difference-in-differences approach. Time period before and after adoption of state parity laws, controlling for whether the patient was enrolled in a plan subject to parity (fully insured) or not (self-funded, exempt via the Employee Retirement Income Security Act). Oral anticancer medication use, out-of-pocket spending, and total health care spending. Of the 63 780 adults aged 18 through 64 years, 51.4% participated in fully insured plans and 48.6% in self-funded plans (57.2% were women; 76.8% were aged 45 to 64 years). The use of oral anticancer medication treatment as a proportion of all anticancer treatment increased from 18% to 22% (adjusted difference-in-differences risk ratio [aDDRR], 1.04; 95% CI, 0.96-1.13; P = .34) comparing months before vs after parity. In plans subject to parity laws, the proportion of prescription fills for orally administered therapy without copayment increased from 15.0% to 53.0%, more than double the increase (12.3%-18.0%) in plans not subject to parity (P < .001). The proportion of patients with out-of-pocket spending of more than $100 per month increased from 8.4% to 11.1% compared with a slight decline from 12.0% to 11.7% in plans not subject to parity (P = .004). In plans subject to parity laws, estimated monthly out-of-pocket spending decreased by $19.44 at the 25th percentile, by $32.13 at the 50th percentile, and by $10.83 at the 75th percentile but increased at the 90th ($37.19) and 95th ($143.25) percentiles after parity (all P < .001, controlling for changes in plans not subject to parity). Parity laws did not increase 6-month total spending for users of any anticancer therapy or for users of oral anticancer therapy alone. While oral chemotherapy parity laws modestly improved financial protection for many patients without increasing total health care spending, these laws alone may be insufficient to ensure that patients are protected from high out-of-pocket medication costs.

Impact of full mental health and substance abuse parity for children in the Federal Employees Health Benefits Program.

PubMed

Azrin, Susan T; Huskamp, Haiden A; Azzone, Vanessa; Goldman, Howard H; Frank, Richard G; Burnam, M Audrey; Normand, Sharon-Lise T; Ridgely, M Susan; Young, Alexander S; Barry, Colleen L; Busch, Alisa B; Moran, Garrett

2007-02-01

The Federal Employees Health Benefits Program implemented full mental health and substance abuse parity in January 2001. Evaluation of this policy revealed that parity increased adult beneficiaries' financial protection by lowering mental health and substance abuse out-of-pocket costs for service users in most plans studied but did not increase rates of service use or spending among adult service users. This study examined the effects of full mental health and substance abuse parity for children. Employing a quasiexperimental design, we compared children in 7 Federal Employees Health Benefits plans from 1999 to 2002 with children in a matched set of plans that did not have a comparable change in mental health and substance abuse coverage. Using a difference-in-differences analysis, we examined the likelihood of child mental health and substance abuse service use, total spending among child service users, and out-of-pocket spending. The apparent increase in the rate of children's mental health and substance abuse service use after implementation of parity was almost entirely due to secular trends of increased service utilization. Estimates for children's mental health and substance abuse spending conditional on this service use showed significant decreases in spending per user attributable to parity for 2 plans; spending estimates for the other plans were not statistically significant. Children using these services in 3 of 7 plans experienced statistically significant reductions in out-of-pocket spending attributable to the parity policy, and the average dollar savings was sizeable for users in those 3 plans. In the remaining 4 plans, out-of-pocket spending also decreased, but these decreases were not statistically significant. Full mental health and substance abuse parity for children, within the context of managed care, can achieve equivalence of benefits in health insurance coverage and improve financial protection without adversely affecting health care costs but may not expand access for children who need these services.

Health financing for the poor produces promising short-term effects on utilization and out-of-pocket expenditure: evidence from Vietnam

PubMed Central

Axelson, Henrik; Bales, Sarah; Minh, Pham Duc; Ekman, Björn; Gerdtham, Ulf-G

2009-01-01

Background Vietnam introduced the Health Care Fund for the Poor in 2002 to increase access to health care and reduce the financial burden of health expenditure faced by the poor and ethnic minorities. It is often argued that effects of financing reforms take a long time to materialize. This study evaluates the short-term impact of the program to determine if pro-poor financing programs can achieve immediate effects on health care utilization and out-of-pocket expenditure. Method Considering that the program is a non-random policy initiative rolled out nationally, we apply propensity score matching with both single differences and double differences to data from the Vietnam Household Living Standards Surveys 2002 (pre-program data) and 2004 (first post-program data). Results We find a small, positive impact on overall health care utilization. We find evidence of two substitution effects: from private to public providers and from primary to secondary and tertiary level care. Finally, we find a strong negative impact on out-of-pocket health expenditure. Conclusion The results indicate that the Health Care Fund for the Poor is meeting its objectives of increasing utilization and reducing out-of-pocket expenditure for the program's target population, despite numerous administrative problems resulting in delayed and only partial implementation in most provinces. The main lessons for low and middle-income countries from Vietnam's early experiences with the Health Care Fund for the Poor are that it managed to achieve positive outcomes in a short time-period, the need to ensure adequate and sustained funding for targeted programs, including marginal administrative costs, develop effective targeting mechanisms and systems for informing beneficiaries and providers about the program, respond to the increased demand for health care generated by the program, address indirect costs of health care utilization, and establish and maintain routine and systematic monitoring and evaluation mechanisms. PMID:19473518

Substrate Specificity of Cysteine Proteases Beyond the S2 Pocket: Mutagenesis and Molecular Dynamics Investigation of Fasciola hepatica Cathepsins L

PubMed Central

Corvo, Ileana; Ferraro, Florencia; Merlino, Alicia; Zuberbühler, Kathrin; O'Donoghue, Anthony J.; Pastro, Lucía; Pi-Denis, Natalia; Basika, Tatiana; Roche, Leda; McKerrow, James H.; Craik, Charles S.; Caffrey, Conor R.; Tort, José F.

2018-01-01

Cysteine proteases are widespread in all life kingdoms, being central to diverse physiological processes based on a broad range of substrate specificity. Paralogous Fasciola hepatica cathepsin L proteases are essential to parasite invasion, tissue migration and reproduction. In spite of similarities in their overall sequence and structure, these enzymes often exhibit different substrate specificity. These preferences are principally determined by the amino acid composition of the active site's S2 subsite (pocket) of the enzyme that interacts with the substrate P2 residue (Schetcher and Berger nomenclature). Although secreted FhCL1 accommodates aliphatic residues in the S2 pocket, FhCL2 is also efficient in cleaving proline in that position. To understand these differences, we engineered the FhCL1 S2 subsite at three amino acid positions to render it identical to that present in FhCL2. The substitutions did not produce the expected increment in proline accommodation in P2. Rather, they decreased the enzyme's catalytic efficiency toward synthetic peptides. Nonetheless, a change in the P3 specificity was associated with the mutation of Leu67 to Tyr, a hinge residue between the S2 and S3 subsites that contributes to the accommodation of Gly in S3. Molecular dynamic simulations highlighted changes in the spatial distribution and secondary structure of the S2 and S3 pockets of the mutant FhCL1 enzymes. The reduced affinity and catalytic efficiency of the mutant enzymes may be due to a narrowing of the active site cleft that hinders the accommodation of substrates. Because the variations in the enzymatic activity measured could not be exclusively allocated to those residues lining the active site, other more external positions might modulate enzyme conformation, and, therefore, catalytic activity. PMID:29725596

Novel quinolone chalcones targeting colchicine-binding pocket kill multidrug-resistant cancer cells by inhibiting tubulin activity and MRP1 function.

PubMed

Lindamulage, I Kalhari; Vu, Hai-Yen; Karthikeyan, Chandrabose; Knockleby, James; Lee, Yi-Fang; Trivedi, Piyush; Lee, Hoyun

2017-08-31

Agents targeting colchicine-binding pocket usually show a minimal drug-resistance issue, albeit often associated with high toxicity. Chalcone-based compounds, which may bind to colchicine-binding site, are found in many edible fruits, suggesting that they can be effective drugs with less toxicity. Therefore, we synthesized and examined 24 quinolone chalcone compounds, from which we identified ((E)-3-(3-(2-Methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-17) and ((E)-6-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-20) as promising leads. In particular, CTR-20 was effective against 65 different cancer cell lines originated from 12 different tissues, largely in a cancer cell-specific manner. We found that both CTR-17 and CTR-20 reversibly bind to the colchicine-binding pocket on β-tubulin. Interestingly however, both the CTRs were highly effective against multidrug-resistant cancer cells while colchicine, paclitaxel and vinblastine were not. Our study with CTR-20 showed that it overcomes multidrug-resistance through its ability to impede MRP1 function while maintaining strong inhibition against microtubule activity. Data from mice engrafted with the MDA-MB-231 triple-negative breast cancer cells showed that both CTR-17 and CTR-20 possess strong anticancer activity, alone or in combination with paclitaxel, without causing any notable side effects. Together, our data demonstrates that both the CTRs can be effective and safe drugs against many different cancers, especially against multidrug-resistant tumors.

Pilot Study of Patient and Caregiver Out-of-Pocket Costs of Allogeneic Hematopoietic Cell Transplantation

PubMed Central

Majhail, Navneet S; Rizzo, J Douglas; Hahn, Theresa; Lee, Stephanie J; McCarthy, Philip L; Ammi, Monique; Denzen, Ellen; Drexler, Rebecca; Flesch, Susan; James, Heather; Omondi, Nancy; Pedersen, Tanya L; Murphy, Elizabeth; Pederson, Kate

2012-01-01

Patient/caregiver out-of pocket costs associated with hematopoietic-cell transplantation (HCT) are not well known. We conducted a pilot study to evaluate patient/caregiver out-of-pocket costs in the first 3 months after allogeneic HCT. Thirty patients were enrolled at three sites. Prior to HCT, participants completed a baseline survey regarding household income and insurance coverage. Subsequently, they maintained a paper-based diary to track daily out-of-pocket expenses for the first 3 months after HCT. Telephone interviews were conducted to followup on missing/incomplete diaries and on study completion. Twenty-five patients/caregivers completed the baseline survey. Among these, the median pre-tax household income was $66,500 (range, $30-$375,000) and 48% had to temporarily relocate close to the transplant center. Insurance coverage was managed care plan (56%), Medicaid (20%), Medicare (17%) and other (8%). Twenty-two patients/caregivers completed ≥4 diaries; the median out-of-pocket expenses were $2,440 (range, $199-$13,769). Patients/caregivers who required temporary lodging had higher out-of-pocket expenses compared to those who did not (median, $5,247 vs. $716). Patients/caregivers can incur substantial out-of-pocket costs over the first 3 months, especially if they need to temporarily relocate close to the transplant center. Our study lays the foundation for future research on early and long-term financial impact of allogeneic HCT on patients/caregivers. PMID:23222378

Skin lesions over the pocket area that may mimic cardiac implantable electronic device infection: A case series.

PubMed

Korantzopoulos, Panagiotis; Plakoutsi, Sofia; Florou, Elizabeth; Bechlioulis, Aris

2018-05-21

The early and correct diagnosis of cardiac implantable electronic device (CIED) infections is critical given that early aggressive treatment with complete removal of the system along with antimicrobial therapy dramatically improves outcomes. Pocket infection manifested by local signs of inflammation is the most common form of CIED infections. Conditions mimicking pocket infection have been described in the literature. These include various types of malignancy and rarely allergic reactions/contact dermatitis to pacemaker compounds. We aimed to describe skin lesions and disorders over the pocket area that mimic CIED infection. We present a series of 5 cases with skin lesions that mimic pocket infection. We document these cases with corresponding photographs. Most of them have not been described in this setting. We report the following cases of conditions that proved not to be CIED infection: One case of superficial cellulitis, one case of herpes zoster over the pocket area, one case of spontaneous bruising over the pocket a long time after implantation in a patient taking oral anticoagulation, and 2 cases of contact dermatitis due to prolonged postoperative application of povidone iodine. All cases had favorable outcome after conservative treatment and no CIED infection was developed during follow-up. Clinicians should be aware of rare conditions that mimic CIED infection. Incorrect diagnosis of these disorders may falsely lead to CIED extraction. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Retiree out-of-pocket healthcare spending: a study of consumer expectations and policy implications.

PubMed

Hoffman, Allison K; Jackson, Howell E

2013-01-01

Even though most American retirees benefit from Medicare coverage, a mounting body of research predicts that many will face large and increasing out-of-pocket expenditures for healthcare costs in retirement and that many already struggle to finance these costs. It is unclear, however, whether the general population understands the likely magnitude of these out-of-pocket expenditures well enough to plan for them effectively. This study is the first comprehensive examination of Americans' expectations regarding their out-of-pocket spending on healthcare in retirement. We surveyed over 1700 near retirees and retirees to assess their expectations regarding their own spending and then compared their responses to experts' estimates. Our main findings are twofold. First, overall expectations of out-of-pocket spending are mixed. While a significant proportion of respondents estimated out-of-pocket costs in retirement at or above expert estimates of what the typical retiree will spend, a disproportionate number estimated their future spending substantially below what experts view as likely. Estimates by members of some demographic subgroups, including women and younger respondents, deviated relatively further from the experts' estimates. Second, respondents consistently misjudged spending uncertainty. In particular, respondents significantly underestimated how much individual health experience and changes in government policy can affect individual out-of-pocket spending. We discuss possible policy responses, including efforts to improve financial planning and ways to reduce unanticipated financial risk through reform of health insurance regulation.

A three-dimensional model for analyzing the effects of salmon redds on hyporheic exchange and egg pocket habitat

Treesearch

Daniele Tonina; John M. Buffington

2009-01-01

A three-dimensional fluid dynamics model is developed to capture the spatial complexity of the effects of salmon redds on channel hydraulics, hyporheic exchange, and egg pocket habitat. We use the model to partition the relative influences of redd topography versus altered hydraulic conductivity (winnowing of fines during spawning) on egg pocket conditions for a...

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

PubMed

Rohof, W O; Bennink, R J; de Ruigh, A A; Hirsch, D P; Zwinderman, A H; Boeckxstaens, G E

2012-12-01

The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

Modulation of protein function by exogenous ligands in protein cavities: CO binding to a myoglobin cavity mutant containing unnatural proximal ligands.

PubMed

Decatur, S M; DePillis, G D; Boxer, S G

1996-04-02

A variety of heterocyclic ligands can be exchanged into the proximal cavity of sperm whale myoglobin mutant H93G, providing a simple method for introduction of the equivalent of unnatural amino acid side chains into a functionally critical location in this protein. These modified proteins bind CO on the distal side. 1H NMR data on H93G(Im)CO, where Im is imidazole, demonstrate that the structure of the distal heme pocket in H93G(Im)CO is very similar to that of wild type; thus, the effects of the proximal ligand's properties on CO binding can be studied with minimal perturbation of distal pocket structure. The exogenous proximal ligands used in this study include imidazole (Im), 4-methylimidazole (4-MeIm), 4-bromoimidazole (4-BrIm), N-methylimidazole (N-MeIm), pyridine (Pyr), and 3-fluoropyridine (3-FPyr). Substitution of the proximal ligand is found to produce substantial changes in the CO on and off rates, the equilibrium binding constant, and the vibrational stretch frequency of CO. Many of the changes are as large as those reported for distal pocket mutants prepared by site-directed mutagenesis. The ability to systematically vary the nature of the proximal ligand is exploited to test the effects of particular properties of the proximal ligand on CO binding. For example, 4-MeIm and 4-BrIm are similar in size and shape but differ significantly in pKa. The same relationship is true for Pyr and 3-FPyr. By comparison of the IR spectra and CO recombination kinetics of these complexes, the effects of proximal ligand pKa on the CO binding are assessed. Likewise, N-MeIm and 4-MeIm are similar in size and pKa but differ in their ability to hydrogen bond to amino acid residues in the proximal cavity. Comparisons of IR spectra and CO binding kinetics in these complexes reveal that proximal ligand conformation and hydrogen bonding affect the kinetics of CO binding. The mechanism of proximal ligand exchange between solution and the proximal cavity in CO complexes was investigated by obtaining the 19F NMR spectrum of H93G(3-FPyr)CO, whose 19F signal can be observed without interference from resonances of the protein. The proximal ligand is found to exchange within a few seconds by saturation transfer. This exchange rate is about 2 orders of magniture faster than what is observed for the isoelectronic metcyano complex [Decatur, S. M., & Boxer, S. G. (1995) Biochemistry 34, 2122-2129]; in both the ferrous CO and ferric cyano complexes, the proximal ligand exchange rate is independent of ligand concentration. These results suggest that the rate-limiting step in proximal ligand exchange is breakage of the iron-ligand bond, followed by rapid diffusion of the ligand through the protein to bulk solution.

Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate

PubMed Central

Sung, Nuri; Lee, Jungsoon; Kim, Ji-Hyun; Chang, Changsoo; Joachimiak, Andrzej; Lee, Sukyeong; Tsai, Francis T. F.

2016-01-01

Heat-shock protein of 90 kDa (Hsp90) is an essential molecular chaperone that adopts different 3D structures associated with distinct nucleotide states: a wide-open, V-shaped dimer in the apo state and a twisted, N-terminally closed dimer with ATP. Although the N domain is known to mediate ATP binding, how Hsp90 senses the bound nucleotide and facilitates dimer closure remains unclear. Here we present atomic structures of human mitochondrial Hsp90N (TRAP1N) and a composite model of intact TRAP1 revealing a previously unobserved coiled-coil dimer conformation that may precede dimer closure and is conserved in intact TRAP1 in solution. Our structure suggests that TRAP1 normally exists in an autoinhibited state with the ATP lid bound to the nucleotide-binding pocket. ATP binding displaces the ATP lid that signals the cis-bound ATP status to the neighboring subunit in a highly cooperative manner compatible with the coiled-coil intermediate state. We propose that TRAP1 is a ligand-activated molecular chaperone, which couples ATP binding to dramatic changes in local structure required for protein folding. PMID:26929380

Tough stimuli-responsive supramolecular hydrogels with hydrogen-bonding network junctions.

PubMed

Guo, Mingyu; Pitet, Louis M; Wyss, Hans M; Vos, Matthijn; Dankers, Patricia Y W; Meijer, E W

2014-05-14

Hydrogels were prepared with physical cross-links comprising 2-ureido-4[1H]-pyrimidinone (UPy) hydrogen-bonding units within the backbone of segmented amphiphilic macromolecules having hydrophilic poly(ethylene glycol) (PEG). The bulk materials adopt nanoscopic physical cross-links composed of UPy-UPy dimers embedded in segregated hydrophobic domains dispersed within the PEG matrix as comfirmed by cryo-electron microscopy. The amphiphilic network was swollen with high weight fractions of water (w(H2O) ≈ 0.8) owing to the high PEG weight fraction within the pristine polymers (w(PEG) ≈ 0.9). Two different PEG chain lengths were investigated and illustrate the corresponding consequences of cross-link density on mechanical properties. The resulting hydrogels exhibited high strength and resilience upon deformation, consistent with a microphase separated network, in which the UPy-UPy interactions were adequately shielded within hydrophobic nanoscale pockets that maintain the network despite extensive water content. The cumulative result is a series of tough hydrogels with tunable mechanical properties and tractable synthetic preparation and processing. Furthermore, the melting transition of PEG in the dry polymer was shown to be an effective stimulus for shape memory behavior.

Looking Under a Leidenfrost Drop

NASA Astrophysics Data System (ADS)

Burton, Justin; Sharpe, Aaron; van der Veen, Roeland; Franco, Andres; Nagel, Sidney

2011-11-01

The Leidenfrost effect can be observed when small water drops move around effortlessly without sticking on a hot pan. The transition to a levitated state, where the drops rest on an insulating layer of vapor, occurs at the Leidenfrost temperature. Experiment and theory have examined the lifetime and maximum size of Leidenfrost drops. However, the liquid-vapor interface beneath the drop has not been fully charcterized. We report experiments using laser-light interference to measure the geometry of the liquid-vapor interface. By imaging the interference fringes produced between the bottom surface of the liquid and the hot substrate, we can measure the curvature of the vapor pocket beneath the drop as well as the azimuthal undulations along the neck that sits closest to the surface. From these measurements, we can extrapolate the shape of the bottom of the drop, which fluctuates in time with a period of a few milliseconds for millimeter-sized water drops. Our measurements of the azimuthal neck radius agree with predictions: the difference between the drop and neck radii, (Rd -Rn) ~0.53 λ in the limit of large drops where λ is the capillary length of the fluid. For small drops we recover the result found in that Rn ~Rd2 / λ .

Radiographic bone fill following debridement of a periodontal abscess. A case report.

PubMed

Khocht, A; Faldu, M G

1998-01-01

A periodontal abscess often develops in association with deepened periodontal pockets. Traditional management is by establishing drainage and prescribing antibiotics. This is usually followed by surgical pocket reduction. This case report discusses the remarkable healing of a periodontal abscess by establishing drainage alone without resorting to surgical pocket reduction. A 42-year-old white male presented with swollen gingivae associated with the mesiolingual of tooth #23. Increased probing depth and suppuration were evident. Radiographic bone loss on mesial #23 was present. A diagnosis of periodontal abscess was established. The abscess was drained through the orifice of the pocket. The patient failed to return for follow-up as instructed. A year later, the patient came back. Clinical evaluation showed healthy gingival tissues with probing depth of 3 mm on the mesiolingual of tooth #23. Radiographic evaluation showed bone fill of the osseous defect on the mesial of #23. The results of this case suggest that sufficient time should be allowed for healing prior to surgical pocket reduction.

Families at financial risk due to high ratio of out-of-pocket health care expenditures to total income.

PubMed

Bennett, Kevin J; Dismuke, Clara E

2010-05-01

High out-of-pocket expenditures for health care can put individuals and families at financial risk. Several groups, including racial/ethnic minority groups, the uninsured, rural residents, and those in poorer health are at risk for this increased burden. The analysis utilized 2004-2005 MEPS data. The dependent variables were the out-of-pocket health care spending to total income ratios for total spending, office-based visits, and prescription drugs. Multivariate analyses with instrumental variables controlled for respondent characteristics. Gender, age, rurality, insurance coverage, health status, and health care utilization were all associated with higher out-of-pocket to income ratios. Certain groups, such as women, the elderly, those in poor health, and rural residents, are at a greater financial risk due to their higher out-of-pocket to total income spending ratios. Policymakers must be aware of these increased risks in order to provide adequate resources and targeted interventions to alleviate some of this burden.

Do medical out-of-pocket expenses thrust families into poverty?

PubMed

O'Hara, Brett

2004-02-01

This paper estimates the impact of medical out-of-pocket expenses on families' well-being using the Survey of Income and Program Participation. Medical out-of-pocket expenses include the out-of-pocket costs from medical services and the family's share of health insurance premiums. Demographic characteristics, insurance status, and medical usage of the family are analyzed to determine which characteristics are most likely to impoverish a family. Families impoverished because of medical out-of-pocket expenses are far more likely to have older heads of the family, at least one family member in poor health, or some adults without health insurance. Families without at least one person who worked full time for the entire year were also likely to be impoverished. However, children in the family had little effect on the probability that the family became impoverished. This odd result is probably due to the high correlation between parental health insurance coverage and the health insurance coverage of their children.

Slab edge insulating form system and methods

DOEpatents

Lee, Brain E [Corral de Tierra, CA; Barsun, Stephan K [Davis, CA; Bourne, Richard C [Davis, CA; Hoeschele, Marc A [Davis, CA; Springer, David A [Winters, CA

2009-10-06

A method of forming an insulated concrete foundation is provided comprising constructing a foundation frame, the frame comprising an insulating form having an opening, inserting a pocket former into the opening; placing concrete inside the foundation frame; and removing the pocket former after the placed concrete has set, wherein the concrete forms a pocket in the placed concrete that is accessible through the opening. The method may further comprise sealing the opening by placing a sealing plug or sealing material in the opening. A system for forming an insulated concrete foundation is provided comprising a plurality of interconnected insulating forms, the insulating forms having a rigid outer member protecting and encasing an insulating material, and at least one gripping lip extending outwardly from the outer member to provide a pest barrier. At least one insulating form has an opening into which a removable pocket former is inserted. The system may also provide a tension anchor positioned in the pocket former and a tendon connected to the tension anchor.

An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase

NASA Astrophysics Data System (ADS)

Csizmok, Veronika; Orlicky, Stephen; Cheng, Jing; Song, Jianhui; Bah, Alaji; Delgoshaie, Neda; Lin, Hong; Mittag, Tanja; Sicheri, Frank; Chan, Hue Sun; Tyers, Mike; Forman-Kay, Julie D.

2017-01-01

The ubiquitin ligase SCFCdc4 mediates phosphorylation-dependent elimination of numerous substrates by binding one or more Cdc4 phosphodegrons (CPDs). Methyl-based NMR analysis of the Cdc4 WD40 domain demonstrates that Cyclin E, Sic1 and Ash1 degrons have variable effects on the primary Cdc4WD40 binding pocket. Unexpectedly, a Sic1-derived multi-CPD substrate (pSic1) perturbs methyls around a previously documented allosteric binding site for the chemical inhibitor SCF-I2. NMR cross-saturation experiments confirm direct contact between pSic1 and the allosteric pocket. Phosphopeptide affinity measurements reveal negative allosteric communication between the primary CPD and allosteric pockets. Mathematical modelling indicates that the allosteric pocket may enhance ultrasensitivity by tethering pSic1 to Cdc4. These results suggest negative allosteric interaction between two distinct binding pockets on the Cdc4WD40 domain may facilitate dynamic exchange of multiple CPD sites to confer ultrasensitive dependence on substrate phosphorylation.

Research on the properties of circadian systems amenable to study in space. [using pocket mice in Skylab experiment S-071 for the study of the effects of prolonged weightlessness

NASA Technical Reports Server (NTRS)

Lindberg, R. G.; Hayden, P.

1974-01-01

Three areas of inquiry are reported for the Skylab Experiment S-071 whose objective was to study the circadian system of a mammal during space flight. The thermoregulatory behavior of the Perognathus longimembris, or little pocket mouse, was studied under conditions of constant dark and constant temperature in the prolonged weightless environment of Skylab. The following specific questions were studied: (1) the effects of weightlessness on circadian periodicity in the little pocket mouse; (2) stability of the free-running circadian period of body temperature of the little pocket mouse exposed to simulated launch stress; and (3) characteristics of the circadian rhythm of body temperature in the little pocket mouse. Diagrams of the electronic circuitry and hardware used in the experiment are shown and results are given in both graphical and tabular form. The methods used in the experiment are fully documented, along with conclusions and recommendations for future research.

Equity in out-of-pocket payment in Chile

PubMed Central

Mondaca, Alicia Lorena Núñez; Chi, Chunhuei

2017-01-01

ABSTRACT OBJECTIVE To assess the distribution of financial burden in Chile, with a focus on the burden and progressivity of out-of-pocket payment. METHODS Based on the principle of ability to pay, we explore factors that contribute to inequities in the health system finance and issues about the burden of out-of-pocket payment, as well as the progressivity and redistributive effect of out-of-pocket payment in Chile. Our analysis is based on data from the 2006 National Survey on Satisfaction and Out-of-Pocket Payments. RESULTS Results from this study indicate evidence of inequity, in spite of the progressivity of the healthcare system. Our analysis also identifies relevant policy variables such as education, insurance system, and method of payment that should be taken into consideration in the ongoing debates and research in improving the Chilean system. CONCLUSIONS In order to reduce the detected disparities among income groups, healthcare priorities should target low-income groups. Furthermore, policies should explore changes in the access to education and its impact on equity. PMID:28492762

Equity in out-of-pocket payment in Chile.

PubMed

Mondaca, Alicia Lorena Núñez; Chi, Chunhuei

2017-05-04

To assess the distribution of financial burden in Chile, with a focus on the burden and progressivity of out-of-pocket payment. Based on the principle of ability to pay, we explore factors that contribute to inequities in the health system finance and issues about the burden of out-of-pocket payment, as well as the progressivity and redistributive effect of out-of-pocket payment in Chile. Our analysis is based on data from the 2006 National Survey on Satisfaction and Out-of-Pocket Payments. Results from this study indicate evidence of inequity, in spite of the progressivity of the healthcare system. Our analysis also identifies relevant policy variables such as education, insurance system, and method of payment that should be taken into consideration in the ongoing debates and research in improving the Chilean system. In order to reduce the detected disparities among income groups, healthcare priorities should target low-income groups. Furthermore, policies should explore changes in the access to education and its impact on equity.

Adjunctive clinical effect of a water-cooled Nd:YAG laser in a periodontal maintenance care programme: a randomized controlled trial.

PubMed

Slot, Dagmar E; Timmerman, Mark F; Versteeg, Paula A; van der Velden, Ubele; van der Weijden, Fridus A

2012-12-01

Various laser systems are currently available for intra-oral use. Neodymium:Yttrium-Aluminium Garnet lasers(Nd:YAG) have been approved by the US Food and Drug Administration for soft tissue treatment in the oral cavity. The aim of this study was to test whether the use of a water-cooled Nd:YAG laser during a maintenance care programme as an adjunct to supragingival and subgingival debridement (scaling and root planing, SRP) with hand and ultrasonic instruments results in clinical improvement compared with SRP alone. This study was an examiner-blind, randomized and controlled clinical trial using a split-mouth design. Thirty subjects were selected, originally diagnosed with moderate to severe generalized periodontitis, following a periodontal maintenance care programme (PMC). Immediately after SRP in two randomly assigned contra-lateral quadrants, all pockets ≥5 mm were additionally treated with a Nd:YAG laser (1064 nm, 4W, 250-μsec pulse). Clinical assessments [probing pocket depth PPD, bleeding on pocket probing (BOPP)] were performed pre-treatment and at 6 months. Based on these assessments, the periodontal inflamed surface area (PISA) was calculated. At 6 months, the clinical parameters had significantly improved for both regimens. No statistically significant differences between treatment modalities were observed for PPD and BOPP scores at any time. PISA scores supported these findings. In residual pockets ≥5 mm, treated in a PMC, the adjunctive use of an Nd:YAG laser does not provide a clinically significant additional advantage. © 2012 John Wiley & Sons A/S.

Differential sensitivity of Chironomus and human hemoglobin to gamma radiation

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

Gaikwad, Pallavi S.; Molecular Biology Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085; Panicker, Lata

Chironomus ramosus is known to tolerate high doses of gamma radiation exposure. Larvae of this insect possess more than 95% of hemoglobin (Hb) in its circulatory hemolymph. This is a comparative study to see effect of gamma radiation on Hb of Chironomus and humans, two evolutionarily diverse organisms one having extracellular and the other intracellular Hb respectively. Stability and integrity of Chironomus and human Hb to gamma radiation was compared using biophysical techniques like Dynamic Light Scattering (DLS), UV-visible spectroscopy, fluorescence spectrometry and CD spectroscopy after exposure of whole larvae, larval hemolymph, human peripheral blood, purified Chironomus and human Hb.more » Sequence- and structure-based bioinformatics methods were used to analyze the sequence and structural similarities or differences in the heme pockets of respective Hbs. Resistivity of Chironomus Hb to gamma radiation is remarkably higher than human Hb. Human Hb exhibited loss of heme iron at a relatively low dose of gamma radiation exposure as compared to Chironomus Hb. Unlike human Hb, the heme pocket of Chironomus Hb is rich in aromatic amino acids. Higher hydophobicity around heme pocket confers stability of Chironomus Hb compared to human Hb. Previously reported gamma radiation tolerance of Chironomus can be largely attributed to its evolutionarily ancient form of extracellular Hb as evident from the present study. -- Highlights: •Comparison of radiation tolerant Chironomus Hb and radiation sensitive Human Hb. •Amino acid composition of midge and human heme confer differential hydrophobicity. •Heme pocket of evolutionarily ancient midge Hb provide gamma radiation resistivity.« less

Species-Specific Activation of TLR4 by Hypoacylated Endotoxins Governed by Residues 82 and 122 of MD-2

PubMed Central

Oblak, Alja; Jerala, Roman

2014-01-01

The Toll-like receptor 4/MD-2 receptor complex recognizes endotoxin, a Gram-negative bacterial cell envelope component. Recognition of the most potent hexaacylated form of endotoxin is mediated by the sixth acyl chain that protrudes from the MD-2 hydrophobic pocket and bridges TLR4/MD-2 to the neighboring TLR4 ectodomain, driving receptor dimerization via hydrophobic interactions. In hypoacylated endotoxins all acyl chains could be accommodated within the binding pocket of the human hMD-2. Nevertheless, tetra- and pentaacylated endotoxins activate the TLR4/MD-2 receptor of several species. We observed that amino acid residues 82 and 122, located at the entrance to the endotoxin binding site of MD-2, have major influence on the species-specific endotoxin recognition. We show that substitution of hMD-2 residue V82 with an amino acid residue with a bulkier hydrophobic side chain enables activation of TLR4/MD-2 by pentaacylated and tetraacylated endotoxins. Interaction of the lipid A phosphate group with the amino acid residue 122 of MD-2 facilitates the appropriate positioning of the hypoacylated endotoxin. Moreover, mouse TLR4 contributes to the agonistic effect of pentaacylated msbB endotoxin. We propose a molecular model that explains how the molecular differences between the murine or equine MD-2, which both have sufficiently large hydrophobic pockets to accommodate all five or four acyl chains, influence the positioning of endotoxin so that one of the acyl chains remains outside the pocket and enables hydrophobic interactions with TLR4, leading to receptor activation. PMID:25203747

Species-specific activation of TLR4 by hypoacylated endotoxins governed by residues 82 and 122 of MD-2.

PubMed

Oblak, Alja; Jerala, Roman

2014-01-01

The Toll-like receptor 4/MD-2 receptor complex recognizes endotoxin, a Gram-negative bacterial cell envelope component. Recognition of the most potent hexaacylated form of endotoxin is mediated by the sixth acyl chain that protrudes from the MD-2 hydrophobic pocket and bridges TLR4/MD-2 to the neighboring TLR4 ectodomain, driving receptor dimerization via hydrophobic interactions. In hypoacylated endotoxins all acyl chains could be accommodated within the binding pocket of the human hMD-2. Nevertheless, tetra- and pentaacylated endotoxins activate the TLR4/MD-2 receptor of several species. We observed that amino acid residues 82 and 122, located at the entrance to the endotoxin binding site of MD-2, have major influence on the species-specific endotoxin recognition. We show that substitution of hMD-2 residue V82 with an amino acid residue with a bulkier hydrophobic side chain enables activation of TLR4/MD-2 by pentaacylated and tetraacylated endotoxins. Interaction of the lipid A phosphate group with the amino acid residue 122 of MD-2 facilitates the appropriate positioning of the hypoacylated endotoxin. Moreover, mouse TLR4 contributes to the agonistic effect of pentaacylated msbB endotoxin. We propose a molecular model that explains how the molecular differences between the murine or equine MD-2, which both have sufficiently large hydrophobic pockets to accommodate all five or four acyl chains, influence the positioning of endotoxin so that one of the acyl chains remains outside the pocket and enables hydrophobic interactions with TLR4, leading to receptor activation.

Characteristics and tolerances of the pocket mouse and incidence of disease. [CNS lesions during space flights

NASA Technical Reports Server (NTRS)

Lindberg, R. G.; Kraft, L. M.; Simmonds, R. C.; Bailey, O. T.; Dunlap, W. A.; Haymaker, W.

1975-01-01

Studies carried out on the pocket mouse colony on Apollo XVII are reported. They revealed no serological evidence of viral disease, no pathogenic enterobacteria or respiratory Mycoplasma on culture, a 25% incidence of sarcosporidiosis, and a 2% incidence of chronic meningitis or meningoencephalitis. It is concluded that the pocket mouse is a highly adaptive animal and very well-suited to space flight.

How the ACA's Health Insurance Expansions Have Affected Out-of-Pocket Cost-Sharing and Spending on Premiums.

PubMed

Glied, Sherry; Solís-Román, Claudia; Parikh, Shivani

2016-09-01

One important benefit gained by the millions of Americans with health insurance through the Affordable Care Act (ACA) is protection from high out-of-pocket health spending. While Medicaid unambiguously reduces out-of-pocket premium and medical costs for low-income people, it is less certain that marketplace coverage and other types of insurance purchased to comply with the law's individual mandate also protect from high health spending. Goal: To compare out-of-pocket spending in 2014 to spending in 2013; assess how this spending changed in states where many people enrolled in the marketplaces relative to states where few people enrolled; and project the decline in the percentage of people paying high amounts out-of-pocket. Methods: Linear regression models were used to estimate whether people under age 65 spent above certain thresholds. Key findings and conclusions: The probability of incurring high out-of-pocket costs and premium expenses declined as marketplace enrollment increased. The percentage reductions were greatest among those with incomes between 250 percent and 399 percent of poverty, those who were eligible for premium subsidies, and those who previously were uninsured or had very limited nongroup coverage. These effects appear largely attributable to marketplace enrollment rather than to other ACA provisions or to economic trends.

Dynamic control of droplets and pockets formation in homogeneous porous media immiscible displacements

NASA Astrophysics Data System (ADS)

Lins, T. F.; Azaiez, J.

2018-03-01

Interfacial instabilities of immiscible two-phase radial flow displacements in homogeneous porous media are analyzed for constant and time-dependent sinusoidal cyclic injection schemes. The analysis is carried out through numerical simulations based on the immersed interface and level set methods. The effects of the fluid properties and the injection flow parameters, namely, the period and the amplitude, on the formation of droplets and pockets are analyzed. It was found that larger capillary numbers or smaller viscosity ratios lead to more droplets/pockets that tend to appear earlier in time. Furthermore, the period and amplitude of the cyclic schemes were found to have a strong effect on droplets/pockets formations, and depending on their values, these can be enhanced or attenuated. In particular, the results revealed that there is a critical amplitude above which droplets and pockets formation is suppressed up to a specified time. This critical amplitude depends on the fluid properties, namely, the viscosity ratio and surface tension as well as on the period of the time-dependent scheme. The results of this study indicate that it is possible to use time-dependent cyclic schemes to control the formation and development of droplets/pockets in the flow and in particular to delay their appearance through an appropriate combination of the displacement scheme's amplitude and period.

Holography and eternal inflation

NASA Astrophysics Data System (ADS)

Yeh, Chen-Pin

The holographic principle states that the number of fundamental degrees of freedom in a specific region of spacetime is bounded by the area of its boundary. In the content of string theory, the AdS/CFT duality demonstrates the holographic principle in the background anti-de Sitter space. However for the more physically relevant background, it is hard to find such duality. The background that is particularly interesting is the eternal inflation. In this thesis we study the holographic dual of the eternal inflation. In the same spirit as AdS/CFT, the holographic theory is a conformal field theory on the boundary of the geometry. We study the scalar and graviton two point functions in a simplified eternal inflation background, which describes a flat pocket universe tunnels from a de Sitter background. The two point functions extrapolated to the boundary are shown to have the properties required by the conformal symmetry. We go on to study the possible collision between different pocket universes. We showed that after collisions, the resulting pocket universe with nontrivial boundary topology is possible. This implies that the boundary theory will not only have fluctuation in geometry but also in topology. It will also have potential observation consequences on the cosmological observation.

Household Expenditures for Medicines and the Role of Free Medicines in the Brazilian Public Health System

PubMed Central

Barros, Aluísio J. D.; Camargo, Aline Lins; Hallal, Pedro C.; Vandoros, Sotiris; Wagner, Anita; Ross-Degnan, Dennis

2011-01-01

Objectives. We sought to investigate, across different socioeconomic groups, the proportion of household medicine expenses that were paid by households and the proportion paid by the Brazilian national health system. Methods. We carried out a survey in Porto Alegre, Brazil, that included 2988 individuals of all ages. We defined 2 expenditure variables: “out-of-pocket medicines value” (the sum of retail prices of all medicines used by family members within the previous 15 days and paid for out of pocket) and “free medicines value” (a similar definition for medicines obtained without charge). Results. In 2003, the Brazilian national health system provided, free of charge, 78% of the monetary value of medicines reported (79% in the bottom wealth quintile and 32% in the top 2 quintiles). The mean out-of-pocket expense for medicines was 6 times greater among the top wealth quintiles compared with those in lower quintiles, but free medicines constituted a 3-times-greater proportion of potential expenditures for medicines among the bottom quintile than among the top 2 quintiles. Conclusions. Free provision of medicines seems to be saving substantial amounts of medicine expenditures for poor people in Brazil. PMID:20724692

Probing the Fermi surface and magnetotransport properties of MoAs2

NASA Astrophysics Data System (ADS)

Singha, Ratnadwip; Pariari, Arnab; Gupta, Gaurav Kumar; Das, Tanmoy; Mandal, Prabhat

2018-04-01

Transition-metal dipnictides (TMDs) have recently been identified as possible candidates to host a topology-protected electronic band structure. These materials belong to an isostructural family and show several exotic transport properties. Especially, the large values of magnetoresistance (MR) and carrier mobility have drawn significant attention from the perspective of technological applications. In this paper, we investigate the magnetotransport and Fermi surface properties of single-crystalline MoAs2, another member of this group of compounds. A field-induced resistivity plateau and a large MR have been observed, which are comparable to those in several topological systems. Interestingly, in contrast to other isostructural materials, the carrier density in MoAs2 is quite high and shows single-band-dominated transport. The Fermi pockets, which have been identified from the quantum oscillation, are the largest among the members of this group and have significant anisotropy with crystallographic direction. Our first-principles calculations reveal a substantial difference between the band structures of MoAs2 and that of other TMDs. The calculated Fermi surface consists of one electron pocket and another "open-orbit" hole pocket, which has not been observed in TMDs so far.

Relative positioning of classical benzodiazepines to the γ2-subunit of GABAA receptors.

PubMed

Middendorp, Simon J; Hurni, Evelyn; Schönberger, Matthias; Stein, Marco; Pangerl, Michael; Trauner, Dirk; Sigel, Erwin

2014-08-15

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain. Benzodiazepine exert their action via a high affinity-binding site at the α/γ subunit interface on some of these receptors. Diazepam has sedative, hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. It acts by potentiating the current evoked by the agonist GABA. Understanding specific interaction of benzodiazepines in the binding pocket of different GABAA receptor isoforms might help to separate these divergent effects. As a first step, we characterized the interaction between diazepam and the major GABAA receptor isoform α1β2γ2. We mutated several amino acid residues on the γ2-subunit assumed to be located near or in the benzodiazepine binding pocket individually to cysteine and studied the interaction with three ligands that are modified with a cysteine-reactive isothiocyanate group (-NCS). When the reactive NCS group is in apposition to the cysteine residue this leads to a covalent reaction. In this way, three amino acid residues, γ2Tyr58, γ2Asn60, and γ2Val190 were located relative to classical benzodiazepines in their binding pocket on GABAA receptors.

Retention of pediatric bag-mask ventilation efficacy skill by inexperienced medical student resuscitators using standard bag-mask ventilation masks, pocket masks, and blob masks.

PubMed

Kitagawa, Kory H; Nakamura, Nina M; Yamamoto, Loren

2006-03-01

To measure the ventilation efficacy with three single-sized mask types on infant and child manikin models. Medical students were recruited as study subjects inasmuch as they are inexperienced resuscitators. They were taught proper bag-mask ventilation (BMV) according to the American Heart Association guidelines on an infant and a child manikin. Subjects completed a BMV attempt successfully using the adult standard mask (to simulate the uncertainty of mask selection), pocket mask, and blob mask. Each attempt consisted of 5 ventilations assessed by chest rise of the manikin. Study subjects were asked which mask was easiest to use. Four to six weeks later, subjects repeated the procedure with no instructions (to simulate an emergency BMV encounter without immediate pre-encounter teaching). Forty-six volunteer subjects were studied. During the first attempt, subjects preferred the standard and blob masks over the pocket mask. For the second attempt, the blob mask was preferred over the standard mask, and few liked the pocket mask. Using the standard, blob, and pocket masks on the child manikin, 39, 42, and 20 subjects, respectively, were able to achieve adequate ventilation. Using the standard, blob, and pocket masks on the infant manikin, 45, 45, and 11 subjects, respectively, were able to achieve adequate ventilation. Both the standard and blob masks are more effective than the pocket mask at achieving adequate ventilation on infant and child manikins in this group of inexperienced medical student resuscitators, who most often preferred the blob mask.

The ACA's Zero Cost-Sharing Mandate and Trends in Out-of-Pocket Expenditures on Well-Child and Screening Mammography Visits.

PubMed

Kirby, James B; Davidoff, Amy J; Basu, Jayasree

2016-12-01

Starting in September of 2010, the Patient Protection and Affordable Care Act required most health insurance policies to cover evidence-based preventive care with no cost-sharing (no copays, coinsurance, or deductibles). It is unknown, however, whether declines in out-of-pocket costs for preventive services are large enough to prompt increases in utilization, the ultimate goal of the policy. In this study, we use a nationally representative sample of ambulatory care visits to estimate the impact of the zero cost-sharing mandate on out-of-pocket expenditures on well-child and screening mammography visits. Estimates are made using 2-part interrupted time-series models, with well-woman visits serving as the control group because they were not covered under the zero cost-sharing mandate until after our study period. Results indicate a substantial reduction in out-of-pocket costs attributable to the Affordable Care Act. Between January 2011 and September 2012, the zero cost-sharing mandate reduced per-visit out-of-pocket costs for well-child visits from $18.46 to $8.08 (56%) and out-of-pocket costs for screening mammography visits from $25.43 to $6.50 (74%). No reduction was apparent for well-woman visits. The Affordable Care Act's zero cost-sharing mandate for preventive care has had a large impact on out-of-pocket expenditures for well-child and mammography visits. To increase preventive service use, research is needed to better understand barriers to obtaining preventive care that are not directly related to cost.

Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.

PubMed

Srinivasan, Bharath; Rodrigues, João V; Tonddast-Navaei, Sam; Shakhnovich, Eugene; Skolnick, Jeffrey

2017-07-21

In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.

Impact of the application of the Value Added Tax to imaging tests on out-of-pocket health expenses of households in Chile.

PubMed

Cuadrado, Cristóbal; Silva-Illanes, Nicolás

2015-12-09

Out-of-pocket healthcare expense represents a challenge for health systems for it constitutes a barrier to health care, impacting the equality of access to healthcare systems, something particularly important in the Chilean health system. In this context, the Government recently raised the possibility of incorporating a tax on imaging tests, creating debate over its potential consequences. To explore the impact on household out-of-pocket healthcare expense by the implementation of a value added tax to imaging tests in Chile. Cross-sectional study using data of household expenditures from the VII Household Budget Survey. Out-of-pocket healthcare expense and catastrophic household expenses are calculated comparing two scenarios, with and without the inclusion of the proposed tax. Analyses are presented by income deciles to explore the differential equality impact. 42.8% of diagnostic test expense on household corresponds to imaging studies. Under a scenario of tax implementation, a relative increase of 1.1% of out-of-pocket expenses and 2.2% of catastrophic household expenses is observed. The groups that suffer the greatest impact are those with lower income levels, concentrating in the first fifth deciles. We conclude that, although the increase in the average out-of- pocket spending is moderate, this policy may involve a significant increase in the catastrophic expense of the population with the lowest incomes, thereby increasing health inequalities. Considering the challenges of health system financing in Chile, it appears that such fiscal policy would only worsen the possibility of moving towards lower levels of out-of-pocket of household expenses.

Posttuberculosis tracheobronchial stenosis: use of CT to optimize the time of silicone stent removal.

PubMed

Verma, Akash; Park, Hye Yun; Lim, So Yeon; Um, Sang-Won; Koh, Won-Jung; Suh, Gee Young; Chung, Man Pyo; Kwon, O Jung; Kim, Hojoong

2012-05-01

To evaluate whether air pockets (tracheobronchial air columns in the space between the outer surface of the stent and the adjacent airway wall) discernible at computed tomography (CT) can help optimize the time of stent removal in patients with posttuberculosis tracheobronchial stenosis (PTTS). The study was approved by the institutional review board, and informed consent was obtained from all patients. Data from 41 patients (five men, 36 women) with a median age of 39 years (range, 21-64 years) who underwent silicone stent placement owing to PTTS, followed by CT and stent removal 6-12 months after clinical stabilization, were investigated retrospectively. Two radiologists determined whether the extent of air pockets on CT scans was associated with clinical success, which was defined as maintenance of a prosthesis-free airway for more than 2 years after stent removal. Radiologic features were compared for outcome by using a Wilcoxon two-sample test or Fisher exact test. Stents were removed successfully in 31 patients (76%). Air pockets longer than 1 cm or longer than 2 cm were associated with successful stent removal (P = .04 and P = .006, respectively). The sensitivity and specificity of air pocket length in the prediction of successful stent removal were 84% and 50%, respectively, for air pockets longer than 1 cm and 68% and 70% for air pockets longer than 2 cm. The extent of air pockets at chest CT shows correlation with the success of stent removal, indicates regression of stenosis, and may help guide the optimal time for stent removal.

Pore-scale imaging of capillary trapped supercritical CO2 as controlled by water-wet vs. CO2-wet media and grain shapes

NASA Astrophysics Data System (ADS)

Chaudhary, K.; Cardenas, M.; Wolfe, W. W.; Maisano, J. A.; Ketcham, R. A.; Bennett, P.

2013-12-01

The capillary trapping of supercritical CO2 (s-CO2) is postulated to comprise up to 90% of permanently trapped CO2 injected during geologic sequestration. Successive s-CO2/brine flooding experiments under reservoir conditions showed that water-wet rounded beads trapped 15% of injected s-CO2 both as clusters and as individual ganglia, whereas CO2¬-wet beads trapped only 2% of the injected s-CO2 as minute pockets in pore constrictions. Angular water-wet grains trapped 20% of the CO2 but flow was affected by preferential flow. Thus, capillary trapping is a viable mechanism for the permanent CO2 storage, but its success is constrained by the media wettability.

Characterization of Simulium (Simulium) hackeri Edwards (Diptera: Simuliidae) from Malaysia: Morphological description of the pupa and larva, and DNA barcoding.

PubMed

Ya'cob, Zubaidah; Takaoka, Hiroyuki; Low, Van Lun; Sofian-Azirun, Mohd

2018-04-27

Simulium (Simulium) hackeri Edwards, 1928 of the Simulium variegatum species-group from Malaysia was described initially based on the female specimen from Cameron Highlands, Pahang. In the present study, the pupa and larva of this species are described for the first time. Their morphological characters resemble those of the Simulium variegatum species-group by having six gill filaments per side, abdomen with dorsal spine-combs at least on segments 7 and 8, cocoon with wall-pocket shaped and with or without an anterodorsal projection. Postgenal cleft of the larva medium-sized, rarely small, ventral papillae small or absent. The DNA barcode of this species is also reported herein. Copyright © 2018 Elsevier B.V. All rights reserved.

Magnetic field induced strong valley polarization in the three-dimensional topological semimetal LaBi

NASA Astrophysics Data System (ADS)

Kumar, Nitesh; Shekhar, Chandra; Klotz, J.; Wosnitza, J.; Felser, Claudia

2017-10-01

LaBi is a three-dimensional rocksalt-type material with a surprisingly quasi-two-dimensional electronic structure. It exhibits excellent electronic properties such as the existence of nontrivial Dirac cones, extremely large magnetoresistance, and high charge-carrier mobility. The cigar-shaped electron valleys make the charge transport highly anisotropic when the magnetic field is varied from one crystallographic axis to another. We show that the electrons can be polarized effectively in these electron valleys under a rotating magnetic field. We achieved a polarization of 60% at 2 K despite the coexistence of three-dimensional hole pockets. The valley polarization in LaBi is compared to the sister compound LaSb where it is found to be smaller. The performance of LaBi is comparable to the highly efficient bismuth.

Preliminary design of a solar heat receiver for a Brayton cycle space power system

NASA Technical Reports Server (NTRS)

Cameron, H. M.; Mueller, L. A.; Namkoong, D.

1972-01-01

The preliminary design of a solar heat receiver for use as a heat source for an earth-orbiting 11-kWe Brayton-cycle engine is described. The result was a cavity heat receiver having the shape of a frustum of a cone. The wall of the cone is formed by 48 heat-transfer tubes, each tube containing pockets of lithium fluoride for storing heat for as much as 38 minutes of fullpower operation in the shade. Doors are provided in order to dump excess heat especially during operation in orbits with full sun exposure. The receiver material is predominantly columbium - 1-percent-zironium (Cb-1Zr) alloy. Full-scale testing of three heat-transfer tubes for more than 2000 hours and 1250 sun-shade cycles verified the design concept.

Correlates of out-of-pocket and catastrophic health expenditures in Tanzania: results from a national household survey.

PubMed

Brinda, Ethel Mary; Andrés, Antonio Rodríguez; Andrés, Rodriguez Antonio; Enemark, Ulrika

2014-03-05

Inequality in health services access and utilization are influenced by out-of-pocket health expenditures in many low and middle-income countries (LMICs). Various antecedents such as social factors, poor health and economic factors are proposed to direct the choice of health care service use and incurring out-of-pocket payments. We investigated the association of these factors with out-of-pocket health expenditures among the adult and older population in the United Republic of Tanzania. We also investigated the prevalence and associated determinants contributing to household catastrophic health expenditures. We accessed the data of a multistage stratified random sample of 7279 adult participants, aged between 18 and 59 years, as well as 1018 participants aged above 60 years, from the first round of the Tanzania National Panel survey. We employed multiple generalized linear and logistic regression models to evaluate the correlates of out-of-pocket as well as catastrophic health expenditures, accounting for the complex sample design effects. Increasing age, female gender, obesity and functional disability increased the adults' out-of-pocket health expenditures significantly, while functional disability and visits to traditional healers increased the out-of-pocket health expenditures in older participants. Adult participants, who lacked formal education or worked as manual laborers earned significantly less (p < 0.001) and spent less on health (p < 0.001), despite having higher levels of disability. Large household size, household head's occupation as a manual laborer, household member with chronic illness, domestic violence against women and traditional healer's visits were significantly associated with high catastrophic health expenditures. We observed that the prevalence of inequalities in socioeconomic factors played a significant role in determining the nature of both out-of-pocket and catastrophic health expenditures. We propose that investment in social welfare programs and strengthening the social security mechanisms could reduce the financial burden in United Republic of Tanzania.

Correlates of out-of-pocket and catastrophic health expenditures in Tanzania: results from a national household survey

PubMed Central

2014-01-01

Background Inequality in health services access and utilization are influenced by out-of-pocket health expenditures in many low and middle-income countries (LMICs). Various antecedents such as social factors, poor health and economic factors are proposed to direct the choice of health care service use and incurring out-of-pocket payments. We investigated the association of these factors with out-of-pocket health expenditures among the adult and older population in the United Republic of Tanzania. We also investigated the prevalence and associated determinants contributing to household catastrophic health expenditures. Methods We accessed the data of a multistage stratified random sample of 7279 adult participants, aged between 18 and 59 years, as well as 1018 participants aged above 60 years, from the first round of the Tanzania National Panel survey. We employed multiple generalized linear and logistic regression models to evaluate the correlates of out-of-pocket as well as catastrophic health expenditures, accounting for the complex sample design effects. Results Increasing age, female gender, obesity and functional disability increased the adults’ out-of-pocket health expenditures significantly, while functional disability and visits to traditional healers increased the out-of-pocket health expenditures in older participants. Adult participants, who lacked formal education or worked as manual laborers earned significantly less (p < 0.001) and spent less on health (p < 0.001), despite having higher levels of disability. Large household size, household head’s occupation as a manual laborer, household member with chronic illness, domestic violence against women and traditional healer’s visits were significantly associated with high catastrophic health expenditures. Conclusion We observed that the prevalence of inequalities in socioeconomic factors played a significant role in determining the nature of both out-of-pocket and catastrophic health expenditures. We propose that investment in social welfare programs and strengthening the social security mechanisms could reduce the financial burden in United Republic of Tanzania. PMID:24597486

Health service use, out-of-pocket payments and catastrophic health expenditure among older people in India: the WHO Study on global AGEing and adult health (SAGE).

PubMed

Brinda, Ethel Mary; Kowal, Paul; Attermann, Jørn; Enemark, Ulrika

2015-05-01

Healthcare financing through out-of-pocket payments and inequities in healthcare utilisation are common in low and middle income countries (LMICs). Given the dearth of pertinent studies on these issues among older people in LMICs, we investigated the determinants of health service use, out-of-pocket and catastrophic health expenditures among older people in one LMIC, India. We accessed data from a nationally representative, multistage sample of 2414 people aged 65 years and older from the WHO's Study on global AGEing and adult health in India. Sociodemographic characteristics, health profiles, health service utilisation and out-of-pocket health expenditure were assessed using standard instruments. Multivariate zero-inflated negative binomial regression models were used to evaluate the determinants of health service visits. Multivariate Heckman sample selection regression models were used to assess the determinants of out-of-pocket and catastrophic health expenditures. Out-of-pocket health expenditures were higher among participants with disability and lower income. Diabetes, hypertension, chronic pulmonary disease, heart disease and tuberculosis increased the number of health visits and out-of-pocket health expenditures. The prevalence of catastrophic health expenditure among older people in India was 7% (95% CI 6% to 8%). Older men and individuals with chronic diseases were at higher risk of catastrophic health expenditure, while access to health insurance lowered the risk. Reducing out-of-pocket health expenditure among older people is an important public health issue, in which social as well as medical determinants should be prioritised. Enhanced public health sector performance and provision of publicly funded insurance may protect against catastrophic health expenses and healthcare inequities in India. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Are women benefiting from the Affordable Care Act? A real-world evaluation of the impact of the Affordable Care Act on out-of-pocket costs for contraceptives.

PubMed

Law, A; Wen, L; Lin, J; Tangirala, M; Schwartz, J S; Zampaglione, E

2016-05-01

The Affordable Care Act (ACA) mandated that, starting between August 1, 2012 and July 31, 2013, health plans cover most Food and Drug Administration (FDA)-approved contraceptive methods for women without cost sharing. This study examined the impact of the ACA on out-of-pocket expenses for contraceptives. Women (ages 15-44years) with claims for any contraceptives in years 2011, 2012 and 2013 were identified from the MarketScan Commercial database. The proportions of women using contraceptives [including permanent contraceptives (PCs) and non-PCs: oral contraceptives (OCs), injectables, patches, rings, implants and intrauterine devices (IUDs)] in study years were determined, as well as changes in out-of-pocket expenses for contraceptives during 2011-2013. Demographics, including age, U.S. geographic region of residence and health plan type, were also evaluated. The number of women identified with any contraceptive usage in 2011 was 2,447,316 (mean age: 27.6years), in 2012 was 2,515,296 (mean age: 27.4years) and in 2013 was 2,243,253 (mean age: 27.4years). In 2011, 2012 and 2013, the proportions of women with any contraceptive usage were 26.3%, 26.2% and 26.9%, respectively. Over the three study years, mean total out-of-pocket expenses for PCs and non-PCs decreased from $298 to $82 and from $94 to $30, respectively. For non-PCs, mean total out-of-pocket expenses for OCs and IUDs decreased from $86 to $26 and from $83 to $20. Implementation of the ACA has saved women a substantial amount in out-of-pocket expenses for contraceptives. Mean total out-of-pocket expenses for FDA-approved contraceptives decreased approximately 70% from 2011 to 2013. Implementation of the ACA has saved women a substantial amount in out-of-pocket expenses for contraceptives. Longer-term studies, including clinical outcomes, are warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of out-of-pocket spending caps on financial burden of those with group health insurance.

PubMed

Riggs, Kevin R; Buttorff, Christine; Alexander, G Caleb

2015-05-01

The Affordable Care Act (ACA) mandates that all private health insurance include out-of-pocket spending caps. Insurance purchased through the ACA's Health Insurance Marketplace may qualify for income-based caps, whereas group insurance will not have income-based caps. Little is known about how out-of-pocket caps impact individuals' health care financial burden. We aimed to estimate what proportion of non-elderly individuals with group insurance will benefit from out-of-pocket caps, and the effect that various cap levels would have on their financial burden. We applied the expected uniform spending caps, hypothetical reduced uniform spending caps (reduced by one-third), and hypothetical income-based spending caps (similar to the caps on Health Insurance Marketplace plans) to nationally representative data from the Medical Expenditure Panel Survey (MEPS). Participants were non-elderly individuals (aged < 65 years) with private group health insurance in the 2011 and 2012 MEPS surveys (n =26,666). (1) The percentage of individuals with reduced family out-of-pocket spending as a result of the various caps; and (2) the percentage of individuals experiencing health care services financial burden (family out-of-pocket spending on health care, not including premiums, greater than 10% of total family income) under each scenario. With the uniform caps, 1.2% of individuals had lower out-of-pocket spending, compared with 3.8% with reduced uniform caps and 2.1% with income-based caps. Uniform caps led to a small reduction in percentage of individuals experiencing financial burden (from 3.3% to 3.1%), with a modestly larger reduction as a result of reduced uniform caps (2.9%) and income-based caps (2.8%). Mandated uniform out-of-pocket caps for those with group insurance will benefit very few individuals, and will not result in substantial reductions in financial burden.

Out-of-pocket fertility patient expense: data from a multicenter prospective infertility cohort.

PubMed

Wu, Alex K; Odisho, Anobel Y; Washington, Samuel L; Katz, Patricia P; Smith, James F

2014-02-01

The high costs of fertility care may deter couples from seeking care. Urologists often are asked about the costs of these treatments. To our knowledge previous studies have not addressed the direct out-of-pocket costs to couples. We characterized these expenses in patients seeking fertility care. Couples were prospectively recruited from 8 community and academic reproductive endocrinology clinics. Each participating couple completed face-to-face or telephone interviews and cost diaries at study enrollment, and 4, 10 and 18 months of care. We determined overall out-of-pocket costs, in addition to relationships between out-of-pocket costs and treatment type, clinical outcomes and socioeconomic characteristics on multivariate linear regression analysis. A total of 332 couples completed cost diaries and had data available on treatment and outcomes. Average age was 36.8 and 35.6 years in men and women, respectively. Of this cohort 19% received noncycle based therapy, 4% used ovulation induction medication only, 22% underwent intrauterine insemination and 55% underwent in vitro fertilization. The median overall out-of-pocket expense was $5,338 (IQR 1,197-19,840). Couples using medication only had the lowest median out-of-pocket expenses at $912 while those using in vitro fertilization had the highest at $19,234. After multivariate adjustment the out-of-pocket expense was not significantly associated with successful pregnancy. On multivariate analysis couples treated with in vitro fertilization spent an average of $15,435 more than those treated with intrauterine insemination. Couples spent about $6,955 for each additional in vitro fertilization cycle. These data provide real-world estimates of out-of-pocket costs, which can be used to help couples plan for expenses that they may incur with treatment. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

The effects of mandated health insurance benefits for autism on out-of-pocket costs and access to treatment.

PubMed

Chatterji, Pinka; Decker, Sandra L; Markowitz, Sara

2015-01-01

As of 2014, 37 states have passed mandates requiring many private health insurance policies to cover diagnostic and treatment services for autism spectrum disorders (ASDs). We explore whether ASD mandates are associated with out-of-pocket costs, financial burden, and cost or insurance-related problems with access to treatment among privately insured children with special health care needs (CSHCNs). We use difference-in-difference and difference-in-difference-in-difference approaches, comparing pre--post mandate changes in outcomes among CSHCN who have ASD versus CSHCN other than ASD. Data come from the 2005 to 2006 and the 2009 to 2010 waves of the National Survey of CSHCN. Based on the model used, our findings show no statistically significant association between state ASD mandates and caregivers' reports about financial burden, access to care, and unmet need for services. However, we do find some evidence that ASD mandates may have beneficial effects in states in which greater percentages of privately insured individuals are subject to the mandates. We caution that we do not study the characteristics of ASD mandates in detail, and most ASD mandates have gone into effect very recently during our study period.

Modelling the seismic properties of fast-spreading ridge crustal Low-Velocity Zones: insights from Oman gabbro textures

NASA Astrophysics Data System (ADS)

Lamoureux, Gwenaëlle; Ildefonse, Benoı̂t; Mainprice, David

1999-11-01

Although considerable progress has been made in the study of fast-spreading, mid-ocean ridge magma chambers over the past fifteen years, the fraction of melt present in the chamber remains poorly constrained and controversial. We present new constraints obtained by modelling the seismic properties of partially molten gabbros at the ridge axis. P-wave velocities at low frequencies are calculated in the foliation/lineation reference frame using a differential effective medium technique. The model takes into account the lattice preferred orientation of the crystalline phase and the average shape of the melt phase. The structural parameters are obtained from the Oman ophiolite. The structural reference frame is given by the general trend of the gabbro foliation and the melt fraction and shape are estimated using the textures of nine upper gabbro samples. The estimated melt fraction and shape depend on the assumptions regarding which part of the observed textures represent the melt in the gabbroic mush of the magma chamber. However, we can put limits on the reasonable values for the melt fraction and shape. Our results are consistent with a melt fraction of the order of 10 to 20% in the Low-Velocity Zone (i.e. the magma chamber), which is anisotropically distributed with the melt pockets preferentially aligned parallel to the foliation and approximated by oblate ellipsoids with approximate dimensions of 4 : 4 : 1. These results are also consistent with the seismic structure of the East Pacific rise at 9°30'. The anisotropic melt distribution can, at least partially, explain the vertical velocity gradient described in the LVZ.

Niemann-Pick type C disease: a QM/MM study of conformational changes in cholesterol in the NPC1(NTD) and NPC2 binding pockets.

PubMed

Elghobashi-Meinhardt, Nadia

2014-10-21

Niemann-Pick Type C disease is characterized by disrupted lipid trafficking within the late endosomal (LE)/lysosomal (Lys) cellular compartments. Cholesterol transport within the LE/Lys is believed to take place via a concerted hand-off mechanism in which a small (131aa) soluble cholesterol binding protein, NPC2, transfers cholesterol to the N-terminal domain (NTD) of a larger (1278aa) membrane-bound protein, NPC1(NTD). The transfer is thought to occur through the formation of a stable intermediate complex NPC1(NTD)-NPC2, in which the sterol apertures of the two proteins align to allow passage of the cholesterol molecule. In the working model of the NPC1(NTD)-NPC2 complex, the sterol apertures are aligned, but the binding pockets are bent with respect to one another. In order for cholesterol to slide from one binding pocket to the other, a conformational change must occur in the proteins, in the ligand, or in both. Here, we investigate the possibility that the ligand undergoes a conformational change, or isomerization, to accommodate the bent transfer pathway. To understand what structural factors influence the isomerization rate, we calculate the energy barrier to cholesterol isomerization in both the NPC1(NTD) and NPC2 binding pockets. Here, we use a combined quantum mechanical/molecular mechanical (QM/MM) energy function to calculate the isomerization barrier within the native NPC1(NTD) and NPC2 binding pockets before protein-protein docking as well as in the binding pockets of the NPC1(NTD)-NPC2 complex after docking has occurred. The results indicate that cholesterol isomerization in the NPC2 binding pocket is energetically favorable, both before and after formation of the NPC1(NTD)-NPC2 complex. The NPC1(NTD) binding pocket is energetically unfavorable to conformational rearrangement of the hydrophobic ligand because it contains more water molecules near the ligand tail and amino acids with polar side chains. For three NPC1(NTD) mutants investigated, L175Q/L176Q, L175A/L176A, and E191A/Y192A, the isomerization barriers were all found to be higher than the barrier calculated in the NPC2 binding pocket. Our results indicate that cholesterol isomerization in the NPC2 binding pocket, either before or after docking, may ensure an efficient transfer of cholesterol to NPC1(NTD).

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

Assessment of Oral Conditions and Quality of Life in Morbid Obese and Normal Weight Individuals: A Cross-Sectional Study.

PubMed

Yamashita, Joselene Martinelli; Moura-Grec, Patrícia Garcia de; Freitas, Adriana Rodrigues de; Sales-Peres, Arsênio; Groppo, Francisco Carlos; Ceneviva, Reginaldo; Sales-Peres, Sílvia Helena de Carvalho

2015-01-01

The aim of this study was to identify the impact of oral disease on the quality of life of morbid obese and normal weight individuals. Cohort was composed of 100 morbid-obese and 50 normal-weight subjects. Dental caries, community periodontal index, gingival bleeding on probing (BOP), calculus, probing pocket depth, clinical attachment level, dental wear, stimulated salivary flow, and salivary pH were used to evaluate oral diseases. Socioeconomic and the oral impacts on daily performances (OIDP) questionnaires showed the quality of life in both groups. Unpaired Student, Fisher's Exact, Chi-Square, Mann-Whitney, and Multiple Regression tests were used (p<0.05). Obese showed lower socio-economic level than control group, but no differences were found considering OIDP. No significant differences were observed between groups considering the number of absent teeth, bruxism, difficult mastication, calculus, initial caries lesion, and caries. However, saliva flow was low, and the salivary pH was changed in the obese group. Enamel wear was lower and dentine wear was higher in obese. More BOP, insertion loss, and periodontal pocket, especially the deeper ones, were found in obese subjects. The regression model showed gender, smoking, salivary pH, socio-economic level, periodontal pocket, and periodontal insertion loss significantly associated to obesity. However, both OIDP and BOP did not show significant contribution to the model. The quality of life of morbid obese was more negatively influenced by oral disease and socio-economic factors than in normal weight subjects.

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.

Effectiveness of adjunctive subgingival administration of amino acids and sodium hyaluronate gel on clinical and immunological parameters in the treatment of chronic periodontitis

PubMed Central

Bevilacqua, Lorenzo; Eriani, Jessica; Serroni, Ilde; Liani, Giuliana; Borelli, Violetta; Castronovo, Gaetano; Di Lenarda, Roberto

2012-01-01

Summary Aims The aim of this clinical trial was to compare clinical and biochemical healing outcomes following ultrasonic mechanical instrumentation versus ultrasonic mechanical instrumentation associated with topical subgingival application of amino acids and sodium hyaluronate gel. Methods Eleven systemically healthy subjects with moderate-severe chronic periodontitis, who had four sites with pocket probing depth and clinical attachment level greater than or equal to 5 mm were randomly assigned to two different types of treatment: two pockets were treated with ultrasonic debridement (Control Group) and two pockets with ultrasonic mechanical instrumentation associated with 0,5 ml of amino acids and sodium hyaluronate gel (Test Group). Probing depth, clinical attachment level, plaque index and bleeding on probing were recorded at baseline, 45 and 90 days. Levels of calprotectin and myeloperoxidase activity in gingival crevicular fluid were assessed at baseline and on day 7 and 45. Results Statistical significance was found between baseline and day 45 in relation to probing depth reduction and bleeding on probing between groups for both of the tested treatments. Significant reductions in μg/sample of calprotectin and myeloperoxidase were found after 1-week and an increase at 45 days in both groups. There were no statistically significant differences between other variables evaluated in this study. Conclusions These data suggest that subgingival application of hyaluronic acid following ultrasonic mechanical instrumentation is beneficial for improving periodontal parameters. PMID:23087790

Out-of-pocket expenditure by private households for dental services - empirical evidence from Austria.

PubMed

Sanwald, Alice; Theurl, Engelbert

2016-12-01

Dental services differ from other health services in several dimensions. One important difference is that a substantial share of costs of dental services-especially costs beyond routine dental treatment-is paid directly by the patient out-of-pocket. This study analyses the socio-economic determinants of out-of-pocket expenditure for dental services (OOPE) in Austria at the household level. Cross-sectional information on OOPE and household characteristics provided by the Austrian household budget survey 2009/10 was analysed. A two-part model (Logit/GLM) and one-part GLM was applied. The probability of OOPE is strongly affected by the life cycle (structure) of the household. It is higher for higher age classes, higher income, and partially higher levels of education. The type of public insurance has an influence on expenditure probability while the existence of private health insurance has no significant effect. In contrast to the highly statistically significant coefficients in the first stage, the covariates of the second stage remain predominantly insignificant. According to the results, the level of expenditure is driven mainly by the level of education and income. The results of the one-part GLM confirm the results of the two-part model. The results allow new insights into the determinants of OOPE for dental care. The household level turns out to be an adequate basis to study the determinants of OOPE, although caution should be applied before jumping to conclusions for the individual level.

Recognition of Nucleoside Monophosphate Substrates by Haemophilus influenzae Class C Acid Phosphatase

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

Singh, Harkewal; Schuermann, Jonathan P.; Reilly, Thomas J.

2010-12-08

The e (P4) phosphatase from Haemophilus influenzae functions in a vestigial NAD{sup +} utilization pathway by dephosphorylating nicotinamide mononucleotide to nicotinamide riboside. P4 is also the prototype of class C acid phosphatases (CCAPs), which are nonspecific 5{prime},3{prime}-nucleotidases localized to the bacterial outer membrane. To understand substrate recognition by P4 and other class C phosphatases, we have determined the crystal structures of a substrate-trapping mutant P4 enzyme complexed with nicotinamide mononucleotide, 5{prime}-AMP, 3{prime}-AMP, and 2{prime}-AMP. The structures reveal an anchor-shaped substrate-binding cavity comprising a conserved hydrophobic box that clamps the nucleotide base, a buried phosphoryl binding site, and three solvent-filled pocketsmore » that contact the ribose and the hydrogen-bonding edge of the base. The span between the hydrophobic box and the phosphoryl site is optimal for recognizing nucleoside monophosphates, explaining the general preference for this class of substrate. The base makes no hydrogen bonds with the enzyme, consistent with an observed lack of base specificity. Two solvent-filled pockets flanking the ribose are key to the dual recognition of 5{prime}-nucleotides and 3{prime}-nucleotides. These pockets minimize the enzyme's direct interactions with the ribose and provide sufficient space to accommodate 5{prime} substrates in an anti conformation and 3{prime} substrates in a syn conformation. Finally, the structures suggest that class B acid phosphatases and CCAPs share a common strategy for nucleotide recognition.« less

An Ultrasonographic Periodontal Probe

NASA Astrophysics Data System (ADS)

Bertoncini, C. A.; Hinders, M. K.

2010-02-01

Periodontal disease, commonly known as gum disease, affects millions of people. The current method of detecting periodontal pocket depth is painful, invasive, and inaccurate. As an alternative to manual probing, an ultrasonographic periodontal probe is being developed to use ultrasound echo waveforms to measure periodontal pocket depth, which is the main measure of periodontal disease. Wavelet transforms and pattern classification techniques are implemented in artificial intelligence routines that can automatically detect pocket depth. The main pattern classification technique used here, called a binary classification algorithm, compares test objects with only two possible pocket depth measurements at a time and relies on dimensionality reduction for the final determination. This method correctly identifies up to 90% of the ultrasonographic probe measurements within the manual probe's tolerance.

Changes in out-of-pocket charges associated with obstetric care provided under Medicare in Australia.

PubMed

Callander, Emily; Fox, Haylee

2018-06-01

Recent health reforms alongside unregulated provider fees have led to increased attention being given to out-of-pocket healthcare costs. This study utilised annual statistics published by the Department of Health for services provided under the Medicare Benefits Schedule (MBS) from 1992/3 to 2016/17 to identify changes in out-of-pocket charges for obstetric items over time, and estimate the change in demand for obstetric items in response to price increases. Since 1992/3 out-of-pocket charges increased by 1035% for out-of-hospital items and 77% for in-hospital items. Demand for obstetric items has reduced with increasing charges. © 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Generating "fragment-based virtual library" using pocket similarity search of ligand-receptor complexes.

PubMed

Khashan, Raed S

2015-01-01

As the number of available ligand-receptor complexes is increasing, researchers are becoming more dedicated to mine these complexes to aid in the drug design and development process. We present free software which is developed as a tool for performing similarity search across ligand-receptor complexes for identifying binding pockets which are similar to that of a target receptor. The search is based on 3D-geometric and chemical similarity of the atoms forming the binding pocket. For each match identified, the ligand's fragment(s) corresponding to that binding pocket are extracted, thus forming a virtual library of fragments (FragVLib) that is useful for structure-based drug design. The program provides a very useful tool to explore available databases.

Crystal Structure of Neurotropism-Associated Variable Surface Protein 1 (VSP1) of Borrelia Turicatae

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

Lawson,C.; Yung, B.; Barbour, A.

2006-01-01

Vsp surface lipoproteins are serotype-defining antigens of relapsing fever spirochetes that undergo multiphasic antigenic variation to allow bacterial persistence in spite of an immune response. Two isogenic serotypes of Borrelia turicatae strain Oz1 differ in their Vsp sequences and in disease manifestations in infected mice: Vsp1 is associated with the selection of a neurological niche, while Vsp2 is associated with blood and skin infection. We report here crystal structures of the Vsp1 dimer at 2.7 and 2.2 Angstroms. The structures confirm that relapsing fever Vsp proteins share a common helical fold with OspCs of Lyme disease-causing Borrelia. The fold featuresmore » an inner stem formed by highly conserved N and C termini and an outer 'dome' formed by the variable central residues. Both Vsp1 and OspC structures possess small water-filled cavities, or pockets, that are lined largely by variable residues and are thus highly variable in shape. These features appear to signify tolerance of the Vsp-OspC fold for imperfect packing of residues at its antigenic surface. Structural comparison of Vsp1 with a homology model for Vsp2 suggests that observed differences in disease manifestation may arise in part from distinct differences in electrostatic surface properties; additional predicted positively charged surface patches on Vsp2 compared to Vsp1 may be sufficient to explain the relative propensity of Vsp2 to bind to acidic glycosaminoglycans.« less

The evaluation of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontitis

PubMed Central

Chadha, Vandana Srikrishna; Bhat, Khandige Mahalinga

2012-01-01

Background: Investigators have sought different methods to deliver antimicrobials to periodontal pockets. This study was designed to assess the efficacy of locally made doxycycline gel versus locally made doxycycline implant as biodegradable controlled local delivery systems, by evaluating the pharmacological drug release and improvement in gingival status, gain in attachment, and reduction in pocket depth. Materials and Methods: Thirty patients with localized periodontal pockets ≥5 mm were randomly divided into three groups. The first group received the doxycycline gel, the second the doxycycline implant, and the third received only scaling and root planing (the control group). The patients in the first two groups were selected for the drug release. Clinical parameters such as gingival index, plaque index, probing depth, and attachment levels were recorded at baseline and the 90th day. Gingival crevicular fluid (GCF) and saliva samples were collected 1 hour following gel and implant placement and then on the 10th, 30th, and 60th days. Results: There was a statistically significant difference in the release of doxycycline from the gel when compared with the implant in the GCF and saliva on the 10th and 30th days. All the three groups showed improvement in clinical parameters. The improvements in both gel and implant groups were greater when compared with the control group with no statistically significant difference between the implant and gel systems. Conclusion: The use of local delivery of doxycycline through gel and Implant media further enhances the positive changes obtained following scaling and root planing. The release of doxycycline from the implant and the gel was comparable. PMID:23055585

Effects of rodent species, seed species, and predator cues on seed fate

NASA Astrophysics Data System (ADS)

Sivy, Kelly J.; Ostoja, Steven M.; Schupp, Eugene W.; Durham, Susan

2011-07-01

Seed selection, removal and subsequent management by granivorous animals is thought to be a complex interaction of factors including qualities of the seeds themselves (e.g., seed size, nutritional quality) and features of the local habitat (e.g. perceived predator risk). At the same time, differential seed selection and dispersal is thought to have profound effects on seed fate and potentially vegetation dynamics. In a feeding arena, we tested whether rodent species, seed species, and indirect and direct predation cues influence seed selection and handling behaviors (e.g., scatter hoarding versus larder hoarding) of two heteromyid rodents, Ord's kangaroo rat ( Dipodomys ordii) and the Great Basin pocket mouse ( Perognathus parvus). The indirect cue was shrub cover, a feature of the environment. Direct cues, presented individually, were (1) control, (2) coyote ( Canis latrans) vocalization, (3) coyote scent, (4) red fox ( Vulpes vulpes) scent, or (5) short-eared owl ( Asio flammeus) vocalization. We offered seeds of three sizes: two native grasses, Indian ricegrass ( Achnatherum hymenoides) and bluebunch wheatgrass ( Pseudoroegneria spicata), and the non-native cereal rye ( Secale cereale), each in separate trays. Kangaroo rats preferentially harvested Indian ricegrass while pocket mice predominately harvested Indian ricegrass and cereal rye. Pocket mice were more likely to scatter hoard preferred seeds, whereas kangaroo rats mostly consumed and/or larder hoarded preferred seeds. No predator cue significantly affected seed preferences. However, both species altered seed handling behavior in response to direct predation cues by leaving more seeds available in the seed pool, though they responded to different predator cues. If these results translate to natural dynamics on the landscape, the two rodents are expected to have different impacts on seed survival and plant recruitment via their different seed selection and seed handling behaviors.

Twisting a β-Carotene, an Adaptive Trick from Nature for Dissipating Energy during Photoprotection*

PubMed Central

Sobotka, Roman; Kish, Elizabeth; Shukla, Mahendra Kumar; Pascal, Andrew A.; Polívka, Tomáš; Robert, Bruno

2017-01-01

Cyanobacteria possess a family of one-helix high light-inducible proteins (Hlips) that are homologous to light-harvesting antenna of plants and algae. An Hlip protein, high light-inducible protein D (HliD) purified as a small complex with the Ycf39 protein is evaluated using resonance Raman spectroscopy. We show that the HliD binds two different β-carotenes, each present in two non-equivalent binding pockets with different conformations, having their (0,0) absorption maxima at 489 and 522 nm, respectively. Both populations of β-carotene molecules were in all-trans configuration and the absorption position of the farthest blue-shifted β-carotene was attributed entirely to the polarizability of the environment in its binding pocket. In contrast, the absorption maximum of the red-shifted β-carotene was attributed to two different factors: the polarizability of the environment in its binding pocket and, more importantly, to the conformation of its β-rings. This second β-carotene has highly twisted β-rings adopting a flat conformation, which implies that the effective conjugation length N is extended up to 10.5 modifying the energetic levels. This increase in N will also result in a lower S1 energy state, which may provide a permanent energy dissipation channel. Analysis of the carbonyl stretching region for chlorophyll a excitations indicates that the HliD binds six chlorophyll a molecules in five non-equivalent binding sites, with at least one chlorophyll a presenting a slight distortion to its macrocycle. The binding modes and conformations of HliD-bound pigments are discussed with respect to the known structures of LHCII and CP29. PMID:27994060

Treatment of oral malodor and periodontal disease using an antibiotic rinse.

PubMed

Southward, Ken; Bosy, Anne

2013-07-01

The purpose of this study was to determine the effectiveness of an antibiotic rinse preparation, containing metronidazole and nystatin, in decreasing oral malodor and periodontal disease for individuals whose chief complaint was halitosis. This topical approach to oral biofilm control, by proactively managing the most pathogenic bacteria, differs from the traditional approach of reactively treating the symptoms by attempting to reduce all oral bacteria. The late Dr. Loesche, University of Michigan, School of Dentistry, had previously described these different paradigms as the specific plaque hypothesis and the non-specific plaque hypothesis, respectively. Patients in this study were measured before and after treatment for volatile sulphur compounds using a portable sulphide monitor, a digital gas chromatograph, and organoleptic assessment. The presence of periodontal disease was determined by 6-point periodontal probing, to assess pocket depth and bleeding points. Of the 1000 patient charts sent electronically to the University of Michigan for analysis, 649 participants were selected based on complete pre- and post-treatment data, and statistically analyzed by a statistician, who was an expert in case study analysis. The post-treatment reduction of oral malodor was 80% (P = 0.0001). The difference in bleeding points pre- and post-treatment was 87% (P = 0.0001). There was a decrease in the number of teeth with 6 and 7 mm pockets by 76% and teeth with 5 mm pockets decreased by 84% (P = 0.0001). Treatment with the antibiotic rinse had a positive change in the periodontal status and breath odor of these patients. These data indicate that there is considerable advantage to the use of topical antibiotic rinses. A substantial decrease in both halitosis and periodontal disease markers can be achieved without the risk of the systemic effects of an oral antibiotic.

Assessment of the intensity and spatial variability of urban heat islands over the Indian cities for Regional Climate Analysis

NASA Astrophysics Data System (ADS)

Sultana, S.; Satyanarayana, A. N. V.

2016-12-01

The Urban heat island (UHI) in general developed over cities, due to the drastic changes in land use and land cover (LULC), has profound impact on the atmospheric circulation patterns due to the changes in the energy transport mechanism which in turn affect the regional climate. In this study, an attempt has been made to quantify the intensity of UHI, and to identify the pockets of UHI over cities during last decade over fast developing cosmopolitan Indian cities such as New Delhi, Mumbai and Kolkata. For this purpose, Landsat TM and ETM+ images during winter period, in about 5 year intervals from 2002 to 2013, has been selected to retrieve the brightness temperatures and land use/cover, from which Land Surface Temperature (LST) has been estimated using Normalized Difference Vegetation Index (NDVI). Normalized Difference Build-up Index (NDBI) and Normalized Difference Bareness Index (NDBaI) are estimated to extract build-up areas and bare land from the satellite images to identify the UHI pockets over the study area. For this purpose image processing and GIS tools were employed. Results reveal a significant increase in the intensity of UHI and increase in its area of influence over all the three cities. An increase of 2 to 2.5 oC of UHI intensity over the study regions has been noticed. The range of increase in UHI intensity is found to be more over New Delhi compared to Mumbai and Kolkata which is more or less same. The number of hotspot pockets of UHI has also been increased as seen from the spatial distribution of LST, NDVI and NDBI. This result signifies the impact of rapid urbanization and infrastructural developments has a direct consequence in modulating the regional climate over the Indian cities.

Utilisation of maternal health care in western rural China under a new rural health insurance system (New Co-operative Medical System).

PubMed

Long, Qian; Zhang, Tuohong; Xu, Ling; Tang, Shenglan; Hemminki, Elina

2010-10-01

To investigate factors influencing maternal health care utilisation in western rural China and its relation to income before (2002) and after (2007) introducing a new rural health insurance system (NCMS). Data from cross-sectional household-based health surveys carried out in ten western rural provinces of China in 2003 and 2008 were used in the study. The study population comprised women giving birth in 2002 or 2007, with 917 and 809 births, respectively. Correlations between outcomes and explanatory variables were studied by logistic regression models and a log-linear model. Between 2002 and 2007, having no any pre-natal visit decreased from 25% to 12% (difference 13%, 95% CI 10-17%); facility-based delivery increased from 45% to 80% (difference 35%, 95% CI 29-37%); and differences in using pre-natal and delivery care between the income groups narrowed. In a logistic regression analysis, women with lower education, from minority groups, or high parity were less likely to use pre-natal and delivery care in 2007. The expenditure for facility-based delivery increased over the period, but the out-of-pocket expenditure for delivery as a percentage of the annual household income decreased. In 2007, it was 14% in the low-income group. NCMS participation was found positively correlated with lower out-of-pocket expenditure for facility-based delivery (coefficient -1.14 P < 0.05) in 2007. Facility-based delivery greatly increased between 2002 and 2007, coinciding with the introduction of the NCMS. The rural poor were still facing substantial payment for facility-based delivery, although NCMS participation reduced the out-of-pocket expenditure on average. © 2010 Blackwell Publishing Ltd.

Effects of rodent species, seed species, and predator cues on seed fate

USGS Publications Warehouse

Sivy, Kelly J.; Ostoja, Steven M.; Schupp, Eugene W.; Durham, Susan

2011-01-01

Seed selection, removal and subsequent management by granivorous animals is thought to be a complex interaction of factors including qualities of the seeds themselves (e.g., seed size, nutritional quality) and features of the local habitat (e.g. perceived predator risk). At the same time, differential seed selection and dispersal is thought to have profound effects on seed fate and potentially vegetation dynamics. In a feeding arena, we tested whether rodent species, seed species, and indirect and direct predation cues influence seed selection and handling behaviors (e.g., scatter hoarding versus larder hoarding) of two heteromyid rodents, Ord's kangaroo rat (Dipodomys ordii) and the Great Basin pocket mouse (Perognathus parvus). The indirect cue was shrub cover, a feature of the environment. Direct cues, presented individually, were (1) control, (2) coyote (Canis latrans) vocalization, (3) coyote scent, (4) red fox (Vulpes vulpes) scent, or (5) short-eared owl (Asio flammeus) vocalization. We offered seeds of three sizes: two native grasses, Indian ricegrass (Achnatherum hymenoides) and bluebunch wheatgrass (Pseudoroegneria spicata), and the non-native cereal rye (Secale cereale), each in separate trays. Kangaroo rats preferentially harvested Indian ricegrass while pocket mice predominately harvested Indian ricegrass and cereal rye. Pocket mice were more likely to scatter hoard preferred seeds, whereas kangaroo rats mostly consumed and/or larder hoarded preferred seeds. No predator cue significantly affected seed preferences. However, both species altered seed handling behavior in response to direct predation cues by leaving more seeds available in the seed pool, though they responded to different predator cues. If these results translate to natural dynamics on the landscape, the two rodents are expected to have different impacts on seed survival and plant recruitment via their different seed selection and seed handling behaviors.

Mitigation and treatment of pollutants from railway and highway runoff by pocket wetland system; A case study.

PubMed

Senduran, Cem; Gunes, Kemal; Topaloglu, Duygu; Dede, Omer Hulusi; Masi, Fabio; Kucukosmanoglu, Ozen Arli

2018-08-01

This study performed in Sapanca Lake catchment area, used as a drinking water resource. Two highways located at northern and southern shores, and a railway at its south are significant sources of pollution. As a possible solution for protecting water quality a pocket wetland constructed and operated. Performances statistically interpreted by Spearman's Correlation test and univariate analysis of variance on collected data. The mean removal efficiencies obtaited were 52% (TSS), 4% (Nitrate), 26% (TN), -5% (TOC), 63% (TP), 4.5% (Chloride), 3% (Sulfate), 33% (Cr), 39% (Co), -19.5% (Ni), 7% (Cu), 55% (Zn), 36% (As), 38% (Cd) and 18% (Pb). TSS removal was in positive significant medium correlation with Co, Cu, Zn, and Pb removal respectively (p < 0.05). Other statistically significant positive high correlations calculated between removal efficiency of Nitrate-TN, Chloride-Sulfate, Cr-Co-Cu-As-Cd. According to ANOVA and Kruskal-Wallis test results, removal efficiencies of TSS and TOC partially affected by different temperature (p < 0.1 for TSS and p < 0.05 for TOC) and pH ranges (p < 0.1 for both removal efficiencies), TP removal efficiency significantly affected by different pH ranges (p < 0.001), and Chloride and Sulfate removal efficiencies were significantly (p < 0.001) affected by different temperature ranges. Regardless of geographical location and climatic factors, pocket wetland systems can be relied upon for minimizing heavy metals such as Cr, Co, Zn, As, Cd and Pb and critical pollutants such as TP and TSS caused by highway runoff. Copyright © 2018 Elsevier Ltd. All rights reserved.

Out-of-pocket health spending by poor and near-poor elderly Medicare beneficiaries.

PubMed

Gross, D J; Alecxih, L; Gibson, M J; Corea, J; Caplan, C; Brangan, N

1999-04-01

To estimate out-of-pocket health care spending by lower-income Medicare beneficiaries, and to examine spending variations between those who receive Medicaid assistance and those who do not receive such aid. DATA SOURCES AND COLLECTION: 1993 Medicare Current Beneficiary Survey (MCBS) Cost and Use files, supplemented with data from the Bureau of the Census (Current Population Survey); the Congressional Budget Office; the Health Care Financing Administration, Office of the Actuary (National Health Accounts); and the Social Security Administration. We analyzed out-of-pocket spending through a Medicare Benefits Simulation model, which projects out-of-pocket health care spending from the 1993 MCBS to 1997. Out-of-pocket health care spending is defined to include Medicare deductibles and coinsurance; premiums for private insurance, Medicare Part B, and Medicare HMOs; payments for non-covered goods and services; and balance billing by physicians. It excludes the costs of home care and nursing facility services, as well as indirect tax payments toward health care financing. Almost 60 percent of beneficiaries with incomes below the poverty level did not receive Medicaid assistance in 1997. We estimate that these beneficiaries spent, on average, about half their income out-of-pocket for health care, whether they were enrolled in a Medicare HMO or in the traditional fee-for-service program. The 75 percent of beneficiaries with incomes between 100 and 125 percent of the poverty level who were not enrolled in Medicaid spent an estimated 30 percent of their income out-of-pocket on health care if they were in the traditional program and about 23 percent of their income if they were enrolled in a Medicare HMO. Average out-of-pocket spending among fee-for-service beneficiaries varied depending on whether beneficiaries had Medigap policies, employer-provided supplemental insurance, or no supplemental coverage. Those without supplemental coverage spent more on health care goods and services, but spent less than the other groups on prescription drugs and dental care-services not covered by Medicare. While Medicaid provides substantial protection for some lower-income Medicare beneficiaries, out-of-pocket health care spending continues to be a substantial burden for most of this population. Medicare reform discussions that focus on shifting more costs to beneficiaries should take into account the dramatic costs of health care already faced by this vulnerable population.

Out-of-pocket payments for health care services in Bulgaria: financial burden and barrier to access.

PubMed

Atanasova, Elka; Pavlova, Milena; Moutafova, Emanuela; Rechel, Bernd; Groot, Wim

2013-12-01

In recent years, Bulgaria has increasingly relied on out-of-pocket payments as one of the main sources of health care financing. However, it is largely unknown whether the official patient charges, combined with informal payments, are affordable for the population. Our study aimed to explore the scale of out-of-pocket payments for health care services and their affordability. Data were collected in two nationally representative surveys, conducted in Bulgaria in 2010 and 2011, using face-to-face interviews based on a standardized questionnaire. To select respondents, a multi-stage random probability method was used. The questionnaire included questions on the out-of-pocket payments for health care services used by the respondent during the preceding 12 months. In total, 75.7% (2010) and 84.0% (2011) of outpatient service users reported to have paid out-of-pocket, with 12.6% (2010) and 9.7% (2011) of users reporting informal payments. Of those who had used inpatient services, 66.5% (2010) and 63.1% (2011) reported to have made out-of-pocket payments, with 31.8% (2010) and 18.3% (2011) reporting to have paid informally. We found large inability to pay indicated by the need to borrow money and/or forego services. Regression analysis showed that the inability to pay is especially pronounced among those with poor health status and chronic diseases and those on low household incomes. The high level of both formal and informal out-of-pocket payments for health care services in Bulgaria poses a considerable burden for households and undermines access to health services for poorer parts of the population.

Out-of-pocket costs for childhood stroke: the impact of chronic illness on parents' pocketbooks.

PubMed

Plumb, Patricia; Seiber, Eric; Dowling, Michael M; Lee, JoEllen; Bernard, Timothy J; deVeber, Gabrielle; Ichord, Rebecca N; Bastian, Rachel; Lo, Warren D

2015-01-01

Direct costs for children who had stroke are similar to those for adults. There is no information regarding the out-of-pocket costs families encounter. We described the out-of-pocket costs families encountered in the first year after a child's ischemic stroke. Twenty-two subjects were prospectively recruited at four centers in the United States and Canada in 2008 and 2009 as part of the "Validation of the Pediatric NIH Stroke Scale" study; families' indirect costs were tracked for 1 year. Every 3 months, parents reported hours they did not work, nonreimbursed costs for medical visits or other health care, and mileage. They provided estimates of annual income. We calculated total out-of-pocket costs in US dollars and reported costs as a proportion of annual income. Total median out-of-pocket cost for the year after an ischemic stroke was $4354 (range, $0-$28,666; interquartile range, $1008-$8245). Out-of-pocket costs were greatest in the first 3 months after the incident stroke, with the largest proportion because of lost wages, followed by transportation, and nonreimbursed health care. For the entire year, median costs represented 6.8% (range, 0%-81.9%; interquartile range, 2.7%-17.2%) of annual income. Out-of-pocket expenses are significant after a child's ischemic stroke. The median costs are noteworthy provided that the median American household had cash savings of $3650 at the time of the study. These results with previous reports of direct costs provide a more complete view of the overall costs to families and society. Childhood stroke creates an under-recognized cost to society because of decreased parental productivity. Copyright © 2015 Elsevier Inc. All rights reserved.

Parallel pocket incision: Less invasive surgical intervention for the treatment of intractable pressure ulcer with wound edge undermining.

PubMed

Yamamoto, Takumi; Yoshimatsu, Hidehiko; Hayashi, Akitatsu; Koshima, Isao

2015-10-01

The treatment of deep pressure ulcer with a wide wound edge undermining (pocket) is challenging, especially when conservative treatments are ineffective. As most patients with a pressure ulcer suffer from systemic comorbidities, invasive surgery cannot be performed on all patients, and less invasive treatment is required. Less invasive surgical intervention to a deep pressure ulcer, parallel pocket incision (PPI), was performed on 10 patients with intractable pressure ulcers with a pocket formation. In PPI procedures, two parallel skin incisions were made to open up the deepest fold of the pocket and to preserve the skin overlying the pocket lesion; through the created incisions, the necrotic tissues around the deepest fold of the undermining could be easily removed, which facilitated spontaneous wound healing. Postoperative results and complications were evaluated. All PPI procedures were safely performed under local infiltration anesthesia without major postoperative complication; minor bleeding was seen intraoperatively in three patients, which could be easily controlled with electric cautery coagulation. Nine of 10 ulcers were cured after PPI, and one could not be followed up due to the patient's death non-related to the pressure ulcer. For the nine cured patients, the average time for cure was 14.9 weeks, and no recurrence was observed at postoperative 6 months. PPI is a simple, technically easy, and less invasive surgical intervention to an intractable pressure ulcer with a pocket, which can be safely performed under local infiltration anesthesia even on a patient with severe systemic comorbidities. Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Trivalent ions modification for high-silica mordenite: A first principles study

NASA Astrophysics Data System (ADS)

Chen, Fayun; Zhang, Laijun; Feng, Gang; Wang, Xuewen; Zhang, Rongbin; Liu, Jianwen

2018-03-01

Using periodic DFT-D3-U methods, the present work give a mechanistic insight into the high silica B-, Al-, Ga- and Fe-MOR with H, Li, Na, and K as charge balance ions. The acid properties of the zeolite were probed via NH3 and pyridine adsorption. It is found that the charge balance ions influence the location of the trivalent ions, the cell volumes, as well as the synthesis difficulty of the zeolites. The energy differences for B, Al, Ga and Fe in different T sites are small for the H-form zeolites, while large for the Na- and K-form zeolites. For H-form MOR, the proton of the sbnd OH group prefers to bond to O(7) and O(3) and pointing to the 12MR for trivalent ions in T1 sites. The proton bonds to O(3), O(2), O(2) and O(5), respectively, for B, Al, Ga and Fe in T2 site of MOR, with the sbnd OH group pointing to intersection of 12MR and the side-pocket, except for the B-MOR that sbnd OH group pointing to the 12MR. For trivalent ions located in T3 and T4 sites, the protons prefers to bond to O(1) and O(2), respectively, with the sbnd OH group pointing to the intersection of 8MR and side-pocket as well as the intersection of 12MR and side-pocket. All incorporated B, Al, Ga, and Fe framework ions are tetra-coordinated, except the B atoms are tri-coordinated. The NH4-form MOR has smaller cell volume than the other form MOR. Na and K are energetically more favored charge balance ions than Li and NH3 for MOR zeolites synthesis, and the H-form zeolite is the most difficult to be synthesized directly. The strength of the Brønsted acidity follows the order: HBMOR < HFeMOR ≈ HGaMOR < HAlMOR, vs. the Lewis acidity order: HBMOR < HAlMOR < HFeMOR ≈ HGaMOR. NH3 could be adsorbed inside all kinds of channels, and especially favors in the small 8MR vs. pyridine could only be adsorbed in the main channel of MOR due to the steric effect. It indicates that the acid sites in the side pocket and the small 8-membered ring and the side pocket could not be effectively determined just by the pyridine adsorption experiments. In comparison, the NH3 adsorption experiments could detect all kinds of Brønsted sites of the MOR zeolites.

CALUTRON RECEIVER

DOEpatents

Barnes, S.W.

1959-08-25

An improvement in a calutron receiver for collecting the isotopes ts described. The electromagnetic separation of the isotopes produces a mass spectrum of closely adjacent beams of ions at the foci regions, and a dividing wall between the two pockets is arranged at an angle. Substantially all of the tons of the less abundant isotope enter one of the pockets and strike one side of the wall directly, while substantially none of the tons entering the other pocket strikes the wall directly.

Three Dimensional Flow and Pressure Patterns in a Single Pocket of a Hydrostatic Journal Bearing

NASA Technical Reports Server (NTRS)

Braun, M. Jack; Dzodzo, Milorad B.

1996-01-01

The flow in a hydrostatic pocket is described by a mathematical model that uses the three dimensional Navier-Stokes equations written in terms of the primary variables, u, v, w, and p. Using a conservative formulation, a finite volume multi-block method is applied through a collocated, body fitted grid. The flow is simulated in a shallow pocket with a depth/length ratio of 0.02. The flow structures obtained and described by the authors in their previous two dimensional models are made visible in their three dimensional aspect for the Couette flow. It has been found that the flow regimes formed central and secondary vortical cells with three dimensional corkscrew-like structures that lead the fluid on an outward bound path in the axial direction of the pocket. The position of the central vortical cell center is at the exit region of the capillary restrictor feedline. It has also been determined that a fluid turn around zone occupies all the upstream space between the floor of the pocket and the runner, thus preventing any flow exit through the upstream port. The corresponding pressure distribution under the shaft presented as well. It was clearly established that for the Couette dominated case the pressure varies significantly in the pocket in the circumferential direction, while its variation is less pronounced axially.

Research: Comparison of the Accuracy of a Pocket versus Standard Pulse Oximeter.

PubMed

da Costa, João Cordeiro; Faustino, Paula; Lima, Ricardo; Ladeira, Inês; Guimarães, Miguel

2016-01-01

Pulse oximetry has become an essential tool in clinical practice. With patient self-management becoming more prevalent, pulse oximetry self-monitoring has the potential to become common practice in the near future. This study sought to compare the accuracy of two pulse oximeters, a high-quality standard pulse oximeter and an inexpensive pocket pulse oximeter, and to compare both devices with arterial blood co-oximetry oxygen saturation. A total of 95 patients (35.8% women; mean [±SD] age 63.1 ± 13.9 years; mean arterial pressure was 92 ± 12.0 mmHg; mean axillar temperature 36.3 ± 0.4°C) presenting to our hospital for blood gas analysis was evaluated. The Bland-Altman technique was performed to calculate bias and precision, as well as agreement limits. Student's t test was performed. Standard oximeter presented 1.84% bias and a precision error of 1.80%. Pocket oximeter presented a bias of 1.85% and a precision error of 2.21%. Agreement limits were -1.69% to 5.37% (standard oximeter) and -2.48% to 6.18% (pocket oximeter). Both oximeters presented bias, which was expected given previous research. The pocket oximeter was less precise but had agreement limits that were comparable with current evidence. Pocket oximeters can be powerful allies in clinical monitoring of patients based on a self-monitoring/efficacy strategy.

Impacts of chronic non-communicable diseases on households' out-of-pocket healthcare expenditures in Sri Lanka.

PubMed

Pallegedara, Asankha

2018-01-10

This article examines the effects of chronic non-communicable diseases (NCDs) on households' out-of-pocket health expenditures in Sri Lanka. We explore the disease specific impacts on out-of-pocket health care expenses from chronic NCDs such as heart diseases, hypertension, cancer, diabetics and asthma. We use nationwide cross-sectional household income and expenditure survey 2012/2013 data compiled by the department of census and statistics of Sri Lanka. Employing propensity score matching method to account for selectivity bias, we find that chronic NCD affected households appear to spend significantly higher out-of-pocket health care expenditures and encounter grater economic burden than matched control group despite having universal public health care policy in Sri Lanka. The results also suggest that out-of-pocket expenses on medicines and other pharmaceutical products as well as expenses on medical laboratory tests and other ancillary services are particularly higher for households with chronic NCD patients. The findings underline the importance of protecting households against the financial burden due to NCDs.

Household portfolio choices, health status and health care systems: A cross-country analysis based on SHARE

PubMed Central

Atella, Vincenzo; Brunetti, Marianna; Maestas, Nicole

2013-01-01

Health risk is increasingly viewed as an important form of background risk that affects household portfolio decisions. However, its role might be mediated by the presence of a protective full-coverage national health service that could reduce households’ probability of incurring current and future out-of-pocket medical expenditures. We use SHARE data to study the influence of current health status and future health risk on the decision to hold risky assets, across ten European countries with different health systems, each offering a different degree of protection against out-of-pocket medical expenditures. We find robust empirical evidence that perceived health status matters more than objective health status and, consistent with the theory of background risk, health risk affects portfolio choices only in countries with less protective health care systems. Furthermore, portfolio decisions consistent with background risk models are observed only with respect to middle-aged and highly-educated investors. PMID:23885134

BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid.

PubMed

Fricke, Thomas; Buffone, Cindy; Opp, Silvana; Valle-Casuso, Jose; Diaz-Griffero, Felipe

2014-12-11

The recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74. This work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor CPSF6 to the HIV-1 core. Overall this short-form paper suggests that BI-2 is using a similar mechanism to the one used by PF74 to block HIV-1 infection.

Minding money: how understanding of value is culturally promoted.

PubMed

Sato, Tatsuya

2011-03-01

Adding to the issues of cognitive economics (Cortes and Londoño IPBS: Integrative Psychological & Behavioral Science 43(2):178-184, 2009) and the social psychology of "shadow economics" (Salvatore et al. IPBS: Integrative Psychological & Behavioral Science 43(2), 2009), the carrier of economic exchanges, money, plays a key role in children's socialization in different societies. Money given to children, 'pocket money,' is a negotiated settlement between children's social demands and those of their parents. I analyze such negotiations here on the basis of a concrete case of a Korean family in which the provision of pocket money given the child was inconsistent over time. The results indicate the social ecology of money use, in both children and their parents, sets the stage for value construction of the meaning of money.