WorldWideScience

Sample records for single peptide hits

  1. Beware the single hit!

    CERN Multimedia

    2008-01-01

    The first time that single particle effects from cosmic rays on electronics were observed was in 1991, when one of the instruments aboard an ESA satellite broke down after only five days in space. On 5 July, the TS-LEA group will have completed the installation of monitors that will help to reduce similar dangerous effects on LHC electronics.

  2. Development of the IFJ single ion hit facility for cells irradiation

    International Nuclear Information System (INIS)

    Veselov, O.; Polak, W.; Ugenskiene, R.; Hajduk, R.; Lebed, K.; Lekki, J.; Horwacik, T.; Dutkiewicz, E.M.; Maranda, S.; Pieprzyca, T.; Sarnecki, C.; Stachura, Z.; Szklarz, Z.; Styczen, J.

    2005-12-01

    In recent years a single ion hit facility (SIHF) has been constructed at the IFJ ion microprobe. The setup is used for the precise irradiations of living cells by a controlled number of ions. The facility allows investigations in various aspects of biomedical research, such as adaptive response, bystander effect, inverse dose-rate effect, low-dose hypersensitivity, etc. Those investigations have two very important requirements: (i) cells must be examined in their natural state and environment, i.e. without previously being killed, and preferentially, neither fixed nor stained, and (ii) a possibility of automatic irradiation of large number of cells with a computer recognition of their positions must be provided. This work presents some of the crucial features of the off-line and on-line optical systems, including self-developed software responsible for the automatic cell recognition. We also show several tests carried out to determine the efficiency of the whole setup and some segments. In conclusion, the results of our first irradiation measurements performed with living cells are demonstrated. (author)

  3. Differential scanning calorimetry of whole Escherichia coli treated with the antimicrobial peptide MSI-78 indicate a multi-hit mechanism with ribosomes as a novel target

    Directory of Open Access Journals (Sweden)

    Alexander M. Brannan

    2015-12-01

    Full Text Available Differential Scanning Calorimetry (DSC of intact Escherichia coli (E. coli was used to identify non-lipidic targets of the antimicrobial peptide (AMP MSI-78. The DSC thermograms revealed that, in addition to its known lytic properties, MSI-78 also has a striking effect on ribosomes. MSI-78’s effect on DSC scans of bacteria was similar to that of kanamycin, an antibiotic drug known to target the 30S small ribosomal subunit. An in vitro transcription/translation assay helped confirm MSI-78’s targeting of ribosomes. The scrambled version of MSI-78 also affected the ribosome peak of the DSC scans, but required greater amounts of peptide to cause a similar effect to the unscrambled peptide. Furthermore, the effect of the scrambled peptide was not specific to the ribosomes; other regions of the DSC thermogram were also affected. These results suggest that MSI-78’s effects on E. coli are at least somewhat dependent on its particular structural features, rather than a sole function of its overall charge and hydrophobicity. When considered along with earlier work detailing MSI-78’s membrane lytic properties, it appears that MSI-78 operates via a multi-hit mechanism with multiple targets.

  4. Is "hit and run" a single word? The processing of irreversible binomials in neglect dyslexia.

    Science.gov (United States)

    Arcara, Giorgio; Lacaita, Graziano; Mattaloni, Elisa; Passarini, Laura; Mondini, Sara; Benincà, Paola; Semenza, Carlo

    2012-01-01

    The present study is the first neuropsychological investigation into the problem of the mental representation and processing of irreversible binomials (IBs), i.e., word pairs linked by a conjunction (e.g., "hit and run," "dead or alive"). In order to test their lexical status, the phenomenon of neglect dyslexia is explored. People with left-sided neglect dyslexia show a clear lexical effect: they can read IBs better (i.e., by dropping the leftmost words less frequently) when their components are presented in their correct order. This may be taken as an indication that they treat these constructions as lexical, not decomposable, elements. This finding therefore constitutes strong evidence that IBs tend to be stored in the mental lexicon as a whole and that this whole form is preferably addressed in the retrieval process.

  5. Effects of drain-wall in mitigating N-hit single event transient via 45 nm CMOS process

    International Nuclear Information System (INIS)

    Xu, X Y; Tang, M H; Xiao, Y G; Yan, S A; Zhang, W L; Li, Z; Xiong, Y; Zhao, W; Guo, H X

    2015-01-01

    A three-dimensional (3D) technology computer-aided design (TCAD) simulation in a novel layout technique for N-hit single event transient (SET) mitigation based on drain-wall layout technique is proposed. Numerical simulations of both single-device and mixed-mode show that the proposed layout technique designed with 45 nm CMOS process can efficiently reduce not only charge collection but also SET pulse widths (W SET ). What is more, simulations show that impacts caused by part of ion-incidents can be shielded with this novel layout technique. When compared with conventional layout technique and guard drain layout technique, we find that the proposed novel layout technique can provide the best benefit of SET mitigation with a small sacrifice in effective area. (paper)

  6. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    International Nuclear Information System (INIS)

    Puddu, A.; Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L.

    2010-01-01

    Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  7. Development of noise-suppressed detector for single ion hit system

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Takuro; Hamano, Tsuyoshi; Suda, Tamotsu; Hirao, Toshio; Kamiya, Tomihiro [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    1997-03-01

    A noise-suppressed detector for single ion detection has been developed, and combined with the heavy ion microbeam apparatus. This detector consists of a pair of micro channel plates (MCP`s) and a very thin carbon foil. The detection signal is formed by the coincidence of the signals from these MCP`s, so that this detector and the coincidence measurement unit can reduce miscounting in the circuit. The detection efficiency for 15 MeV heavy ions was evaluated to be comparable to that of a silicon surface-barrier detector (SSD) and the miscounting rate was 4 orders lower than the noise rate of a single MCP. The rise time of the detection signal was also estimated. (author)

  8. An explanation for the multiplicative and the additive dose-effect relationship with the single-hit model

    International Nuclear Information System (INIS)

    Kottbauer, M.M.; Fleck, C.M.; Schoellnberger, H.

    1997-01-01

    For solid tumors and for leukemia the excess cancer rate after a single radiation dose D is different. The multiplicative model describes the excess solid tumor probability rate which is proportional to the background rate of cancer and dependent on dose D. The additive model describes the excess probability rate for leukaemia which is proportional to the dose D but unrelated to the spontaneous rate of cancer. A second great difference between the two models is the duration of the increased cancer probability rate. The multiplicative mode predicts that the additional cancer risk persist the whole lifetime after exposure and the additive model predicts excess risk over a period of time. With the Single-hit model (SHM) which is a multistage cancer model both dose-response relationships can be described. It will be shown that only small differences in the derivation will lead to the different relationships. We then analyze the incidence data of leukemia (1950-1987) and of all solid tumors (1958-1987) of the atomic bomb survivors. (author)

  9. Pronase E-Based Generation of Fluorescent Peptide Fragments: Tracking Intracellular Peptide Fate in Single Cells.

    Science.gov (United States)

    Mainz, Emilie R; Dobes, Nicholas C; Allbritton, Nancy L

    2015-08-04

    The ability to track intracellular peptide proteolysis at the single cell level is of growing interest, particularly as short peptide sequences continue to play important roles as biosensors, therapeutics, and endogenous participants in antigen processing and intracellular signaling. We describe a rapid and inexpensive methodology to generate fluorescent peptide fragments from a parent sequence with diverse chemical properties, including aliphatic, nonpolar, basic, acidic, and non-native amino acids. Four peptide sequences with existing biochemical applications were fragmented using incubation with Pronase E and/or formic acid, and in each case a complete set of fluorescent fragments was generated for use as proteolysis standards in chemical cytometry. Fragment formation and identity was monitored with capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) and matrix assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-MS) to confirm the presence of all sequences and yield fragmentation profiles across Pronase E concentrations which can readily be used by others. As a pilot study, Pronase E-generated standards from an Abl kinase sensor and an ovalbumin antigenic peptide were then employed to identify proteolysis products arising from the metabolism of these sequences in single cells. The Abl kinase sensor fragmented at 4.2 ± 4.8 zmol μM(-1) s(-1) and the majority of cells possessed similar fragment identities. In contrast, an ovalbumin epitope peptide was degraded at 8.9 ± 0.1 zmol μM(-1) s(-1), but with differential fragment formation between individual cells. Overall, Pronase E-generated peptide standards were a rapid and efficient method to identify proteolysis products from cells.

  10. A theoretical justification for single molecule peptide sequencing.

    Directory of Open Access Journals (Sweden)

    Jagannath Swaminathan

    2015-02-01

    Full Text Available The proteomes of cells, tissues, and organisms reflect active cellular processes and change continuously in response to intracellular and extracellular cues. Deep, quantitative profiling of the proteome, especially if combined with mRNA and metabolite measurements, should provide an unprecedented view of cell state, better revealing functions and interactions of cell components. Molecular diagnostics and biomarker discovery should benefit particularly from the accurate quantification of proteomes, since complex diseases like cancer change protein abundances and modifications. Currently, shotgun mass spectrometry is the primary technology for high-throughput protein identification and quantification; while powerful, it lacks high sensitivity and coverage. We draw parallels with next-generation DNA sequencing and propose a strategy, termed fluorosequencing, for sequencing peptides in a complex protein sample at the level of single molecules. In the proposed approach, millions of individual fluorescently labeled peptides are visualized in parallel, monitoring changing patterns of fluorescence intensity as N-terminal amino acids are sequentially removed, and using the resulting fluorescence signatures (fluorosequences to uniquely identify individual peptides. We introduce a theoretical foundation for fluorosequencing and, by using Monte Carlo computer simulations, we explore its feasibility, anticipate the most likely experimental errors, quantify their potential impact, and discuss the broad potential utility offered by a high-throughput peptide sequencing technology.

  11. Dynamics of hepatic gene expression and serum cytokine profiles in single and double-hit burn and sepsis animal models

    Directory of Open Access Journals (Sweden)

    Rohit Rao

    2015-06-01

    Full Text Available We simulate the pathophysiology of severe burn trauma and burn-induced sepsis, using rat models of experimental burn injury and cecal ligation and puncture (CLP either individually (singe-hit model or in combination (double-hit model. The experimental burn injury simulates a systemic but sterile pro-inflammatory response, while the CLP simulates the effect of polymicrobial sepsis. Given the liver׳s central role in mediating the host immune response and onset of hypermetabolism after burn injury, elucidating the alterations in hepatic gene expression in response to injury can lead to a better understanding of the regulation of the inflammatory response, whereas circulating cytokine protein expression, reflects key systemic inflammatory mediators. In this article, we present both the hepatic gene expression and circulating cytokine/chemokine protein expression data for the above-mentioned experimental model to gain insights into the temporal dynamics of the inflammatory and hypermetabolic response following burn and septic injury. This data article supports results discussed in research articles (Yang et al., 2012 [1,4]; Mattick et al. 2012, 2013 [2,3]; Nguyen et al., 2014 [5]; Orman et al., 2011, 2012 [6–8].

  12. Is ‘hit and run’ a single word? The processing of irreversible binomials in neglect dyslexia

    Directory of Open Access Journals (Sweden)

    Giorgio eArcara

    2012-02-01

    Full Text Available The present study is the first neuropsychological investigation into the problem of the mental representation and processing of irreversible binomials, i.e. word pairs linked by a conjunction (e.g. ‘hit and run’, ‘dead or alive’. In order to test their lexical status, the phenomenon of neglect dyslexia is explored.People with left-sided neglect dyslexia show a clear lexical effect: they can read irreversible binomials better (i.e., by dropping the leftmost words less frequently when their components are presented in their correct order. This may be taken as an indication that they treat these constructions as lexical, not decomposable, elements. This finding therefore constitutes strong evidence that irreversible binomials tend to be stored in the mental lexicon as a whole and that this whole form is preferably addressed in the retrieval process.

  13. Is “Hit and Run” a Single Word? The Processing of Irreversible Binomials in Neglect Dyslexia

    Science.gov (United States)

    Arcara, Giorgio; Lacaita, Graziano; Mattaloni, Elisa; Passarini, Laura; Mondini, Sara; Benincà, Paola; Semenza, Carlo

    2012-01-01

    The present study is the first neuropsychological investigation into the problem of the mental representation and processing of irreversible binomials (IBs), i.e., word pairs linked by a conjunction (e.g., “hit and run,” “dead or alive”). In order to test their lexical status, the phenomenon of neglect dyslexia is explored. People with left-sided neglect dyslexia show a clear lexical effect: they can read IBs better (i.e., by dropping the leftmost words less frequently) when their components are presented in their correct order. This may be taken as an indication that they treat these constructions as lexical, not decomposable, elements. This finding therefore constitutes strong evidence that IBs tend to be stored in the mental lexicon as a whole and that this whole form is preferably addressed in the retrieval process. PMID:22347199

  14. A recalculation of the dose-effect-relationship of the ''life span study'' of Hiroshima and Nagasaki with the ''single-hit model''

    International Nuclear Information System (INIS)

    Kottbauer, M.M.; Fleck, C.M.; Schoellnberger, H.

    1996-01-01

    The basis of this new model is the multistage process of carcinogeneses. The Single-Hit Model is a further development of the Armitage-Doll Model [1] for the special case of a short exposure. It provides simultaneously the age-dependent mortality-rate (incidence-rate) of the spontaneous and radiation induced solid tumors and dose-effect relationships at any age after exposure. The model results in a biologically based dose-effect relationship, which is similar to the Relativ-Risk-Model suggested by the ICRP 60 [2]. The present model is able to describe the increased mortality rate of the bomb survivors more accurate than the Relativ-Risk-Model. (orig.) [de

  15. Correlating single-molecule and ensemble-average measurements of peptide adsorption onto different inorganic materials.

    Science.gov (United States)

    Kim, Seong-Oh; Jackman, Joshua A; Mochizuki, Masahito; Yoon, Bo Kyeong; Hayashi, Tomohiro; Cho, Nam-Joon

    2016-06-07

    The coating of solid-binding peptides (SBPs) on inorganic material surfaces holds significant potential for improved surface functionalization at nano-bio interfaces. In most related studies, the goal has been to engineer peptides with selective and high binding affinity for a target material. The role of the material substrate itself in modulating the adsorption behavior of a peptide molecule remains less explored and there are few studies that compare the interaction of one peptide with different inorganic substrates. Herein, using a combination of two experimental techniques, we investigated the adsorption of a 16 amino acid-long random coil peptide to various inorganic substrates - gold, silicon oxide, titanium oxide and aluminum oxide. Quartz crystal microbalance-dissipation (QCM-D) experiments were performed in order to measure the peptide binding affinity for inorganic solid supports at the ensemble average level, and atomic force microscopy (AFM) experiments were conducted in order to determine the adhesion force of a single peptide molecule. A positive trend was observed between the total mass uptake of attached peptide and the single-molecule adhesion force on each substrate. Peptide affinity for gold was appreciably greater than for the oxide substrates. Collectively, the results obtained in this study offer insight into the ways in which inorganic materials can differentially influence and modulate the adhesion of SBPs.

  16. The shape and dynamics of the generation of the splash forms in single-phase systems after drop hitting

    Science.gov (United States)

    Sochan, Agata; Beczek, Michał; Mazur, Rafał; RyŻak, Magdalena; Bieganowski, Andrzej

    2018-02-01

    The splash phenomenon is being increasingly explored with the use of modern measurement tools, including the high-speed cameras. Recording images at a rate of several thousand frames per second facilitates parameterization and description of the dynamics of splash phases. This paper describes the impact of a single drop of a liquid falling on the surface of the same liquid. Three single-phase liquid systems, i.e., water, petrol, and diesel fuel, were examined. The falling drops were characterized by different kinetic energy values depending on the height of the fall, which ranged from 0.1 to 7.0 m. Four forms, i.e., waves, crowns, semi-closed domes, and domes, were distinguished depending on the drop energy. The analysis of the recorded images facilitated determination of the static and dynamic parameters of each form, e.g., the maximum height of each splash form, the width of the splash form at its maximum height, and the rate of growth of the splash form. We, Re, Fr, and K numbers were determined for all analyzed liquid systems. On the basis of the obtained values of dimensionless numbers, the areas of occurrence of characteristic splash forms were separated.

  17. Short Peptides Enhance Single Cell Adhesion and Viability onMicroarrays

    Energy Technology Data Exchange (ETDEWEB)

    Veiseh, Mandana; Veiseh, Omid; Martin, Michael C.; Asphahani,Fareid; Zhang, Miqin

    2007-01-19

    Single cell patterning holds important implications forbiology, biochemistry, biotechnology, medicine, and bioinformatics. Thechallenge for single cell patterning is to produce small islands hostingonly single cells and retaining their viability for a prolonged period oftime. This study demonstrated a surface engineering approach that uses acovalently bound short peptide as a mediator to pattern cells withimproved single cell adhesion and prolonged cellular viabilityon goldpatterned SiO2 substrates. The underlying hypothesis is that celladhesion is regulated bythe type, availability, and stability ofeffective cell adhesion peptides, and thus covalently bound shortpeptides would promote cell spreading and, thus, single cell adhesion andviability. The effectiveness of this approach and the underlyingmechanism for the increased probability of single cell adhesion andprolonged cell viability by short peptides were studied by comparingcellular behavior of human umbilical cord vein endothelial cells on threemodelsurfaces whose gold electrodes were immobilized with fibronectin,physically adsorbed Arg-Glu-Asp-Val-Tyr, and covalently boundLys-Arg-Glu-Asp-Val-Tyr, respectively. The surface chemistry and bindingproperties were characterized by reflectance Fourier transform infraredspectroscopy. Both short peptides were superior to fibronectin inproducing adhesion of only single cells, whereas the covalently boundpeptide also reduced apoptosis and necrosisof adhered cells. Controllingcell spreading by peptide binding domains to regulate apoptosis andviability represents a fundamental mechanism in cell-materialsinteraction and provides an effective strategy in engineering arrays ofsingle cells.

  18. An Algorithm of an X-ray Hit Allocation to a Single Pixel in a Cluster and Its Test-Circuit Implementation

    Energy Technology Data Exchange (ETDEWEB)

    Deptuch, G. W. [AGH-UST, Cracow; Fahim, F. [Fermilab; Grybos, P. [AGH-UST, Cracow; Hoff, J. [Fermilab; Maj, P. [AGH-UST, Cracow; Siddons, D. P. [Brookhaven; Kmon, P. [AGH-UST, Cracow; Trimpl, M. [Fermilab; Zimmerman, T. [Fermilab

    2017-05-06

    An on-chip implementable algorithm for allocation of an X-ray photon imprint, called a hit, to a single pixel in the presence of charge sharing in a highly segmented pixel detector is described. Its proof-of-principle implementation is also given supported by the results of tests using a highly collimated X-ray photon beam from a synchrotron source. The algorithm handles asynchronous arrivals of X-ray photons. Activation of groups of pixels, comparisons of peak amplitudes of pulses within an active neighborhood and finally latching of the results of these comparisons constitute the three procedural steps of the algorithm. A grouping of pixels to one virtual pixel that recovers composite signals and event driven strobes to control comparisons of fractional signals between neighboring pixels are the actuators of the algorithm. The circuitry necessary to implement the algorithm requires an extensive inter-pixel connection grid of analog and digital signals that are exchanged between pixels. A test-circuit implementation of the algorithm was achieved with a small array of 32×32 pixels and the device was exposed to an 8 keV highly collimated to a diameter of 3 μm X-ray beam. The results of these tests are given in the paper assessing physical implementation of the algorithm.

  19. Responses of peptide-specific T cells to stimulation with polystyrene beads carrying HLA class I molecules loaded with single peptides.

    Science.gov (United States)

    Chersi, Alberto; Galati, Rossella; Accapezzato, Daniele; Francavilla, Vittorio; Barnaba, Vincenzo; Butler, Richard H; Tanigaki, Nobuyuki

    2004-08-01

    Cell-sized microbeads carrying single peptide-loaded HLA class I molecules were prepared for HLA-A2 and HLA-B7 by a simple procedure which transfers single peptide-loaded HLA class I molecules from cultured cells to polystyrene beads using anti-peptide antibodies directed to an intracellular segment of HLA-A alpha chains. The surface density of peptide-loaded HLA class I molecules on beads was comparable to that on the peptide-loaded cells. HLA-A2 beads loaded with an HCV peptide HCV1073 were tested for stimulation activity on an HCV1073-specific CD8+ T cell clone NS3-1. A substantial level of gamma-IFN production was induced. The stimulation was peptide-specific. The efficiency was dependent on the bead concentration and the surface HLA class I density on beads and enhanced significantly by co-coupling of anti-CD28 to peptide-loaded beads. The peptide-loading efficiency on HLA class I molecules and the transfer efficiency of HLA class I molecules to polystyrene beads were reasonably high for HLA-A2 and HLA-B7. Thus, polystyrene beads carrying these single peptide-loaded HLA class I molecules are potentially useful in further analysis of the co-stimulatory or inhibitory factors involved in CD8+ T cell responses and eventually in detection of cytotoxic T cells in PBLs.

  20. Expression of multiple transgenes from a single construct using viral 2A peptides in Drosophila.

    Science.gov (United States)

    Daniels, Richard W; Rossano, Adam J; Macleod, Gregory T; Ganetzky, Barry

    2014-01-01

    Expression of multiple reporter or effector transgenes in the same cell from a single construct is increasingly necessary in various experimental paradigms. The discovery of short, virus-derived peptide sequences that mediate a ribosome-skipping event enables generation of multiple separate peptide products from one mRNA. Here we describe methods and vectors to facilitate easy production of polycistronic-like sequences utilizing these 2A peptides tailored for expression in Drosophila both in vitro and in vivo. We tested the separation efficiency of different viral 2A peptides in cultured Drosophila cells and in vivo and found that the 2A peptides from porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A) worked best. To demonstrate the utility of this approach, we used the P2A peptide to co-express the red fluorescent protein tdTomato and the genetically-encoded calcium indicator GCaMP5G in larval motorneurons. This technique enabled ratiometric calcium imaging with motion correction allowing us to record synaptic activity at the neuromuscular junction in an intact larval preparation through the cuticle. The tools presented here should greatly facilitate the generation of 2A peptide-mediated expression of multiple transgenes in Drosophila.

  1. Single molecule studies of surface-induced secondary structure in a model peptide

    Science.gov (United States)

    English, Douglas S.; Cunningham, Joy A.; Wehri, Sarah C.; Petrik, Amy F.; Okamoto, Kenji

    2004-10-01

    We have proposed using single molecule fluorescence resonant energy transfer (SM-FRET) to investigate the induction of secondary structure in model, surface-active peptides upon binding at an interface. The ability for SM-FRET to distinguish structural heterogeneity will offer a distinct advantage over traditional biophysical methods in these types of studies. Ensemble methods mask heterogeneity and only provide an average measure of secondary structural features. Because secondary structure contributes greatly to the energetics of dehydrating the amide backbone, detailed information of conformational distributions is crucial to the understanding of the thermodynamic cycle involved. Here we present results from our first efforts at using SM-FRET to study an amphipathic α-helix forming peptide immobilized at the solid-liquid interface between an aqueous solution and an octadecylsilane modified glass surface. This system serves as a model for future studies of peptide partitioning to lipid bilayers and other relevant interfaces.

  2. The SVT Hit Buffer

    International Nuclear Information System (INIS)

    Belforte, S.; Dell'Orso, M.; Donati, S.

    1996-01-01

    The Hit Buffer is part of the Silicon Vertex Tracker, a trigger processor dedicated to the reconstruction of particle trajectories in the Silicon Vertex Detector and the Central Tracking Chamber of the Collider Detector at Fermilab. The Hit Buffer is a high speed data-traffic node, where thousands of words are received in arbitrary order and simultaneously organized in an internal structured data base, to be later promptly retrieved and delivered in response to specific requests. The Hit Buffer is capable of processing data at a rate of 25 MHz, thanks to the use of special fast devices like Cache-Tag RAMs and high performance Erasable Programmable Logic Devices from the XILINX XC7300 family

  3. High energy ion hit technique to local area using microbeam

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Ryuichi; Kamiya, Tomihiro; Suda, Tamotsu; Sakai, Takuro; Hirao, Toshio; Kobayashi, Yasuhiko; Watanabe, Hiroshi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    1997-03-01

    Single energetic ion hit technique has been developed as an application of ion microbeam technique, in order to study the effect of local damage or injury to materials and living organisms. The overall performance is basically defined by those of separate techniques: microbeam formation, microbeam positioning, single ion detection, detection signal processing, hit timing control, and hit verification. Recent progress on the developments of these techniques at JAERI-TIARA facility are reviewed. (author)

  4. Propensity of a single-walled carbon nanotube-peptide to mimic a KK10 peptide in an HLA-TCR complex

    Science.gov (United States)

    Feng, Mei; Bell, David R.; Zhou, Ruhong

    2017-12-01

    The application of nanotechnology to improve disease diagnosis, treatment, monitoring, and prevention is the goal of nanomedicine. We report here a theoretical study of a functionalized single-walled carbon nanotube (CNT) mimic binding to a human leukocyte antigen-T cell receptor (HLA-TCR) immune complex as a first attempt of a potential nanomedicine for human immunodeficiency virus (HIV) vaccine development. The carbon nanotube was coated with three arginine residues to imitate the HIV type 1 immunodominant viral peptide KK10 (gag 263-272: KRWIILGLNK), named CNT-peptide hereafter. Through molecular dynamics simulations, we explore the CNT-peptide and KK10 binding to an important HLA-TCR complex. Our results suggest that the CNT-peptide and KK10 bind comparably to the HLA-TCR complex, but the CNT-peptide forms stronger interactions with the TCR. Desorption simulations highlight the innate flexibility of KK10 over the CNT-peptide, resulting in a slightly higher desorption energy required for KK10 over the CNT-peptide. Our findings indicate that the designed CNT-peptide mimic has favorable propensity to activate TCR pathways and should be further explored to understand therapeutic potential.

  5. Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma - a single centre's experience

    DEFF Research Database (Denmark)

    Pedersen, Mette Ø; Gang, Anne O; Poulsen, Tim S

    2012-01-01

    Concurrent BCL2 and MYC translocations, so called double hit (DH), are a rare finding in large B-cell lymphoma (LBCL). Based on data from retrospective series, DH has been correlated with aggressive clinical behaviour and poor outcome. We conducted a consecutive study of DH incidence and correlat......Concurrent BCL2 and MYC translocations, so called double hit (DH), are a rare finding in large B-cell lymphoma (LBCL). Based on data from retrospective series, DH has been correlated with aggressive clinical behaviour and poor outcome. We conducted a consecutive study of DH incidence...... and correlation with pathologic and clinical characteristics, including response to Rituximab-containing chemotherapy and survival, in an unselected cohort of patients with LBCL. Translocations involving BCL2 and MYC loci were examined with fluorescent in situ hybridization (FISH) in 157 patients with diffuse...... MYC translocation partner gene. Screening of patients with BCLU and DLBCL of GCB type for DH BCL2/MYC translocation including MYC translocation partner gene may provide important prognostic information....

  6. Accessing Specific Peptide Recognition by Combinatorial Chemistry

    DEFF Research Database (Denmark)

    Li, Ming

    in recognition, a hook peptide library was built as sequence blocks containing two L-prolines, facilitating peptide back-bones to organize into a bend “hook” shape. Selection of pairs recognizing each other by entanglement with the conformational shape as a fundamental mechanism of molecular recognition...... was studied with this hook peptide library via the beadbead adhesion screening approach. The recognition pairs interlocked and formed a complex. (chapter 8) During accessing peptide molecular recognition by combinatorial chemistry, we faced several problems, which were solved by a range of analytical...... separation of is developed and used to select the best hits from the “hook” peptide library. The association strength of complex was also evaluated by MS-MS analysis. (chapter 8) a microchannel flow device was designed and utilized to measure binding constants on a single bead. (chapter 5) An important...

  7. Single hydration of the peptide bond: the case of the Vince lactam.

    Science.gov (United States)

    Écija, Patricia; Basterretxea, Francisco J; Lesarri, Alberto; Millán, Judith; Castaño, Fernando; Cocinero, Emilio J

    2012-10-18

    2-Azabicyclo[2.2.1]hept-5-en-3-one (ABH or Vince lactam) and its monohydrated complex (ABH···H(2)O) have been observed in a supersonic jet by Fourier transform microwave spectroscopy. ABH is broadly used in the synthesis of therapeutic drugs, whereas the ABH···H(2)O system offers a simple model to explain the conformational preferences of water linked to a constrained peptidic bond. A single predominant form of the Vince lactam and its singly hydrated complex have been detected, determining the rotational constants, centrifugal distortion constants, and nuclear quadrupole coupling tensor. The monohydrated complex is stabilized by two hydrogen bonds (C═O···H-O and N-H···O) closing a six-membered ring. The complexation energy has been estimated to be ∼10 kJ mol(-1) from experimental results. In addition, the observed structure in the gas phase has been compared with solid-phase diffraction data. The structural parameters and binding energies of ABH···H(2)O have also been compared with similar molecules containing peptide bonds. Ab initio (MP2) and density functional (M06-2X and B3LYP) methods have supported the experimental work, describing the rotational parameters and conformational landscape of the title compound and its singly hydrated complex.

  8. Piezoelectric peptide-based nanogenerator enhanced by single-electrode triboelectric nanogenerator

    Directory of Open Access Journals (Sweden)

    Vu Nguyen

    2017-07-01

    Full Text Available Peptide has recently been demonstrated as a sustainable and smart material for piezoelectric energy conversion. Although the power output was improved compared to other biomaterials, the use of a piezoelectric device alone can only capture the energy from the minute deformation in materials. In comparison, the triboelectric effect can convert mechanical energy from large motion. Consequently, utilizing both piezoelectric and triboelectric effects is of significant research interest due to their complementary energy conversion mechanisms. Here we demonstrated a hybrid nanogenerator that combined a peptide-based piezoelectric nanogenerator with a single-electrode triboelectric nanogenerator. Our device structure enabled the voltage and current outputs of each individual type of nanogenerator to be superposed in the hybrid nanogenerator, producing overall constructive outputs. The design of our device also enabled a simplified configuration of hybrid nanogenerator. This study is important not only for the enhancement of peptide-based piezoelectric device but also for the future design of hybrid piezoelectric and triboelectric nanogenerators.

  9. Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

    Directory of Open Access Journals (Sweden)

    Hwankyu Lee

    2014-03-01

    Full Text Available Polyethylene glycol (PEG has been conjugated to many drugs or drug carriers to increase their solubility and circulating lifetime, and reduce toxicity. This has motivated many experimental studies to understand the effect of PEGylation on delivery efficiency. To complement the experimental findings and uncover the mechanism that cannot be captured by experiments, all-atom and coarse-grained molecular dynamics (MD simulations have been performed. This has become possible, due to recent advances in simulation methodologies and computational power. Simulations of PEGylated peptides show that PEG chains wrap antimicrobial peptides and weaken their binding interactions with lipid bilayers. PEGylation also influences the helical stability and tertiary structure of coiled-coil peptides. PEGylated dendrimers and single-walled carbon nanotubes (SWNTs were simulated, showing that the PEG size and grafting density significantly modulate the conformation and structure of the PEGylated complex, the interparticle aggregation, and the interaction with lipid bilayers. In particular, simulations predicted the structural transition between the dense core and dense shell of PEGylated dendrimers, the phase behavior of self-assembled complexes of lipids, PEGylated lipids, and SWNTs, which all favorably compared with experiments. Overall, these new findings indicate that simulations can now predict the experimentally observed structure and dynamics, as well as provide atomic-scale insights into the interactions of PEGylated complexes with other molecules.

  10. A Nanodiamond-peptide Bioconjugate for Fluorescence and ODMR Microscopy of a Single Actin Filament.

    Science.gov (United States)

    Genjo, Takuya; Sotoma, Shingo; Tanabe, Ryotaro; Igarashi, Ryuji; Shirakawa, Masahiro

    2016-01-01

    Recently, the importance of conformational changes in actin filaments induced by mechanical stimulation of a cell has been increasingly recognized, especially in terms of mechanobiology. Despite its fundamental importance, however, long-term observation of a single actin filament by fluorescent microscopy has been difficult because of the low photostability of traditional fluorescent molecules. This paper reports a novel molecular labeling system for actin filaments using fluorescent nanodiamond (ND) particles harboring nitrogen-vacancy centers; ND has flexible chemical modifiability, extremely high photostability and biocompatibility, and provides a variety of physical information quantitatively via optically detected magnetic resonance (ODMR) measurements. We performed the chemical surface modification of an ND with the actin filament-specific binding peptide Lifeact and observed colocalization of pure Lifeact-modified ND and actin filaments by the ODMR selective imaging protocol, suggesting the capability of long-term observation and quantitative analysis of a single molecule by using an ND particle.

  11. Spontaneous formation of structurally diverse membrane channel architectures from a single antimicrobial peptide

    Science.gov (United States)

    Wang, Yukun; Chen, Charles H.; Hu, Dan; Ulmschneider, Martin B.; Ulmschneider, Jakob P.

    2016-11-01

    Many antimicrobial peptides (AMPs) selectively target and form pores in microbial membranes. However, the mechanisms of membrane targeting, pore formation and function remain elusive. Here we report an experimentally guided unbiased simulation methodology that yields the mechanism of spontaneous pore assembly for the AMP maculatin at atomic resolution. Rather than a single pore, maculatin forms an ensemble of structurally diverse temporarily functional low-oligomeric pores, which mimic integral membrane protein channels in structure. These pores continuously form and dissociate in the membrane. Membrane permeabilization is dominated by hexa-, hepta- and octamers, which conduct water, ions and small dyes. Pores form by consecutive addition of individual helices to a transmembrane helix or helix bundle, in contrast to current poration models. The diversity of the pore architectures--formed by a single sequence--may be a key feature in preventing bacterial resistance and could explain why sequence-function relationships in AMPs remain elusive.

  12. Gene delivery: A single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus

    OpenAIRE

    Zanta, Maria Antonietta; Belguise-Valladier, Pascale; Behr, Jean-Paul

    1999-01-01

    Translocation of exogenous DNA through the nuclear membrane is a major concern of gene delivery technologies. To take advantage of the cellular import machinery, we have synthesized a capped 3.3-kbp CMVLuciferase-NLS gene containing a single nuclear localization signal peptide (PKKKRKVEDPYC). Transfection of cells with the tagged gene remained effective down to nanogram amounts of DNA. Transfection enhancement (10- to 1,000-fold) as a result of the signal peptide was observed irrespective of ...

  13. A single-layer peptide nanofiber for enhancing the cytotoxicity of trastuzumab (anti-HER)

    Energy Technology Data Exchange (ETDEWEB)

    Malik, Ruchi; Wagh, Anil; Qian, Steven; Law, Benedict, E-mail: Shek.law@ndsu.edu [College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Department of Pharmaceutical Sciences (United States)

    2013-06-15

    A multivalent system is often employed to enhance the effectiveness of a targeted therapy. In the present study, we report a single-layer peptide nanofiber (NFP) as a multivalent targeting platform to improve the cytotoxicity of trastuzumab (anti-HER), a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2) in approximately 20 % of breast cancer patients. The trastuzumab-conjugated nanofiber (anti-HER/NFP) was 100 Multiplication-Sign 4 nm in size and was assembled from multiple peptide units (mPEG-BK(FITC)SGASNRA-kldlkldlkldl-CONH{sub 2}). The optimized preparation was attached with approximately 10 antibodies at the surface. Because of an increase in the multivalency, anti-HER/NFP was able to truncate more cell surface HER-2 and, thus, showed an enhanced cytotoxicity toward HER-2 positive SKBr-3 human breast cancer as compared to the free anti-HER. Western blot analysis and fluorescence microscopic studies confirmed that there was a significant downregulation of the HER-2 level and also inhibition of the cell survival cell signaling pathways including the phosphatidylinositol 3-kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathway. Our data suggested that NFP can be useful as a multivalent platform for immunotherapy, especially in combination with other chemotherapeutic agents in the future.

  14. Single-molecule spectroscopy of amino acids and peptides by recognition tunnelling

    Science.gov (United States)

    Zhao, Yanan; Ashcroft, Brian; Zhang, Peiming; Liu, Hao; Sen, Suman; Song, Weisi; Im, Jongone; Gyarfas, Brett; Manna, Saikat; Biswas, Sovan; Borges, Chad; Lindsay, Stuart

    2014-06-01

    The human proteome has millions of protein variants due to alternative RNA splicing and post-translational modifications, and variants that are related to diseases are frequently present in minute concentrations. For DNA and RNA, low concentrations can be amplified using the polymerase chain reaction, but there is no such reaction for proteins. Therefore, the development of single-molecule protein sequencing is a critical step in the search for protein biomarkers. Here, we show that single amino acids can be identified by trapping the molecules between two electrodes that are coated with a layer of recognition molecules, then measuring the electron tunnelling current across the junction. A given molecule can bind in more than one way in the junction, and we therefore use a machine-learning algorithm to distinguish between the sets of electronic `fingerprints' associated with each binding motif. With this recognition tunnelling technique, we are able to identify D and L enantiomers, a methylated amino acid, isobaric isomers and short peptides. The results suggest that direct electronic sequencing of single proteins could be possible by sequentially measuring the products of processive exopeptidase digestion, or by using a molecular motor to pull proteins through a tunnel junction integrated with a nanopore.

  15. Single-Residue Sensitivity in Neutron Reflectivity and Resonant X-ray Reflectivity from Langmuir Monolayers of Synthetic Peptides

    Science.gov (United States)

    Strzalka, Joseph; Satija, Sushil; Dimasi, Elaine; Kuzmenko, Ivan; Gog, Thomas; Blasie, J. Kent

    2004-03-01

    Labeling groups with ^2H to distinguish them in the scattering length density (SLD) profile constitutes the chief advantage of neutron reflectivity (NR) in studying Langmuir monolayers (LM) of lipids and proteins. Solid phase synthesis (SPPS) permits the labeling of a single residue in a peptide. Recent work demonstrates the sensitivity of NR to single ^2H-labeled residues in LM of vectorially oriented α -helical bundle peptides. NR requires comparison of isomorphic samples of all-^1H and ^2H-labeled peptides. Alternately, resonant x-ray reflectivity (RXR) uses only one sample. RXR exploits energy-dependent changes in the scattering factor from heavy atoms to distinguish them within the SLD profile. Peptides may be labeled by SPPS (e.g. Br-Phe), or may have inherent labels (e.g. Fe in heme proteins). As test cases, we studied LM of Br-labeled lipids and peptides with RXR. Both approaches require a model-independent means of obtaining SLD profiles from the reflectivity data. We have applied box-refinement to obtain the gradient SLD profile. This is fit uniquely with a sum of Gaussians and integrated analytically [Blasie et al., PRB 67 224201 (2003)] to provide the SLD profile. Label positions can then be determined to sub-Ångstrom accuracy. This work supported by the NIH (GM55876).

  16. Single-Molecule Protein Folding: A Study of the Surface-Mediated Conformational Dynamics of a Model Amphipathic Peptide

    Science.gov (United States)

    Cunningham, Joy; English, Douglas

    2004-03-01

    Most surface-active polypeptides, composed of 10-50 amino acids, are devoid of well-defined tertiary structure. The conformation of these proteins is greatly dependent upon their environment and may assume totally different characteristics in an aqueous environment, in a detergent micelle, or in an organic solvent. Most antimicrobial peptides are helix-forming and are activated upon interaction with a membrane-mimicking environment. We are seeking to physically characterize the mechanism of membrane-peptide interaction through studying a simple model peptide, MT-1. MT-1 was designed as a nonhomologous analogue of melittin, the principle component in bee venom. We are using single molecule spectroscopy to examine the induction of secondary structure upon interaction of MT-1 with various membrane-mimicking interfaces. Specifically, we monitor coil-to-helix transition through single molecule fluorescence resonance energy transfer (sm-FRET) to determine conformational distributions of folded and unfolded peptides at an interface. Studies with MT-1 will focus upon the biologically relevant issues of orientation, aggregation, and folding at surfaces using both ensemble and single molecule experiments.

  17. Combined determination of copper ions and β-amyloid peptide by a single ratiometric electrochemical biosensor.

    Science.gov (United States)

    Yu, Yanyan; Wang, Peng; Zhu, Xiaodan; Peng, Qiwen; Zhou, Yi; Yin, Tianxiao; Liang, Yixin; Yin, Xiaoxing

    2017-12-18

    Copper ions (Cu 2+ ) play a critical role in biological processes and are directly involved in β-amyloid peptide (Aβ) aggregation, which is responsible for the occurrence and development of Alzheimer's disease (AD). Therefore, combined determination of Cu 2+ and Aβ in one analytical system is of great significance to understand the exact nature of the AD event. This work presents a novel ratiometric electrochemical biosensor for the dual determination of Cu 2+ and Aβ 1-42 . This unique sensor is based on a 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) (ABTS) and poly(diallyldimethylammonium chloride) (PDDA)-bi functionalized single-walled carbon nanotubes (ABTS-PDDA/CNTs) composite. The inclusion of ABTS not only enhanced the sensitivity, but it also acted as an inner reference molecule to improve detection accuracy. The specific recognition of Cu 2+ was realized by neurokinin B (NKB) coatings on the ABTS-PDDA/CNTs surface to form a [Cu II (NKB) 2 ] complex with Cu 2+ . The ABTS-PDDA/CNTs-NKB modified electrode also displayed an excellent electrochemical response toward the Aβ 1-42 monomer, when a certain amount of the Aβ 1-42 monomer was added to Cu 2+ -contained PBS buffer, which was due to the release of Cu 2+ from the [Cu II (NKB) 2 ] complex through Aβ binding to Cu 2+ . Meanwhile, our work showed that Cu 2+ bound Aβ 1-42 was concentration-dependent. Consequently, the presented electrochemical approach was capable of quantifying two important biological species associated with AD by one single biosensor, with the detection limits of 0.04 μM for Cu 2+ and 0.5 ng mL -1 for Aβ 1-42 , respectively. Finally, the ratiometric electrode was successfully applied for monitoring Cu 2+ and Aβ 1-42 variations in plasma and hippocampus of normal and AD rats.

  18. Effects of single amino acid substitution on the biophysical properties and biological activities of an amphipathic α-helical antibacterial peptide against Gram-negative bacteria.

    Science.gov (United States)

    Tan, Juanjuan; Huang, Jinfeng; Huang, Yibing; Chen, Yuxin

    2014-07-24

    An antimicrobial peptide, known as V13K, was utilized as the framework to study the effects of charge, hydrophobicity and helicity on the biophysical properties and biological activities of α-helical peptides. Six amino acids (Lys, Glu, Gly, Ser, Ala, and Leu) were individually used to substitute the original hydrophobic valine at the selected sixteenth location on the non-polar face of V13K. The results showed that the single amino acid substitutions changed the hydrophobicity of peptide analogs as monitored by RP-HPLC, but did not cause significant changes on peptide secondary structures both in a benign buffer and in a hydrophobic environment. The biological activities of the analogs exhibited a hydrophobicity-dependent behavior. The mechanism of peptide interaction with the outer membrane and cytoplasmic membrane of Gram-negative bacteria was investigated. We demonstrated that this single amino acid substitution method has valuable potential for the rational design of antimicrobial peptides with enhanced activities.

  19. Quantitative single-vesicle analysis of antimicrobial peptide-induced leakage

    DEFF Research Database (Denmark)

    Kristensen, Kasper; Ehrlich, Nicky; Henriksen, Jonas Rosager

    2013-01-01

    Although the research field of antimicrobial peptides has attracted considerable scientific attention in the past decades, the microbicidal mechanisms of antimicrobial peptides still remain elusive. One of the keys to a more profound comprehension of the function of these peptides is a deeper...... was combined with fluorescence correlation spectroscopy to quantify leakage from a bulk collection of lipid vesicles in aqueous solution. Quantitative correlation between the two techniques was achieved through a detailed experimental protocol. The potential of combining the two techniques was tested using...

  20. Peptide-coated semiconductor quantum dots and their applications in biological imaging of single molecules in live cells and organisms

    Science.gov (United States)

    Pinaud, Fabien Florent

    2007-12-01

    A new surface chemistry has been developed for the solubilization and biofunctionalization of inorganic semiconductor nanocrystals fluorescent probes, also known as quantum dots. This chemistry is based on the surface coating of quantum dots with custom-designed polycysteine peptides and yields water-soluble, small, monodispersed and colloidally stable probes that remain bright and photostable in complex biological milieus. This peptide coating strategy was successfully tested on several types of core and core-shell quantum dots emitting from the visible (e.g. CdSe/ZnS) to the NIR spectrum range (e.g. CdTe/CdSe/ZnS). By taking advantage of the versatile physico-chemical properties of peptides, a peptide "toolkit" was designed and employed to impart several biological functions to individual quantum dots and control their biochemical activity at the nanometer scale. These biofunctionalized peptide-coated quantum dots were exploited in very diverse biological applications. Near-infrared emitting quantum dot probes were engineered with optimized blood circulation and biodistribution properties for in vivo animal imaging. Visible emitting quantum dots were used for single molecule tracking of raft-associated GPI-anchored proteins in live cells. This last application revealed the presence of discrete and non-caveolar lipid microdomains capable of impeding free lateral diffusions in the plasma membrane of Hela cells. Imaging and tracking of peptide-coated quantum dots provided the first direct evidence that microdomains having the composition and behavior expected for lipid rafts can induce molecular compartmentalization in the membrane of living cells.

  1. Factors associated with serum B-type natriuretic peptide in infants with single ventricles.

    Science.gov (United States)

    Butts, Ryan J; Zak, Victor; Hsu, Daphne; Cnota, James; Colan, Steven D; Hehir, David; Kantor, Paul; Levine, Jami C; Margossian, Renee; Richmond, Marc; Szwast, Anita; Williams, Derek; Williams, Richard; Atz, Andrew M

    2014-06-01

    Data regarding the value of B-type natriuretic peptide (BNP) measurements in infants with a single-ventricle (SV) physiology are lacking. This analysis aimed to describe the BNP level changes in infants with an SV physiology before and after superior cavopulmonary connection (SCPC) surgery. Levels of BNP were measured by a core laboratory before SCPC (at 5.0 ± 1.6 months) and at the age of 14 months during a multicenter trial of angiotensin-converting enzyme inhibition therapy for infants with SV. Multivariable longitudinal analysis was used to model the associations between BNP levels and three sets of grouped variables (echocardiography, catheterization, growth). Multivariable analysis was performed to assess associations with patient characteristics at both visits. Associations between BNP levels and neurodevelopmental variables were investigated at the 14 month visit because neurodevelopmental assessment was performed only at this visit. The BNP level was significantly higher before SCPC (n = 173) than at the age of 14 months (n = 134). The respective median levels were 80.8 pg/ml (interquartile range [IQR], 35-187 pg/ml) and 34.5 pg/ml (IQR, 17-67 pg/ml) (p SCPC and in 21 subjects (16 %) at the age of 14 months. In the 117 patients who had BNP measurements at both visits, the median BNP level decreased 32 pg/ml (IQR, 1-79 pg/ml) (p SCPC surgery (p SCPC surgery (p = 0.04), and a lower Bayley psychomotor developmental index (p = 0.02). The levels of BNP decreases in infants with SV from the pre-SCPC visit to the age of 14 months. A higher BNP level is associated with increased ventricular dilation in systole, increased AV valve regurgitation, impaired growth, and poorer neurodevelopmental outcomes. Therefore, BNP level may be a useful seromarker for identifying infants with SV at risk for worse outcomes.

  2. Mixed Hitting-Time Models

    NARCIS (Netherlands)

    Abbring, J.H.

    2009-01-01

    We study mixed hitting-time models, which specify durations as the first time a Levy process (a continuous-time process with stationary and independent increments) crosses a heterogeneous threshold. Such models of substantial interest because they can be reduced from optimal-stopping models with

  3. Grasping and hitting moving objects.

    Science.gov (United States)

    Schot, Willemijn D; Brenner, Eli; Smeets, Jeroen B J

    2011-08-01

    Some experimental evidence suggests that grasping should be regarded as independent control of the thumb and the index finger (digit control hypothesis). To investigate this further, we compared how the tips of the thumb and the index finger moved in space when grasping spheres to how they moved when they were hitting the sphere using only one digit. In order to make the tasks comparable, we designed the experiment in such a way that subjects contacted the spheres in about the same way in the hitting task as when grasping it. According to the digit control hypothesis, the two tasks should yield similar digit trajectories in space. People hit and grasped stationary and moving spheres. We compared the similarity of the digits' trajectories across the two tasks by evaluating the time courses of the paths of the average of the thumb and the index finger. These paths were more similar across tasks than across sphere motion, supporting the notion that grasping is not controlled fundamentally differently than hitting.

  4. Single-step immobilization of cell adhesive peptides on a variety of biomaterial substrates via tyrosine oxidation with copper catalyst and hydrogen peroxide.

    Science.gov (United States)

    Kakinoki, Sachiro; Yamaoka, Tetsuji

    2015-04-15

    Immobilization of biologically active peptides which were isolated from extracellular matrix proteins is a powerful strategy for the design and functionalization of biomaterial substrates. However, the method of peptide immobilization was restricted, that is, peptide is often immobilized through the reactive groups inherent in substrates with multistep reactions. Here, we report a single-step immobilization of fibronectin-derived cell adhesive peptide (Arg-Glu-Asp-Val; REDV) onto polymer materials by use of tyrosine oxidation with copper catalyst and hydrogen peroxide. REDV peptide was successfully immobilized on tissue culture polystyrene, poly(ethylene terephthalate), poly(vinyl chloride), expanded-poly(tetrafluoroethylene), and poly(l-lactic acid), resulting in enhanced adhesion of human umbilical vein endothelial cells. This method is a single-step reaction under very mild conditions and is available for the biological functionalization of various medical devices.

  5. Electron transfer dissociation facilitates the measurement of deuterium incorporation into selectively labeled peptides with single residue resolution

    DEFF Research Database (Denmark)

    Zehl, Martin; Rand, Kasper D; Jensen, Ole N

    2008-01-01

    Mass spectrometry is routinely applied to measure the incorporation of deuterium into proteins and peptides. The exchange of labile, heteroatom-bound hydrogens is mainly used to probe the structural dynamics of proteins in solution, e.g., by hydrogen-exchange mass spectrometry, but also to study...... the gas-phase structure and fragmentation mechanisms of polypeptide ions. Despite considerable effort in recent years, there is no widely established mass spectrometric method to localize the incorporated deuterium to single amino acid residues, and typically, only the overall deuterium content...... of peptides or proteins is obtained. The main reason for this is that CID and related techniques induce intramolecular migration of hydrogens ("hydrogen scrambling") upon vibrational excitation of the even-electron precursor ion, thus randomizing the positional distribution of the incorporated deuterium atoms...

  6. Single-vesicle detection and analysis of peptide-induced membrane permeabilization

    DEFF Research Database (Denmark)

    Kristensen, Kasper; Ehrlich, Nicky; Henriksen, Jonas Rosager

    2015-01-01

    2. The FCS results show that leakage induced by magainin 2 is less dependent on the size of the encapsulated fluorescent molecules than leakage induced by mastoparan X and melittin. The confocal imaging results show that all three peptides induce leakage by a heterogeneous process in which one...

  7. Enhanced Peptide Detection Toward Single-Neuron Proteomics by Reversed-Phase Fractionation Capillary Electrophoresis Mass Spectrometry

    Science.gov (United States)

    Choi, Sam B.; Lombard-Banek, Camille; Muñoz-LLancao, Pablo; Manzini, M. Chiara; Nemes, Peter

    2017-11-01

    The ability to detect peptides and proteins in single cells is vital for understanding cell heterogeneity in the nervous system. Capillary electrophoresis (CE) nanoelectrospray ionization (nanoESI) provides high-resolution mass spectrometry (HRMS) with trace-level sensitivity, but compressed separation during CE challenges protein identification by tandem HRMS with limited MS/MS duty cycle. Here, we supplemented ultrasensitive CE-nanoESI-HRMS with reversed-phase (RP) fractionation to enhance identifications from protein digest amounts that approximate to a few mammalian neurons. An 1 to 20 μg neuronal protein digest was fractionated on a RP column (ZipTip), and 1 ng to 500 pg of peptides were analyzed by a custom-built CE-HRMS system. Compared with the control (no fractionation), RP fractionation improved CE separation (theoretical plates 274,000 versus 412,000 maximum, resp.), which enhanced detection sensitivity (2.5-fold higher signal-to-noise ratio), minimized co-isolation spectral interferences during MS/MS, and increased the temporal rate of peptide identification by up to 57%. From 1 ng of protein digest (development of the brain, including those involved in synaptic transmission and plasticity and cytoskeletal organization. [Figure not available: see fulltext.

  8. Antimicrobial Peptides in 2014

    Directory of Open Access Journals (Sweden)

    Guangshun Wang

    2015-03-01

    Full Text Available This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.

  9. Multi-hit time-to-amplitude CAMAC module (MTAC)

    International Nuclear Information System (INIS)

    Kang, H.

    1980-10-01

    A Multi-Hit Time-to-Amplitude Module (MTAC) for the SLAC Mark III drift chamber system has been designed to measure drift time by converting time-proportional chamber signals into analog levels, and converting the analog data by slow readout via a semi-autonomous controller in a CAMAC crate. The single width CAMAC module has 16 wire channels, each with a 4-hit capacity. An externally generated common start initiates an internal precision ramp voltage which is then sampled using a novel shift register gating scheme and CMOS sampling switches. The detailed design and performance specifications are described

  10. Grasping and hitting moving objects

    OpenAIRE

    Schot, Willemijn D.; Brenner, Eli; Smeets, Jeroen B. J.

    2011-01-01

    Some experimental evidence suggests that grasping should be regarded as independent control of the thumb and the index finger (digit control hypothesis). To investigate this further, we compared how the tips of the thumb and the index finger moved in space when grasping spheres to how they moved when they were hitting the sphere using only one digit. In order to make the tasks comparable, we designed the experiment in such a way that subjects contacted the spheres in about the same way in the...

  11. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax® encapsulated CTL/T helper peptides

    Directory of Open Access Journals (Sweden)

    MacDonald Lisa

    2007-06-01

    Full Text Available Abstract The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax®,VM is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48–58 weeks old bearing large palpable TC1/A2 tumors. The VM-based vaccines contained one or more peptides having human CTL epitopes derived from HPV 16 E6 and E7. VM formulations contained a single peptide, a mixture of four peptides or the same four peptides linked together in a single long peptide. All VM formulations contained PADRE and CpG as adjuvants and ISA51 as the hydrophobic component of the water-in-oil emulsion. VM-formulated vaccines containing the four peptides as a mixture or linked together in one long peptide eradicated 19-day old established tumors within 21 days of immunization. Peptide-specific cytotoxic cellular responses were confirmed by ELISPOT and intracellular staining for IFN-γ producing CD8+ T cells. Mice rendered tumor-free by vaccination were re-challenged in the opposite flank with 10 million HLF-16 tumor cells, another HLA-A2/E6/E7 expressing tumor cell line. None of these mice developed tumors following the re-challenge. In summary, this report describes a VM-formulated therapeutic vaccine with the following unprecedented outcome: a eradication of large tumors (> 700 mm3 b in mice of advanced age c in less than three weeks post-immunization d following a single vaccination.

  12. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax encapsulated CTL/T helper peptides.

    Science.gov (United States)

    Daftarian, Pirouz M; Mansour, Marc; Pohajdak, Bill; Fuentes-Ortega, Antar; Korets-Smith, Ella; Macdonald, Lisa; Weir, Genevieve; Brown, Robert G; Kast, W Martin

    2007-06-07

    The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax,VM) is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48-58 weeks old) bearing large palpable TC1/A2 tumors. The VM-based vaccines contained one or more peptides having human CTL epitopes derived from HPV 16 E6 and E7. VM formulations contained a single peptide, a mixture of four peptides or the same four peptides linked together in a single long peptide. All VM formulations contained PADRE and CpG as adjuvants and ISA51 as the hydrophobic component of the water-in-oil emulsion. VM-formulated vaccines containing the four peptides as a mixture or linked together in one long peptide eradicated 19-day old established tumors within 21 days of immunization. Peptide-specific cytotoxic cellular responses were confirmed by ELISPOT and intracellular staining for IFN-gamma producing CD8+ T cells. Mice rendered tumor-free by vaccination were re-challenged in the opposite flank with 10 million HLF-16 tumor cells, another HLA-A2/E6/E7 expressing tumor cell line. None of these mice developed tumors following the re-challenge. In summary, this report describes a VM-formulated therapeutic vaccine with the following unprecedented outcome: a) eradication of large tumors (> 700 mm3) b) in mice of advanced age c) in less than three weeks post-immunization d) following a single vaccination.

  13. Construction of a single polypeptide that matures and exports the lasso peptide microcin J25.

    Science.gov (United States)

    Pan, Si Jia; Rajniak, Jakub; Cheung, Wai Ling; Link, A James

    2012-02-13

    Roped in: The lasso peptide microcin J25 (MccJ25) is matured by two enzymes and is exported by a putative ABC transporter. We probed the function of the maturation enzymes using mutagenesis. We demonstrate that fusions of the enzymes with intervening linkers can produce MccJ25. Even a 151 kDa tripartite fusion between the ABC transporter and the two enzymes is capable of producing and exporting MccJ25. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. One-hit wonders of genomic instability

    Directory of Open Access Journals (Sweden)

    Strunnikov Alexander V

    2010-05-01

    Full Text Available Abstract Recent data show that cells from many cancers exhibit massive chromosome instability. The traditional view is that the gradual accumulation of mutations in genes involved in transcriptional regulation and cell cycle controls results in tumor development. This, however, does not exclude the possibility that some mutations could be more potent than others in destabilizing the genome by targeting both chromosomal integrity and corresponding checkpoint mechanisms simultaneously. Three such examples of "single-hit" lesions potentially leading to heritable genome destabilization are discussed. They include: failure to release sister chromatid cohesion due to the incomplete proteolytic cleavage of cohesin; massive merotelic kinetochore misattachments upon condensin depletion; and chromosome under-replication. In all three cases, cells fail to detect potential chromosomal bridges before anaphase entry, indicating that there is a basic cell cycle requirement to maintain a degree of sister chromatid bridging that is not recognizable as chromosomal damage.

  15. Effects of Single Amino Acid Substitution on the Biophysical Properties and Biological Activities of an Amphipathic α-Helical Antibacterial Peptide Against Gram-Negative Bacteria

    Directory of Open Access Journals (Sweden)

    Juanjuan Tan

    2014-07-01

    Full Text Available An antimicrobial peptide, known as V13K, was utilized as the framework to study the effects of charge, hydrophobicity and helicity on the biophysical properties and biological activities of α-helical peptides. Six amino acids (Lys, Glu, Gly, Ser, Ala, and Leu were individually used to substitute the original hydrophobic valine at the selected sixteenth location on the non-polar face of V13K. The results showed that the single amino acid substitutions changed the hydrophobicity of peptide analogs as monitored by RP-HPLC, but did not cause significant changes on peptide secondary structures both in a benign buffer and in a hydrophobic environment. The biological activities of the analogs exhibited a hydrophobicity-dependent behavior. The mechanism of peptide interaction with the outer membrane and cytoplasmic membrane of Gram-negative bacteria was investigated. We demonstrated that this single amino acid substitution method has valuable potential for the rational design of antimicrobial peptides with enhanced activities.

  16. A single-chain fusion molecule consisting of peptide, major histocompatibility gene complex class I heavy chain and beta2-microglobulin can fold partially correctly, but binds peptide inefficiently

    DEFF Research Database (Denmark)

    Sylvester-Hvid, C; Buus, S

    1999-01-01

    of a recombinant murine MHC-I molecule, which could be produced in large amounts in bacteria. The recombinant MHC-I protein was expressed as a single molecule (PepSc) consisting of the antigenic peptide linked to the MHC-I heavy chain and further linked to human beta2-microglobulin (hbeta2m). The PepSc molecule...... electrophoresis (SDS-PAGE). Serological analysis revealed the presence of some, but not all, MHC-I-specific epitopes. Biochemically, PepSc could bind peptide, however, rather ineffectively. We suggest that a partially correctly refolded MHC-I has been obtained....

  17. Application of Peptide LC Retention Time Information in a Discriminant Function for Peptide Identification by Tandem Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Strittmatter, Eric F.; Kangas, Lars J.; Petritis, Konstantinos; Mottaz, Heather M.; Anderson, Gordon A.; Shen, Yufeng; Jacobs, Jon M.; Camp, David G.; Smith, Richard D.

    2004-07-09

    We describe the application of a peptide retention time reversed phase liquid chromatography (RPLC) prediction model previously reported (Petritis et al. Anal. Chem. 99, 2002, 11049) for improved peptide identification. The model uses peptide sequence information to generate a theoretical (predicted) elution time that can be compared with the observed elution time. Using data from a set of known proteins, the retention time parameter was incorporated into a discriminant function for use with tandem mass spectrometry (MS/MS) data analyzed with the peptide/protein identification program SEQUEST. For singly charged ions, the number of identifications increased by 12% when the elution time metric is included compared to when mass spectral data is the sole source of information in the context of a Drosophila melanogaster database. A 3-4% improvement was obtained for doubly and triply charged ions for the same biological system. Application to the larger Rattus norvegicus (rat) and human proteome databases resulted in an 8-9% overall increase in the number of identifications, when both the discriminant function and elution time are used. The effect of adding “runner-up” hits (peptide matches that are not the highest scoring for a spectra) from SEQUEST is also explored, and we find that the number of confident identifications is further increased when these hits are also considered. Finally, application of the discriminant functions derived in this work with ~2.2 million spectra from 330 LC-MS/MS analyses of peptides from human plasma protein resulted in a 19% increase in confident peptide identifications (9551 vs 8049) using elution time information. Further improvements from the use of elution time information can be expected as both the experimental control of elution time reproducibility and the predictive capability are improved.

  18. Developing Health Information Technology (HIT) Programs and HIT Curriculum: The Southern Polytechnic State University Experience

    Science.gov (United States)

    Zhang, Chi; Reichgelt, Han; Rutherfoord, Rebecca H.; Wang, Andy Ju An

    2014-01-01

    Health Information Technology (HIT) professionals are in increasing demand as healthcare providers need help in the adoption and meaningful use of Electronic Health Record (EHR) systems while the HIT industry needs workforce skilled in HIT and EHR development. To respond to this increasing demand, the School of Computing and Software Engineering…

  19. Constructive Technology Assessment for HIT development

    DEFF Research Database (Denmark)

    Høstgaard, Anna Marie Balling; Bertelsen, Pernille; Petersen, Lone Stub

    2013-01-01

    Experience and time has shown a need for new evaluation methods for evaluating Health Information Technology (HIT), as summative evaluation methods fail to accommodate the rapid and constant changes in HIT over time and to involve end-users, which has been recognized as an important success facto...... during all the phases in the process. Thereby anumber of problems were prevented to occur later on.Thus, the CTA method and its framework are useful for evaluators and project-management in order to facilitate and support successful HIT development.......Experience and time has shown a need for new evaluation methods for evaluating Health Information Technology (HIT), as summative evaluation methods fail to accommodate the rapid and constant changes in HIT over time and to involve end-users, which has been recognized as an important success factor...... in HIT development. A new evaluation methodology, including an analytical framework, has been developed specifically for HIT development: Constructive Technology Assessment (CTA) for HIT. It offers solutions to both the problems associated with summative technology evaluation and a way to involve end...

  20. Retrograde labeling of single neurons in conjunction with MALDI high-energy collision-induced dissociation MS/MS analysis for peptide profiling and structural characterization

    NARCIS (Netherlands)

    El Filali, Z.; Hornshaw, M.; Smit, A.B.; Li, K.W.

    2003-01-01

    To reveal the peptide contents of the visually nonidentifiable neurons from a neuronal circuit of interest, we combined retrograde labeling of neurons with mass spectrometric single cell analysis. We used the neuronal circuit involved in the copulation behavior of a freshwater snail, Lymnaea

  1. Six Peptide Wound Signals Derived from a Single Precursor Protein in Ipomoea batatas Leaves Activate the Expression of the Defense Gene Sporamin*

    Science.gov (United States)

    Chen, Yu-Chi; Siems, William F.; Pearce, Gregory; Ryan, Clarence A.

    2008-01-01

    A mixture of three homologous bioactive hydroxyproline-rich glycopeptides (HypSys peptides) of 18 amino acids in length, differing only at two residues, was isolated from leaves of Ipomoea batatas, the common sweet potato. One of the peptides represented over 95% of the isolated isopeptides, which, at 2.5 nm concentration, induced the expression of sporamin, a major defense protein of I. batatas. The sequence of the major isoform was used to synthesize a primer that identified a cDNA encoding a precursor protein. The protein contained six proline-rich regions whose sequences suggested that they might be HypSys defense signals. One of the encoded peptides, called IbHypSys IV, was identical to one of two minor components of the isolated isopeptides, but neither the major isopeptide nor the other minor isoform was found within the precursor. The six peptides encoded by the precursor gene were synthesized but with hydroxyproline residues at positions found in the native isoforms and lacking carbohydrate moieties. All of the peptides were biologically active when supplied to leaves of sweet potato plants. The gene is the first ortholog of the preproHypSys gene family to be found outside of the Solanaceae family, and its encoded peptide precursor is the first example in plants of a precursor protein with six potential peptide defense signals, a scenario only found previously in animals. The data indicate that multiple copies of the HypSys peptides in a single precursor may have an important role in amplifying wound signaling in leaves in response to herbivore attacks. PMID:18299332

  2. A single nine-amino acid peptide induces virus-specific, CD8+ human cytotoxic T lymphocyte clones of heterogeneous serotype specificities

    OpenAIRE

    1995-01-01

    It is generally accepted that virus-specific CD8+ cytotoxic T lymphocytes (CTLs) recognize nine-amino acid peptides in conjunction with HLA class I molecules. We recently reported that dengue virus- specific CD8+ CTLs of two different serotype specificities, which were established by stimulation with dengue virus, recognize a single nine- amino acid peptide of the nonstructural protein NS3 of dengue virus type 4 (D4V) in an HLA-B35-restricted fashion. To further analyze the relationships betw...

  3. Fusion Peptide Improves Stability and Bioactivity of Single Chain Antibody against Rabies Virus.

    Science.gov (United States)

    Xi, Hualong; Zhang, Kaixin; Yin, Yanchun; Gu, Tiejun; Sun, Qing; Shi, Linqing; Zhang, Renxia; Jiang, Chunlai; Kong, Wei; Wu, Yongge

    2017-04-28

    The combination of rabies immunoglobulin (RIG) with a vaccine is currently effective against rabies infections, but improvements are needed. Genetic engineering antibody technology is an attractive approach for developing novel antibodies to replace RIG. In our previous study, a single-chain variable fragment, scFv57R, against rabies virus glycoprotein was constructed. However, its inherent weak stability and short half-life compared with the parent RIG may limit its diagnostic and therapeutic application. Therefore, an acidic tail of synuclein (ATS) derived from the C-terminal acidic tail of human alpha-synuclein protein was fused to the C-terminus of scFv57R in order to help it resist adverse stress and improve the stability and halflife. The tail showed no apparent effect on the preparation procedure and affinity of the protein, nor did it change the neutralizing potency in vitro. In the ELISA test of molecular stability, the ATS fusion form of the protein, scFv57R-ATS, showed an increase in thermal stability and longer half-life in serum than scFv57R. The protection against fatal rabies virus challenge improved after fusing the tail to the scFv, which may be attributed to the improved stability. Thus, the ATS fusion approach presented here is easily implemented and can be used as a new strategy to improve the stability and half-life of engineered antibody proteins for practical applications.

  4. Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: Evidence for the alternative splicing of a single-copy gene

    International Nuclear Information System (INIS)

    Thiede, M.A.; Strewler, G.J.; Nissenson, R.A.; Rosenblatt, M.; Rodan, G.A.

    1988-01-01

    A peptide secreted by tumors associated with the clinical syndrome of humoral hypercalcemia of malignancy was recently purified from human renal carcinoma cell line 786-0. The N-terminal amino acid sequence of this peptide has considerable similarity with those of parathyroid hormone (PTH) and of peptides isolated from human breast and lung carcinoma (cell line BEN). In this study the authors obtained the nucleotide sequence of a 1595-base cDNA complementary to mRNA encoding the PTH-like peptide produced by 786-0 cells. The cDNA contains an open reading frame encoding a leader sequence of 36 amino acids and a 139-residue peptide, in which 8 of the first 13 residues are identical to the N terminus of PTH. Through the first 828 bases the sequence of this cDNA is identical with one recently isolated from a BEN cell cDNA library; however, beginning with base 829 the sequences diverge, shortening the open reading frame by 2 amino acids. Differential RNA blot analysis revealed that 786-0 cells express two major PTH-like peptide mRNAs with different 3' untranslated sequences, one of which hybridizes with the presently described sequence and the other one with that reported for the BEN cell PTH-like peptide cDNA. Primer-extension analysis of 786-0 poly(A) + RNA together with Southern blot analysis of human DNA confirmed the presence of a single-copy gene coding for multiple mRNAs through alternate splicing. In addition, the 3' untranslated sequence of the cDNA described here has significant similarity to the c-myc protooncogene

  5. The effect of varying the peptide linker length in a single chain variable fragment antibody against wogonin glucuronide.

    Science.gov (United States)

    Paudel, Madan Kumar; Sakamoto, Seiichi; Van Huy, Le; Tanaka, Hiroyuki; Miyamoto, Tomofumi; Morimoto, Satoshi

    2017-06-10

    Peptide linkers of three different lengths were constructed to join the variable regions of the heavy chain (VH) and the light chain (VL) in a single-chain variable fragment antibody (scFv) specific for wogonin glucuronide (Wgn) that has the structure VH-(GGGGS) n -VL (n=3, 5, or 7). The scFv antibodies, which were expressed in Escherichia coli, were derived from an anti-Wgn monoclonal antibody (315A). An indirect competitive enzyme-linked immunosorbent assay (icELISA) was used to evaluate their reactivity and sensitivity, which is also used for quantitative analysis of Wgn. Our results, showed that the reactivity and specificity of the three different scFvs were, in fact, similar. Subsequently, the scFv having a VH-(GGGGS) 3 -VL linker which was slightly better that other two scFvs against Wgn, was applied to indirect competitive ELISA (icELISA) to analyze Scutellariae Radix (S. Radix). The utility of the icELISA was demonstrated for quality control and analysis of S. Radix in this report. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Effects of Voluntary Locomotion and Calcitonin Gene-Related Peptide on the Dynamics of Single Dural Vessels in Awake Mice.

    Science.gov (United States)

    Gao, Yu-Rong; Drew, Patrick J

    2016-02-24

    The dura mater is a vascularized membrane surrounding the brain and is heavily innervated by sensory nerves. Our knowledge of the dural vasculature has been limited to pathological conditions, such as headaches, but little is known about the dural blood flow regulation during behavior. To better understand the dynamics of dural vessels during behavior, we used two-photon laser scanning microscopy (2PLSM) to measure the diameter changes of single dural and pial vessels in the awake mouse during voluntary locomotion. Surprisingly, we found that voluntary locomotion drove the constriction of dural vessels, and the dynamics of these constrictions could be captured with a linear convolution model. Dural vessel constrictions did not mirror the large increases in intracranial pressure (ICP) during locomotion, indicating that dural vessel constriction was not caused passively by compression. To study how behaviorally driven dynamics of dural vessels might be altered in pathological states, we injected the vasodilator calcitonin gene-related peptide (CGRP), which induces headache in humans. CGRP dilated dural, but not pial, vessels and significantly reduced spontaneous locomotion but did not block locomotion-induced constrictions in dural vessels. Sumatriptan, a drug commonly used to treat headaches, blocked the vascular and behavioral the effects of CGRP. These findings suggest that, in the awake animal, the diameters of dural vessels are regulated dynamically during behavior and during drug-induced pathological states. Copyright © 2016 the authors 0270-6474/16/362503-14$15.00/0.

  7. The validation of Huffaz Intelligence Test (HIT)

    Science.gov (United States)

    Rahim, Mohd Azrin Mohammad; Ahmad, Tahir; Awang, Siti Rahmah; Safar, Ajmain

    2017-08-01

    In general, a hafiz who can memorize the Quran has many specialties especially in respect to their academic performances. In this study, the theory of multiple intelligences introduced by Howard Gardner is embedded in a developed psychometric instrument, namely Huffaz Intelligence Test (HIT). This paper presents the validation and the reliability of HIT of some tahfiz students in Malaysia Islamic schools. A pilot study was conducted involving 87 huffaz who were randomly selected to answer the items in HIT. The analysis method used includes Partial Least Square (PLS) on reliability, convergence and discriminant validation. The study has validated nine intelligences. The findings also indicated that the composite reliabilities for the nine types of intelligences are greater than 0.8. Thus, the HIT is a valid and reliable instrument to measure the multiple intelligences among huffaz.

  8. Mass Spectrometry of Single GABAergic Somatic Motorneurons Identifies a Novel Inhibitory Peptide, As-NLP-22, in the Nematode Ascaris suum

    Science.gov (United States)

    Konop, Christopher J.; Knickelbine, Jennifer J.; Sygulla, Molly S.; Wruck, Colin D.; Vestling, Martha M.; Stretton, Antony O. W.

    2015-12-01

    Neuromodulators have become an increasingly important component of functional circuits, dramatically changing the properties of both neurons and synapses to affect behavior. To explore the role of neuropeptides in Ascaris suum behavior, we devised an improved method for cleanly dissecting single motorneuronal cell bodies from the many other cell processes and hypodermal tissue in the ventral nerve cord. We determined their peptide content using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). The reduced complexity of the peptide mixture greatly aided the detection of peptides; peptide levels were sufficient to permit sequencing by tandem MS from single cells. Inhibitory motorneurons, known to be GABAergic, contain a novel neuropeptide, As-NLP-22 (SLASGRWGLRPamide). From this sequence and information from the A. suum expressed sequence tag (EST) database, we cloned the transcript ( As-nlp-22) and synthesized a riboprobe for in situ hybridization, which labeled the inhibitory motorneurons; this validates the integrity of the dissection method, showing that the peptides detected originate from the cells themselves and not from adhering processes from other cells (e.g., synaptic terminals). Synthetic As-NLP-22 has potent inhibitory activity on acetylcholine-induced muscle contraction as well as on basal muscle tone. Both of these effects are dose-dependent: the inhibitory effect on ACh contraction has an IC50 of 8.3 × 10-9 M. When injected into whole worms, As-NLP-22 produces a dose-dependent inhibition of locomotory movements and, at higher levels, complete paralysis. These experiments demonstrate the utility of MALDI TOF/TOF MS in identifying novel neuromodulators at the single-cell level.

  9. Assembly and use of high-density recombinant peptide chips for large-scale ligand screening is a practical alternative to synthetic peptide libraries.

    Science.gov (United States)

    Hundsberger, Harald; Önder, Kamil; Schuller-Götzburg, Peter; Virok, Dezso P; Herzog, Julia; Rid, Raphaela

    2017-06-08

    Recombinant peptide chips could constitute a versatile complementation to state-of-the-art in situ (chemical on-chip) synthesis, particle-based printing, or pre-manufactured peptide spotting. Bottlenecks still impeding a routine implementation - from restricted peptide lengths, low diversity and low array densities to high costs - could so be overcome. To assess overall performance, we assembled recombinant chips composed of 38,400 individual peptide spots on the area of a standard 96-well microtiter plate from comprehensive, highly diverse (>107 single clones) short random peptide libraries. Screening of altogether 476,160 clones against Streptavidin uncovered 2 discrete new binders: a characteristic HPQ-motif containing VSHPQAPF and a cyclic CSGSYGSC peptide. Interactions were technically confirmed by fluorescence polarization as well as biolayer-interferometry, and their potential suitability as novel detection tags evaluated by detection of a peptide-fused exemplary test protein. From our data we conclude that the presented technical pipeline can reliably identify novel hits, useful as first-generation binders or templates for subsequent ligand design plus engineering.

  10. Structural and Functional Characterization of a Single-chain Peptide-MHC Molecule that Modulates both Naive and Activated CD8plus T Cells

    Energy Technology Data Exchange (ETDEWEB)

    D Samanta; G Mukherjee; U Ramagopal; R Chaparro; S Nathenson; T DiLorenzo; S Almo

    2011-12-31

    Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8{sup +} T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8{sup +} T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK{sup d}.IGRP) by using the class I MHC molecule H-2K{sup d} and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP{sub 206-214}), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK{sup d}.IGRP tetramers bound specifically to cognate CD8{sup +} T cells. Tetramer binding induced death of naive T cells and in vitro- and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-{gamma} response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8{sup +} T cells makes them a potential intervention strategy in early and late stages of disease.

  11. Insight into the interactions, residue snorkeling, and membrane disordering potency of a single antimicrobial peptide into different lipid bilayers.

    Directory of Open Access Journals (Sweden)

    Majid Jafari

    Full Text Available Pardaxin, with a bend-helix-bend-helix structure, is a membrane-active antimicrobial peptide that its membrane activity depends on the lipid bilayer composition. Herein, all-atom molecular dynamics (MD simulations were performed to provide further molecular insight into the interactions, structural dynamics, orientation behavior, and cationic residues snorkeling of pardaxin in the DMPC, DPPC, POPC, POPG, POPG/POPE (3:1, and POPG/POPE (1:3 lipid bilayers. The results showed that the C-terminal helix of the peptide was maintained in all six types of the model-bilayers and pardaxin was tilted into the DMPC, DPPC, and POPG/POPE mixed bilayers more than the POPC and POPG bilayers. As well as, the structure of zwitterionic membranes was more affected by the peptide than the anionic bilayers. Taken together, the study demonstrated that the cationic residues of pardaxin snorkeled toward the interface of lipid bilayers and all phenylalanine residues of the peptide played important roles in the peptide-membrane interactions. We hope that this work will provide a better understanding of the interactions of antimicrobial peptides with the membranes.

  12. Low dose endotoxin priming is accountable for coagulation abnormalities and organ damage observed in the Shwartzman reaction. A comparison between a single-dose endotoxemia model and a double-hit endotoxin-induced Shwartzman reaction

    Directory of Open Access Journals (Sweden)

    Cate Hugo

    2006-08-01

    Full Text Available Abstract The clinical response of sepsis to a systemic inflammatory infection may be complicated by disseminated intravascular coagulation or DIC. In order to experimentally study the syndrome of DIC, we aimed for a severe sepsis model complicated by disseminated coagulation. Most -simplified- experimental models describing coagulation abnormalities as a consequence of sepsis are based on single dose endotoxemia. The so called-Shwartzman reaction contrarily, is elicited by a low dose endotoxin priming followed by an LPS challenge and is characterized by pathological manifestations that represent the syndrome of DIC. In order to investigate whether the Shwartzman reaction is superior to a single endotoxin challenge as a model for sepsis-induced DIC and to determine what the pathological effect is of an encounter of low endotoxin prior to an LPS challenge, we undertook the present study. In this study we demonstrate that low-dose endotoxin priming prior to an LPS challenge in the Shwartzman reaction is accountable for micro-vascular thrombosis in lung and liver and subsequent (multi- organ failure, not observed after a single-dose endotoxin challenge, which indicates that the Shwartzman reaction is well suited-model to study sepsis-induced DIC adversities. Remarkably, only minor differences in the innate immune response were established between the single-dose endotoxin challenge and the Shwartzman reaction.

  13. Moving away from the reference genome: evaluating a peptide sequencing tagging approach for single amino acid polymorphism identifications in the genus Populus.

    Science.gov (United States)

    Abraham, Paul; Adams, Rachel M; Tuskan, Gerald A; Hettich, Robert L

    2013-08-02

    The genetic diversity across natural populations of the model organism, Populus, is extensive, containing a single nucleotide polymorphism roughly every 200 base pairs. When deviations from the reference genome occur in coding regions, they can impact protein sequences. Rather than relying on a static reference database to profile protein expression, we employed a peptide sequence tagging (PST) approach capable of decoding the plasticity of the Populus proteome. Using shotgun proteomics data from two genotypes of P. trichocarpa, a tag-based approach enabled the detection of 6653 unexpected sequence variants. Through manual validation, our study investigated how the most abundant chemical modification (methionine oxidation) could masquerade as a sequence variant (Ala→Ser) when few site-determining ions existed. In fact, precise localization of an oxidation site for peptides with more than one potential placement was indeterminate for 70% of the MS/MS spectra. We demonstrate that additional fragment ions made available by high energy collisional dissociation enhances the robustness of the peptide sequence tagging approach (81% of oxidation events could be exclusively localized to a methionine). We are confident that augmenting fragmentation processes for a PST approach will further improve the identification of single amino acid polymorphism in Populus and potentially other species as well.

  14. Water transfer and loss in hit-and-run collisions

    Science.gov (United States)

    Burger, C.; Maindl, T. I.; Schäfer, C.

    2017-09-01

    This work focuses on transfer and loss of volatiles, like water, in hit-and-run collisions, where especially the smaller one of the colliding pair is often stripped of considerable amounts of its initial volatile content, but still survives the encounter more or less intact. We find water losses up to 75 percent in a single collision, depending on various parameters, especially velocity, impact angle and mass ratio, but also on the total colliding mass. The physical state, especially vaporization of volatiles, is found to be particularly important in collisions of approximately Mars-sized bodies, with high impact energies, but still potentially easy volatile escape.

  15. Predominant Occupation of the Class I MHC Molecule H-2Kwm7 with a Single Self-peptide Suggests a Mechanism for its Diabetes-protective Effect

    Energy Technology Data Exchange (ETDEWEB)

    Brims, D.; Qian, J; Jarchum, I; Mikesh, L; Palmieri, E; Ramagopal, U; Malashkevich, V; Chaparro, R; Lund, T; et. al.

    2010-01-01

    Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic {beta} cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD{sup 4+} and CD{sup 8+} T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2K{sup wm7}, which exerts a diabetes-protective effect in NOD mice. We have found that H-2K{sup wm7} molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2K{sup wm7} to support T1D development could be due, at least in part, to the failure of peptides from critical {beta}-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD{sup 8+} T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.

  16. Statistical properties and pre-hit dynamics of price limit hits in the Chinese stock markets.

    Science.gov (United States)

    Wan, Yu-Lei; Xie, Wen-Jie; Gu, Gao-Feng; Jiang, Zhi-Qiang; Chen, Wei; Xiong, Xiong; Zhang, Wei; Zhou, Wei-Xing

    2015-01-01

    Price limit trading rules are adopted in some stock markets (especially emerging markets) trying to cool off traders' short-term trading mania on individual stocks and increase market efficiency. Under such a microstructure, stocks may hit their up-limits and down-limits from time to time. However, the behaviors of price limit hits are not well studied partially due to the fact that main stock markets such as the US markets and most European markets do not set price limits. Here, we perform detailed analyses of the high-frequency data of all A-share common stocks traded on the Shanghai Stock Exchange and the Shenzhen Stock Exchange from 2000 to 2011 to investigate the statistical properties of price limit hits and the dynamical evolution of several important financial variables before stock price hits its limits. We compare the properties of up-limit hits and down-limit hits. We also divide the whole period into three bullish periods and three bearish periods to unveil possible differences during bullish and bearish market states. To uncover the impacts of stock capitalization on price limit hits, we partition all stocks into six portfolios according to their capitalizations on different trading days. We find that the price limit trading rule has a cooling-off effect (object to the magnet effect), indicating that the rule takes effect in the Chinese stock markets. We find that price continuation is much more likely to occur than price reversal on the next trading day after a limit-hitting day, especially for down-limit hits, which has potential practical values for market practitioners.

  17. Statistical Properties and Pre-Hit Dynamics of Price Limit Hits in the Chinese Stock Markets

    Science.gov (United States)

    Wan, Yu-Lei; Xie, Wen-Jie; Gu, Gao-Feng; Jiang, Zhi-Qiang; Chen, Wei; Xiong, Xiong; Zhang, Wei; Zhou, Wei-Xing

    2015-01-01

    Price limit trading rules are adopted in some stock markets (especially emerging markets) trying to cool off traders’ short-term trading mania on individual stocks and increase market efficiency. Under such a microstructure, stocks may hit their up-limits and down-limits from time to time. However, the behaviors of price limit hits are not well studied partially due to the fact that main stock markets such as the US markets and most European markets do not set price limits. Here, we perform detailed analyses of the high-frequency data of all A-share common stocks traded on the Shanghai Stock Exchange and the Shenzhen Stock Exchange from 2000 to 2011 to investigate the statistical properties of price limit hits and the dynamical evolution of several important financial variables before stock price hits its limits. We compare the properties of up-limit hits and down-limit hits. We also divide the whole period into three bullish periods and three bearish periods to unveil possible differences during bullish and bearish market states. To uncover the impacts of stock capitalization on price limit hits, we partition all stocks into six portfolios according to their capitalizations on different trading days. We find that the price limit trading rule has a cooling-off effect (object to the magnet effect), indicating that the rule takes effect in the Chinese stock markets. We find that price continuation is much more likely to occur than price reversal on the next trading day after a limit-hitting day, especially for down-limit hits, which has potential practical values for market practitioners. PMID:25874716

  18. Epigenetic reprogramming: Prdm14 hits the accelerator

    NARCIS (Netherlands)

    Geijsen, N.

    2012-01-01

    The EMBO Journal (2012) 31, 2247 - 2248 doi:10.1038/emboj.2012.117 Published online: 20 April 2012 There is an Article (May 2012) associated with this Have you seen?. Epigenetic reprogramming: Prdm14 hits the accelerator Niels Geijsen1 Hubrecht Institute KNAW, School of Veterinary Medicine, Utrecht

  19. Synthetic surfactant containing SP-B and SP-C mimics is superior to single-peptide formulations in rabbits with chemical acute lung injury

    Directory of Open Access Journals (Sweden)

    Frans J. Walther

    2014-05-01

    Full Text Available Background. Chemical spills are on the rise and inhalation of toxic chemicals may induce chemical acute lung injury (ALI/acute respiratory distress syndrome (ARDS. Although the pathophysiology of ALI/ARDS is well understood, the absence of specific antidotes has limited the effectiveness of therapeutic interventions.Objectives. Surfactant inactivation and formation of free radicals are important pathways in (chemical ALI. We tested the potential of lipid mixtures with advanced surfactant protein B and C (SP-B and C mimics to improve oxygenation and lung compliance in rabbits with lavage- and chemical-induced ALI/ARDS.Methods. Ventilated young adult rabbits underwent repeated saline lung lavages or underwent intratracheal instillation of hydrochloric acid to induce ALI/ARDS. After establishment of respiratory failure rabbits were treated with a single intratracheal dose of 100 mg/kg of synthetic surfactant composed of 3% Super Mini-B (S-MB, a SP-B mimic, and/or SP-C33 UCLA, a SP-C mimic, in a lipid mixture (DPPC:POPC:POPG 5:3:2 by weight, the clinical surfactant Infasurf®, a bovine lung lavage extract with SP-B and C, or synthetic lipids alone. End-points consisted of arterial oxygenation, dynamic lung compliance, and protein and lipid content in bronchoalveolar lavage fluid. Potential mechanism of surfactant action for S-MB and SP-C33 UCLA were investigated with captive bubble surfactometry (CBS assays.Results. All three surfactant peptide/lipid mixtures and Infasurf equally lowered the minimum surface tension on CBS, and also improved oxygenation and lung compliance. In both animal models, the two-peptide synthetic surfactant with S-MB and SP-C33 UCLA led to better arterial oxygenation and lung compliance than single peptide synthetic surfactants and Infasurf. Synthetic surfactants and Infasurf improved lung function further in lavage- than in chemical-induced respiratory failure, with the difference probably due to greater capillary

  20. Study of Charge-Dependent Transport and Toxicity of Peptide-Functionalized Silver Nanoparticles Using Zebrafish Embryos and Single Nanoparticle Plasmonic Spectroscopy

    Science.gov (United States)

    Lee, Kerry J.; Browning, Lauren M.; Nallathamby, Prakash D.; Xu, Xiao-Hong Nancy

    2013-01-01

    Nanomaterials possess unusually high surface area-to-volume ratios, and surface-determined physicochemical properties. It is essential to understand their surface-dependent toxicity in order to rationally design biocompatible nanomaterials for a wide variety of applications. In this study, we have functionalized the surfaces of silver nanoparticles (Ag NPs, 11.7 ± 2.7 nm in diameters) with three biocompatible peptides (CALNNK, CALNNS, CALNNE) to prepare positively (Ag-CALNNK NPs+ζ), negatively (Ag-CALNNS NPs−2ζ), and more negatively charged NPs (Ag-CALNNE NPs−4ζ), respectively. Each peptide differs in a single amino acid at its C-terminus, which minimizes the effects of peptide sequences and serves as a model molecule to create positive, neutral and negative charges on the surface of the NPs at pH 4–10. We have studied their charge-dependent transport into early-developing (cleavage-stage) zebrafish embryos and their effects on embryonic development using dark-field optical microscopy and spectroscopy (DFOMS). We found that all three Ag-peptide NPs passively diffused into the embryos via their chorionic pore canals, and stayed inside the embryos throughout their entire development (120 h), showing charge-independent diffusion modes and charge-dependent diffusion coefficients. Notably, the NPs create charge-dependent toxic effects on embryonic development, showing that the Ag-CALNNK NPs+ζ (positively charged) are the most biocompatible while the Ag-CALNNE NPs–4ζ (more negatively charged) are the most toxic. By comparing with our previous studies of the same sized citrated Ag and Au NPs, the Ag-peptide NPs are much more biocompatible than the citrated Ag NPs, and nearly as biocompatible as the Au NPs, showing the dependence of nanotoxicity upon the surface charges, surface functional groups and chemical compositions of the NPs. This study also demonstrates powerful applications of single NP plasmonic spectroscopy for quantitative analysis of single NPs

  1. Bioavailability of tryptophan from a single oral dose of a trytophan-enriched peptide mixture in healthy men

    NARCIS (Netherlands)

    Brink, E.J.; Boelsma, E.; Steijns, J.; Hendriks, H.F.J.

    2004-01-01

    The aim of the study was to investigate the bioavailability of tryptophan (Trp) from a Trp-enriched peptide mixture in healthy men. A second objective was to investigate the effect of this Trp-enriched protein hydrolysate on potential parameters of serotonergic activity. serum serotonim melatonin

  2. Post-hit dynamics of price limit hits in the Chinese stock markets

    Science.gov (United States)

    Wu, Ting; Wang, Yue; Li, Ming-Xia

    2017-01-01

    Price limit trading rules are useful to cool off traders short-term trading mania on individual stocks. The price dynamics approaching the limit boards are known as the magnet effect. However, the price dynamics after opening price limit hits are not well investigated. Here, we provide a detailed analysis on the price dynamics after the hits of up-limit or down-limit is open based on all A-share stocks traded in the Chinese stock markets. A ;W; shape is found in the expected return, which reveals high probability of a continuous price limit hit on the following day. We also find that price dynamics after opening limit hits are dependent on the market trends. The time span of continuously hitting the price limit is found to an influence factor of the expected profit after the limit hit is open. Our analysis provides a better understanding of the price dynamics around the limit boards and contributes potential practical values for investors.

  3. Health Information Technology (HIT) Adaptation: Refocusing on the Journey to Successful HIT Implementation.

    Science.gov (United States)

    Yen, Po-Yin; McAlearney, Ann Scheck; Sieck, Cynthia J; Hefner, Jennifer L; Huerta, Timothy R

    2017-09-07

    In past years, policies and regulations required hospitals to implement advanced capabilities of certified electronic health records (EHRs) in order to receive financial incentives. This has led to accelerated implementation of health information technologies (HIT) in health care settings. However, measures commonly used to evaluate the success of HIT implementation, such as HIT adoption, technology acceptance, and clinical quality, fail to account for complex sociotechnical variability across contexts and the different trajectories within organizations because of different implementation plans and timelines. We propose a new focus, HIT adaptation, to illuminate factors that facilitate or hinder the connection between use of the EHR and improved quality of care as well as to explore the trajectory of changes in the HIT implementation journey as it is impacted by frequent system upgrades and optimizations. Future research should develop instruments to evaluate the progress of HIT adaptation in both its longitudinal design and its focus on adaptation progress rather than on one cross-sectional outcome, allowing for more generalizability and knowledge transfer. ©Po-Yin Yen, Ann Scheck McAlearney, Cynthia J Sieck, Jennifer L Hefner, Timothy R Huerta. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 07.09.2017.

  4. Structure-based optimization of non-peptidic Cathepsin D inhibitors.

    Science.gov (United States)

    Grädler, Ulrich; Czodrowski, Paul; Tsaklakidis, Christos; Klein, Markus; Werkmann, Daniela; Lindemann, Sven; Maskos, Klaus; Leuthner, Birgitta

    2014-09-01

    We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Cosmic Ray Hit Detection with Homogenous Structures

    Science.gov (United States)

    Smirnov, O. M.

    Cosmic ray (CR) hits can affect a significant number of pixels both on long-exposure ground-based CCD observations and on the Space Telescope frames. Thus, methods of identifying the damaged pixels are an important part of the data preprocessing for practically any application. The paper presents an implementation of a CR hit detection algorithm based on a homogenous structure (also called cellular automata ), a concept originating in artificial intelligence and dicrete mathematics. Each pixel of the image is represented by a small automaton, which interacts with its neighbors and assumes a distinct state if it ``decides'' that a CR hit is present. On test data, the algorithm has shown a high detection rate (~0.7 ) and a low false alarm rate (frame. A homogenous structure is extremely trainable, which can be very important for processing large batches of data obtained under similar conditions. Training and optimizing issues are discussed, as well as possible other applications of this concept to image processing.

  6. On the Hitting Probability of Max-Stable Processes

    OpenAIRE

    Hofmann, Martin

    2012-01-01

    The probability that a max-stable process {\\eta} in C[0, 1] with identical marginal distribution function F hits x \\in R with 0 < F (x) < 1 is the hitting probability of x. We show that the hitting probability is always positive, unless the components of {\\eta} are completely dependent. Moreover, we consider the event that the paths of standard MSP hit some x \\in R twice and we give a sufficient condition for a positive probability of this event.

  7. Eyewitness Identification Reforms: Are Suggestiveness-Induced Hits and Guesses True Hits?

    Science.gov (United States)

    Wells, Gary L; Steblay, Nancy K; Dysart, Jennifer E

    2012-05-01

    Research-based reforms for collecting eyewitness identification evidence (e.g., unbiased pre-lineup instructions, double-blind administration) have been proposed by psychologists and adopted in increasing numbers of jurisdictions across the United States. It is well known that reducing rates of mistaken identifications can also reduce accurate identification rates (hits). But the reforms are largely designed to reduce the suggestiveness of the procedures they are meant to replace. Accordingly, we argue that it is misleading to label any hits obtained because of suggestive procedures as "hits" and then saddle reforms with the charge that they reduce the rate of these illegitimate hits. Eyewitness identification evidence should be based solely on the independent memory of the witness, not aided by biased instructions, cues from lineup administrators, or the use of lineup fillers who make the suspect stand out. Failure to call out these hits as being illegitimate can give solace to those who are motivated to preserve the status quo. © The Author(s) 2012.

  8. Hit-size effectiveness theory applied to high doses of low LET radiation for pink mutations in Tradescantia

    International Nuclear Information System (INIS)

    Varma, M.N.; Bond, V.P.; Matthews, G.

    1985-01-01

    A hit-size effectiveness function which represents the probability of inducing a pink mutation in Tradescantia as a function of lineal energy density has been obtained (1) using observed pink mutation data for seven different radiation qualities and their respective single event microdosimetric spectra. In obtaining this function only the linear portions of dose-response curves were used. A significant improvement of the concepts embodied in the proposed hit-size effectiveness theory would be the demonstration of its applicability at high doses (where multiple hits are produced) and high dose rates (at which no significant biological repair takes place). In this article details are given on preliminary calculations of the pink mutation frequency in Tradescantia at 1, 5, 10, 20, and 60 rads for 250 kVp x rays, using the multi-hit spectra and the hit-size effectiveness function obtained on the basis of single hit microdosimetric spectra as outline in (1). A comparison of the calculated and observed pink mutation frequencies indicate excellent agreement and suggests the possibility of obtaining the hit-size effectiveness function from high dose biological-effect data obtained using low-LET radiations. 6 refs., 3 figs., 3 tabs

  9. Hit-size effectiveness theory applied to high doses of low LET radiation for pink mutations in Tradescantia

    International Nuclear Information System (INIS)

    Varma, M.N.; Bond, V.P.; Matthews, G.

    1985-01-01

    A hit-size effectiveness function which represents the probability of inducing a pink mutation in Trasdescantia as a function of lineal energy density has been obtained earlier using observed pink mutation data for seven different radiation qualities and their respective single event microdosimetric spectra. In obtaining this function only the linear portions of dose-response curves were used. A significant improvement of the concepts embodied in the proposed hit-size effectiveness theory would be the demonstration of its applicability at high doses (where multiple hits are produced) and high dose rates (at which no significant biological repair takes place). In this article details are given on preliminary calculations of the pink mutation frequency in Tradescantia at 1, 5, 10, 20, and 60 rad for 250 kVp X rays, using the multi-hit event spectra and the hit-size effectiveness function obtained on the basis of single hit microdosimetric spectra as outlined in previous work. A comparison of the calculated and observed pink mutation frequencies indicate excellent agreement and suggests the possibility of obtaining the hit-size effectiveness function from high dose biological effect data obtained using low-LET radiations. (author)

  10. Diversity-oriented peptide stapling

    DEFF Research Database (Denmark)

    Tran, Thu Phuong; Larsen, Christian Ørnbøl; Røndbjerg, Tobias

    2017-01-01

    The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide-alkyne cycloaddition (CuAAC) has emerged as a power......The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide-alkyne cycloaddition (CuAAC) has emerged...... incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides (i, i+7)- and (i, i+9)-stapled peptides with a single free alkyne positioned on the staple, that can be further conjugated or dimerised. A unique feature of the present method is that it provides easy access...

  11. Entry of a Six-Residue Antimicrobial Peptide Derived from Lactoferricin B into Single Vesicles and Escherichia coli Cells without Damaging their Membranes.

    Science.gov (United States)

    Moniruzzaman, Md; Islam, Md Zahidul; Sharmin, Sabrina; Dohra, Hideo; Yamazaki, Masahito

    2017-08-22

    Lactoferricin B (LfcinB) and shorter versions of this peptide have antimicrobial activity. However, the elementary processes of interactions of these peptides with lipid membranes and bacteria are still not well understood. To elucidate the mechanism of their antimicrobial activity, we investigated the interactions of LfcinB (4-9) (its sequence of RRWQWR) with Escherichia coli cells and giant unilamellar vesicles (GUVs). LfcinB (4-9) and lissamine rhodamine B red-labeled LfcinB (4-9) (Rh-LfcinB (4-9)) did not induce an influx of a membrane-impermeant fluorescent probe, SYTOX green, from the outside of E. coli cells into their cytoplasm, indicating that no damage occurred in their plasma membrane. To examine the activity of LfcinB (4-9) to enter E. coli cytoplasm, we investigated the interaction of Rh-LfcinB (4-9) with single cells of E. coli containing calcein using confocal microscopy. We found that Rh-LfcinB (4-9) entered the cytoplasm without leakage of calcein. Next, we investigated the interactions of Rh-LfcinB (4-9) with single GUVs of dioleoylphosphatidylglycerol (DOPG) and dioleoylphosphatidylcholine (DOPC) mixtures containing a fluorescent probe, Alexa Fluor 647 hydrazide (AF647), using the single GUV method. The results indicate that Rh-LfcinB (4-9) outside the GUV translocated through the GUV membrane and entered its lumen without leakage of AF647. Interaction of Rh-LfcinB (4-9) with DNA increased its fluorescence intensity greatly. Therefore, we can conclude that Rh-LfcinB (4-9) can translocate across lipid membrane regions of the plasma membrane of E. coli cells to enter their cytoplasm without leakage of calcein and its antimicrobial activity is not due to damage of their plasma membranes.

  12. Single-cell resolution imaging of retinal ganglion cell apoptosis in vivo using a cell-penetrating caspase-activatable peptide probe.

    Directory of Open Access Journals (Sweden)

    Xudong Qiu

    Full Text Available Peptide probes for imaging retinal ganglion cell (RGC apoptosis consist of a cell-penetrating peptide targeting moiety and a fluorophore-quencher pair flanking an effector caspase consensus sequence. Using ex vivo fluorescence imaging, we previously validated the capacity of these probes to identify apoptotic RGCs in cell culture and in an in vivo rat model of N-methyl- D-aspartate (NMDA-induced neurotoxicity. Herein, using TcapQ488, a new probe designed and synthesized for compatibility with clinically-relevant imaging instruments, and real time imaging of a live rat RGC degeneration model, we fully characterized time- and dose-dependent probe activation, signal-to-noise ratios, and probe safety profiles in vivo. Adult rats received intravitreal injections of four NMDA concentrations followed by varying TcapQ488 doses. Fluorescence fundus imaging was performed sequentially in vivo using a confocal scanning laser ophthalmoscope and individual RGCs displaying activated probe were counted and analyzed. Rats also underwent electroretinography following intravitreal injection of probe. In vivo fluorescence fundus imaging revealed distinct single-cell probe activation as an indicator of RGC apoptosis induced by intravitreal NMDA injection that corresponded to the identical cells observed in retinal flat mounts of the same eye. Peak activation of probe in vivo was detected 12 hours post probe injection. Detectable fluorescent RGCs increased with increasing NMDA concentration; sensitivity of detection generally increased with increasing TcapQ488 dose until saturating at 0.387 nmol. Electroretinography following intravitreal injections of TcapQ488 showed no significant difference compared with control injections. We optimized the signal-to-noise ratio of a caspase-activatable cell penetrating peptide probe for quantitative non-invasive detection of RGC apoptosis in vivo. Full characterization of probe performance in this setting creates an important in

  13. Kinetic Study on Peptide-Bound Pyrraline Formation and Elimination in the Maillard Reaction Using Single- and Multiple-Response Models.

    Science.gov (United States)

    Liang, Zhili; Li, Lin; Qi, Haiping; Zhang, Zhenbo Xu Xia; Li, Bing

    2016-10-01

    Pyrraline, an advanced glycation end product (AGE), is related to some chronic diseases and can be employed as an indicator for heat damage in food processing. In this study, the impact of changing the reactant concentration and ratio on the kinetic parameters describing peptide-bound pyrraline (pep-pyr) formation and elimination was evaluated in the Lys-Gly/glucose model systems, with microwave heating treatment ranging from 120 to 200 °C. The maximum pep-pyr concentration increased as follows: 200 °C ˂ 180 °C ˂ 160 °C ˂ 120 °C ˂ 140 °C. First, the pep-pyr formation and elimination was modeled by using a single-response modelling. The formation rate constant (k F ) of pep-pyr was independent of the initial concentration of the reactants and ratios. However, the elimination rate constant of pep-pyr (k E ) increased with increasing reactant concentrations. Second, a multiresponse modelling was performed to illustrate the pathways of pep-pyr formation and elimination. Two adapted models can fit to the experimental data with the goodness-of-fit ranging from 0.663 to 0.920. Glucose-to-fructose isomerization rather than glucose-to-mannose epimerization was detected in an equimolar model system and the model system with an excess of any of the reactants. The caramelization reaction was negligible in the equimolar systems and the model systems with an excess of peptide. The reaction rate constant of glucose-to-fructose isomerization was independent of the initial reactant ratios. It was more difficult for pep-pyr elimination in the model system with an excess of peptide than that in the other 2 model systems (the equimolar system and the system with an excess of glucose), whereas a reverse result in pep-pyr formation was obtained. © 2016 Institute of Food Technologists®.

  14. Health information technology knowledge and skills needed by HIT employers.

    Science.gov (United States)

    Fenton, S H; Gongora-Ferraez, M J; Joost, E

    2012-01-01

    To evaluate the health information technology (HIT) workforce knowledge and skills needed by HIT employers. Statewide face-to-face and online focus groups of identified HIT employer groups in Austin, Brownsville, College Station, Dallas, El Paso, Houston, Lubbock, San Antonio, and webinars for rural health and nursing informatics. HIT employers reported needing an HIT workforce with diverse knowledge and skills ranging from basic to advanced, while covering information technology, privacy and security, clinical practice, needs assessment, contract negotiation, and many other areas. Consistent themes were that employees needed to be able to learn on the job and must possess the ability to think critically and problem solve. Many employers wanted persons with technical skills, yet also the knowledge and understanding of healthcare operations. The HIT employer focus groups provided valuable insight into employee skills needed in this fast-growing field. Additionally, this information will be utilized to develop a statewide HIT workforce needs assessment survey.

  15. The Rock that Hit New York

    Energy Technology Data Exchange (ETDEWEB)

    Meade, Roger Allen [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Keksis, August Lawrence [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-10-03

    On January 12, 1975, a rock seemed to fall from the sky over New York State’s Schoharie County hitting the tractor of a local farmer, who was “preparing his fields for spring planting.” As the farmer later described the event to a reporter from the UFO INVESTIGATOR, the object glanced off the tractor, fell to the ground, and melted its way through a patch of ice that was two and one half inches thick. The farmer, Leonard Tillapaugh, called the county sheriff, Harvey Stoddard, who recovered the rock, noting that it “was still warm.” Why and how a sample of the rock came to Los Alamos is not known. However, it captivated a wide Laboratory audience, was subjected to rigorous testing and evaluation. Los Alamos used the scientific method in the manner promoted by Hynek. Did Los Alamos solve the mystery of the rock’s origin? Not definitively. Although the exact origin could not be determined, it was shown conclusively that the rock was not from outer space. With that said, the saga of Rock that hit New York came to an end. Nothing more was said or written about it. The principals involved have long since passed from the scene. The NICAP ceased operations in 1980. And, the rock, itself, has disappeared.

  16. SICLOPPS cyclic peptide libraries in drug discovery.

    Science.gov (United States)

    Tavassoli, Ali

    2017-06-01

    Cyclic peptide libraries have demonstrated significant potential when employed against challenging targets such as protein-protein interactions. While a variety of methods for library generation exist, genetically encoded libraries hold several advantages over their chemically synthesized counterparts; they are more readily accessible and allow straightforward hit deconvolution. One method for the intracellular generation of such libraries is split-intein circular ligation of peptides and proteins (SICLOPPS). Here we detail and discuss the deployment of SICLOPPS libraries for the identification of cyclic peptide inhibitors of a variety of targets. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

    Directory of Open Access Journals (Sweden)

    Celina Yang

    2018-03-01

    Full Text Available Optimizing the interface between nanoparticles (NPs and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG functionalized gold nanoparticles (GNPs was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid, to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

  18. Hype, Hope, and Hit in Movies

    DEFF Research Database (Denmark)

    Dholakia, Nikhilesh; Turcan, Romeo V.

    2012-01-01

    This paper is part of an ongoing project to develop an interdisciplinary metatheory of bubbles, relevant to the contemporary era of globalization and rapid, technology-aided communication flows. Just in the first few years of the 21st century, several bubbles have appeared – the so-called dotcom...... bubble, the housing bubble, and the financial derivatives bubble.To develop a more general and multidisciplinary conceptual framework for understanding bubbles, we have ongoing projects looking at bubbles of various types: technological, financial, and cultural. This paper focuses on a particular...... cultural field where relatively small bubbles may form. Movies represent a good arena to examine cultural bubbles on a scale that is not daunting, and where the hype-hope-hit dynamics can be observed more frequently than in most other settings....

  19. Peptide Inhibitor of Complement C1 (PIC1) demonstrates antioxidant activity via single electron transport (SET) and hydrogen atom transfer (HAT).

    Science.gov (United States)

    Gregory Rivera, Magdielis; Hair, Pamela S; Cunnion, Kenji M; Krishna, Neel K

    2018-01-01

    Reactive oxygen species (ROS) are natural byproducts of oxidative respiration that are toxic to organs and tissues. To mitigate ROS damage, organisms have evolved a variety of antioxidant systems to counteract these harmful molecules, however in certain pathological conditions these protective mechanisms can be overwhelmed. We have recently demonstrated that Peptide Inhibitor of Complement C1 (PIC1) mitigates peroxidase activity of the heme bearing proteins myeloperoxidase, hemoglobin, and myoglobin through a reversible process. To determine if this property of PIC1 was antioxidant in nature, we tested PIC1 in a number of well-established antioxidant assays. PIC1 showed dose-dependent antioxidant activity in a total antioxidant (TAC) assay, hydroxyl radical antioxidant capacity (HORAC) assay, oxygen radical antioxidant capacity (ORAC) assay as well as the thiobarbituric acid reactive substances (TBARS) assay to screen for PIC1 antioxidant activity in human plasma. The antioxidant activity of PIC1 in the TAC assay, as well as the HORAC/ORAC assay demonstrated that this peptide acts via the single electron transport (SET) and hydrogen atom transfer (HAT) mechanisms, respectively. Consistent with this mechanism of action, PIC1 did not show activity in a metal chelating activity (MCA) assay. PIC1 contains two vicinal cysteine residues and displayed similar antioxidant activity to the well characterized cysteine-containing tripeptide antioxidant molecule glutathione (GSH). Consistent with the role of the cysteine residues in the antioxidant activity of PIC1, oxidation of these residues significantly abrogated antioxidant activity. These results demonstrate that in addition to its described complement inhibiting activity, PIC1 displays in vitro antioxidant activity.

  20. A Two-Hit Model of Autism: Adolescence as the Second Hit

    Science.gov (United States)

    Picci, Giorgia; Scherf, K. Suzanne

    2015-01-01

    Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a “first hit” that sets up a neural system that is “built to fail” in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the “second hit” that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence. PMID:26609500

  1. The peptide motif of the single dominantly expressed class I molecule of the chicken MHC can explain the response to a molecular defined vaccine of infectious bursal disease virus (IBDV).

    Science.gov (United States)

    Butter, Colin; Staines, Karen; van Hateren, Andrew; Davison, T Fred; Kaufman, Jim

    2013-08-01

    In contrast to typical mammals, the chicken MHC (the BF-BL region of the B locus) has strong genetic associations with resistance and susceptibility to infectious pathogens as well as responses to vaccines. We have shown that the chicken MHC encodes a single dominantly expressed class I molecule whose peptide-binding motifs can determine resistance to viral pathogens, such as Rous sarcoma virus and Marek's disease virus. In this report, we examine the response to a molecular defined vaccine, fp-IBD1, which consists of a fowlpox virus vector carrying the VP2 gene of infectious bursal disease virus (IBDV) fused with β-galactosidase. We vaccinated parental lines and two backcross families with fp-IBD1, challenged with the virulent IBDV strain F52/70, and measured damage to the bursa. We found that the MHC haplotype B15 from line 15I confers no protection, whereas B2 from line 61 and B12 from line C determine protection, although another locus from line 61 was also important. Using our peptide motifs, we found that many more peptides from VP2 were predicted to bind to the dominantly expressed class I molecule BF2*1201 than BF2*1501. Moreover, most of the peptides predicted to bind BF2*1201 did in fact bind, while none bound BF2*1501. Using peptide vaccination, we identified one B12 peptide that conferred protection to challenge, as assessed by bursal damage and viremia. Thus, we show the strong genetic association of the chicken MHC to a T cell vaccine can be explained by peptide presentation by the single dominantly expressed class I molecule.

  2. New approaches for efficient solution of hitting set problem

    Science.gov (United States)

    Fijany, Amir; Vatan, Farrokh

    2004-01-01

    A new method for solving the hitting set problem is proposed. This method is based on the mapping of the problem onto an integer programming optimization problem. this new approach provides an algorithm with much better performance compare to the algorithms for the hitting set problem that currently are used for solving the diagnosis problem.

  3. Peptide dendrimers

    Czech Academy of Sciences Publication Activity Database

    Niederhafner, Petr; Šebestík, Jaroslav; Ježek, Jan

    2005-01-01

    Roč. 11, - (2005), 757-788 ISSN 1075-2617 R&D Projects: GA ČR(CZ) GA203/03/1362 Institutional research plan: CEZ:AV0Z40550506 Keywords : multiple antigen peptides * peptide dendrimers * synthetic vaccine * multipleantigenic peptides Subject RIV: CC - Organic Chemistry Impact factor: 1.803, year: 2005

  4. The first neutron beam hits EAR2

    CERN Multimedia

    Antonella Del Rosso

    2014-01-01

    On 25 July 2014, about a year after construction work began, the Experimental Area 2 (EAR2) of CERN’s neutron facility n_TOF recorded its first beam. Unique in many aspects, EAR2 will start its rich programme of experimental physics this autumn.   The last part of the EAR2 beamline: the neutrons come from the underground target and reach the top of the beamline, where they hit the samples. Built about 20 metres above the neutron production target, EAR2 is in fact a bunker connected to the n_TOF underground facilities via a duct 80 cm in diameter, where the beamline is installed. The feet of the bunker support pillars are located on the concrete structure of the n_TOF tunnel and part of the structure lies above the old ISR building. A beam dump located on the roof of the building completes the structure. Neutrons are used by physicists to study neutron-induced reactions with applications in a number of fields, including nuclear waste transmutation, nuclear technology, nuclear astrop...

  5. TEMPO-Assisted Free Radical-Initiated Peptide Sequencing Mass Spectrometry (FRIPS MS) in Q-TOF and Orbitrap Mass Spectrometers: Single-Step Peptide Backbone Dissociations in Positive Ion Mode

    Science.gov (United States)

    Jang, Inae; Lee, Sun Young; Hwangbo, Song; Kang, Dukjin; Lee, Hookeun; Kim, Hugh I.; Moon, Bongjin; Oh, Han Bin

    2017-01-01

    The present study demonstrates that one-step peptide backbone fragmentations can be achieved using the TEMPO [2-(2,2,6,6-tetramethyl piperidine-1-oxyl)]-assisted free radical-initiated peptide sequencing (FRIPS) mass spectrometry in a hybrid quadrupole time-of-flight (Q-TOF) mass spectrometer and a Q-Exactive Orbitrap instrument in positive ion mode, in contrast to two-step peptide fragmentation in an ion-trap mass spectrometer (reference Anal. Chem. 85, 7044-7051 (30)). In the hybrid Q-TOF and Q-Exactive instruments, higher collisional energies can be applied to the target peptides, compared with the low collisional energies applied by the ion-trap instrument. The higher energy deposition and the additional multiple collisions in the collision cell in both instruments appear to result in one-step peptide backbone dissociations in positive ion mode. This new finding clearly demonstrates that the TEMPO-assisted FRIPS approach is a very useful tool in peptide mass spectrometry research.

  6. A kernelisation approach for multiple d-Hitting Set and its application in optimal multi-drug therapeutic combinations.

    Directory of Open Access Journals (Sweden)

    Drew Mellor

    Full Text Available Therapies consisting of a combination of agents are an attractive proposition, especially in the context of diseases such as cancer, which can manifest with a variety of tumor types in a single case. However uncovering usable drug combinations is expensive both financially and temporally. By employing computational methods to identify candidate combinations with a greater likelihood of success we can avoid these problems, even when the amount of data is prohibitively large. Hitting Set is a combinatorial problem that has useful application across many fields, however as it is NP-complete it is traditionally considered hard to solve exactly. We introduce a more general version of the problem (α,β,d-Hitting Set, which allows more precise control over how and what the hitting set targets. Employing the framework of Parameterized Complexity we show that despite being NP-complete, the (α,β,d-Hitting Set problem is fixed-parameter tractable with a kernel of size O(αdk(d when we parameterize by the size k of the hitting set and the maximum number α of the minimum number of hits, and taking the maximum degree d of the target sets as a constant. We demonstrate the application of this problem to multiple drug selection for cancer therapy, showing the flexibility of the problem in tailoring such drug sets. The fixed-parameter tractability result indicates that for low values of the parameters the problem can be solved quickly using exact methods. We also demonstrate that the problem is indeed practical, with computation times on the order of 5 seconds, as compared to previous Hitting Set applications using the same dataset which exhibited times on the order of 1 day, even with relatively relaxed notions for what constitutes a low value for the parameters. Furthermore the existence of a kernelization for (α,β,d-Hitting Set indicates that the problem is readily scalable to large datasets.

  7. Single vagus nerve stimulation reduces early postprandial C-peptide levels but not other hormones or postprandial metabolism.

    Science.gov (United States)

    Tang, M W; van Nierop, F S; Koopman, F A; Eggink, H M; Gerlag, D M; Chan, M W; Zitnik, R; Vaz, F M; Romijn, J A; Tak, P P; Soeters, M R

    2018-02-01

    A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.

  8. Dragging Human Mesenchymal Stem Cells with the Aid of Supramolecular Assemblies of Single-Walled Carbon Nanotubes, Molecular Magnets, and Peptides in a Magnetic Field

    Directory of Open Access Journals (Sweden)

    Ana Cláudia C. de Paula

    2015-01-01

    Full Text Available Human adipose-derived stem cells (hASCs are an attractive cell source for therapeutic applicability in diverse fields for the repair and regeneration of damaged or malfunctioning tissues and organs. There is a growing number of cell therapies using stem cells due to their characteristics of modulation of immune system and reduction of acute rejection. So a challenge in stem cells therapy is the delivery of cells to the organ of interest, a specific site. The aim of this paper was to investigate the effects of a supramolecular assembly composed of single-walled carbon nanotubes (SWCNT, molecular magnets (lawsone-Co-phenanthroline, and a synthetic peptide (FWYANHYWFHNAFWYANHYWFHNA in the hASCs cultures. The hASCs were isolated, characterized, expanded, and cultured with the SWCNT supramolecular assembly (SWCNT-MA. The assembly developed did not impair the cell characteristics, viability, or proliferation. During growth, the cells were strongly attached to the assembly and they could be dragged by an applied magnetic field of less than 0.3 T. These assemblies were narrower than their related allotropic forms, that is, multiwalled carbon nanotubes, and they could therefore be used to guide cells through thin blood capillaries within the human body. This strategy seems to be useful as noninvasive and nontoxic stem cells delivery/guidance and tracking during cell therapy.

  9. Dragging Human Mesenchymal Stem Cells with the Aid of Supramolecular Assemblies of Single-Walled Carbon Nanotubes, Molecular Magnets, and Peptides in a Magnetic Field

    Science.gov (United States)

    de Paula, Ana Cláudia C.; Sáfar, Gustavo A. M.; Góes, Alfredo M.; Bemquerer, Marcelo P.; Ribeiro, Marcos A.; Stumpf, Humberto O.

    2015-01-01

    Human adipose-derived stem cells (hASCs) are an attractive cell source for therapeutic applicability in diverse fields for the repair and regeneration of damaged or malfunctioning tissues and organs. There is a growing number of cell therapies using stem cells due to their characteristics of modulation of immune system and reduction of acute rejection. So a challenge in stem cells therapy is the delivery of cells to the organ of interest, a specific site. The aim of this paper was to investigate the effects of a supramolecular assembly composed of single-walled carbon nanotubes (SWCNT), molecular magnets (lawsone-Co-phenanthroline), and a synthetic peptide (FWYANHYWFHNAFWYANHYWFHNA) in the hASCs cultures. The hASCs were isolated, characterized, expanded, and cultured with the SWCNT supramolecular assembly (SWCNT-MA). The assembly developed did not impair the cell characteristics, viability, or proliferation. During growth, the cells were strongly attached to the assembly and they could be dragged by an applied magnetic field of less than 0.3 T. These assemblies were narrower than their related allotropic forms, that is, multiwalled carbon nanotubes, and they could therefore be used to guide cells through thin blood capillaries within the human body. This strategy seems to be useful as noninvasive and nontoxic stem cells delivery/guidance and tracking during cell therapy. PMID:25688350

  10. Multicomponent Aqueous Synthesis of Iodo-1,2,3-triazoles: Single-Step Models for Dual Modification of Free Peptide and Radioactive Iodo Labeling.

    Science.gov (United States)

    Li, Lingjun; Ding, Shengqiang; Yang, Yanping; Zhu, Anlian; Fan, Xincui; Cui, Mengchao; Chen, Changpo; Zhang, Guisheng

    2017-01-23

    Iodo-1,2,3-triazoles are of considerable interest for chemical and biomedical applications. However, current synthetic methods for preparing iodo-1,2,3-triazoles cannot easily be applied to the direct modification of bioactive molecules in water. Through the combination of water-compatible oxidative iodination and the copper-catalyzed alkyne-azide cycloaddition reaction, a novel copper-catalyzed aqueous multicomponent synthetic method for the preparation of 5-iodo-1,2,3-triazoles has been developed. The method is highly effective and selective for substrates including biologically relevant compounds with nucleoside, sugar, and amino acid moieties. Based on this aqueous tandem reaction, a direct single-step multicomponent dual modification of peptide is developed from readily available starting materials. Furthermore, the method could also be applied to concise and fast multicomponent radioactive 125 I labeling from an aqueous solution of commercially available sodium 125 iodide as a starting material. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. A single mutation in the hepta-peptide active site of Aspergillus niger PhyA phytase leads to myriad of biochemical changes

    Science.gov (United States)

    The active site motif of proteins belonging to ‘Histidine Acid Phosphatase’ (HAP) contains a hepta-peptide region, RHGXRXP. A close comparison among fungal and yeast HAPs has revealed the fourth residue of the hepta-peptide to be E instead of A, which is the case with A. niger phyA phytase. However,...

  12. Synthetic surfactant based on analogues of SP-B and SP-C is superior to single-peptide surfactants in ventilated premature rabbits.

    Science.gov (United States)

    Almlén, Andreas; Walther, Frans J; Waring, Alan J; Robertson, Bengt; Johansson, Jan; Curstedt, Tore

    2010-06-01

    Respiratory distress syndrome (RDS) is currently treated with surfactant preparations obtained from natural sources and attempts to develop equally active synthetic surfactants have been unsuccessful. One difference in composition is that naturally derived surfactants contain the two hydrophobic proteins SP-B and SP-C while synthetic preparations contain analogues of either SP-B or SP-C. It was recently shown that both SP-B and SP-C (or SP-C33, an SP-C analogue) are necessary to establish alveolar stability at end-expiration in a rabbit RDS model, as reflected by high lung gas volumes without application of positive end-expiratory pressure. To study the efficacy of fully synthetic surfactants containing analogues of both SP-B and SP-C compared to surfactants with only one protein analogue. Premature newborn rabbits, treated with synthetic surfactants, were ventilated for 30 min without positive end-expiratory pressure. Tidal volumes as well as lung gas volumes at end-expiration were determined. Treatment with 2% Mini-B (a short-cut version of SP-B) and 2% SP-C33, or its C-terminally truncated form SP-C30, in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, 68:31 (w/w) resulted in median lung gas volumes of 8-9 ml/kg body weight, while animals treated with 2% Mini-B surfactant or 2% SP-C33/SP-C30 surfactant had lung gas volumes of 3-4 ml/kg, and those treated with Curosurf, a porcine surfactant, 15-17 ml/kg. In contrast, mixing SP-C33 with peptides with different distributions of positively charged and hydrophobic residues did not improve lung gas volumes. The data indicate that synthetic surfactants containing analogues of both SP-B and SP-C might be superior to single-peptide surfactants in the treatment of RDS.

  13. Stochastic, weighted hit size theory of cellular radiobiological action

    International Nuclear Information System (INIS)

    Bond, V.P.; Varma, M.N.

    1982-01-01

    A stochastic theory that appears to account well for the observed responses of cell populations exposed in radiation fields of different qualities and for different durations of exposure is described. The theory appears to explain well most cellular radiobiological phenomena observed in at least autonomous cell systems, argues for the use of fluence rate (phi) instead of absorbed dose for quantification of the amount of radiation involved in low level radiation exposure. With or without invoking the cell sensitivity function, the conceptual improvement would be substantial. The approach suggested also shows that the absorbed dose-cell response functions currently employed do not reflect the spectrum of cell sensitivities to increasing cell doses of a single agent, nor can RBE represent the potency ratio for different agents that can produce similar quantal responses. Thus, for accurate comparison of cell sensitivities among different cells in the same individual, or between the cells in different kinds of individuals, it is necessary to quantify cell sensitivity in terms of the hit size weighting or cell sensitivity function introduced here. Similarly, this function should be employed to evaluate the relative potency of radiation and other radiomimetic chemical or physical agents

  14. Peptide-LNA oligonucleotide conjugates

    DEFF Research Database (Denmark)

    Astakhova, I Kira; Hansen, Lykke Haastrup; Vester, Birte

    2013-01-01

    properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper...

  15. The Chelyabinsk Meteorite Hits an Anomalous Zone in the Urals

    Science.gov (United States)

    Kochemasov, G. G.

    2013-09-01

    The Chelyabinsk meteorite is "strange" because it hits an area in the Urals where anomalous events are observed: shining skies, light balls, UFOs, electrphonic bolids. The area tectonically occurs at the intersection of two fold belts: Urals and Timan.

  16. δ-Aminolevulinic Acid Dehydratase Single Nucleotide Polymorphism 2 and Peptide Transporter 2*2 Haplotype May Differentially Mediate Lead Exposure in Male Children

    Science.gov (United States)

    Parisi, Natali; Schaub, Tanner; Gutierrez, Marisela; Ortega, Alma X.

    2011-01-01

    Child low-level lead (Pb) exposure is an unresolved public health problem and an unaddressed child health disparity. Particularly in cases of low-level exposure, source removal can be impossible to accomplish, and the only practical strategy for reducing risk may be primary prevention. Genetic biomarkers of increased neurotoxic risk could help to identify small subgroups of children for early intervention. Previous studies have suggested that, by way of a distinct mechanism, δ-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and/or peptide transporter 2*2 haplotype (hPEPT2*2) increase Pb blood burden in children. Studies have not yet examined whether sex mediates the effects of genotype on blood Pb burden. Also, previous studies have not included blood iron (Fe) level in their analyses. Blood and cheek cell samples were obtained from 306 minority children, ages 5.1 to 12.9 years. 208Pb and 56Fe levels were determined with inductively coupled plasma–mass spectrometry. General linear model analyses were used to examine differences in Pb blood burden by genotype and sex while controlling for blood Fe level. The sample geometric mean Pb level was 2.75 µg/dl. Pb blood burden was differentially higher in ALAD2 heterozygous boys and hPEPT2*2 homozygous boys. These results suggest that the effect of ALAD2 and hPEPT2*2 on Pb blood burden may be sexually dimorphic. ALAD2 and hPEPT2*2 may be novel biomarkers of health and mental health risks in male children exposed to low levels of Pb. PMID:21327641

  17. Combined hit theory-microdosimetric explanation of cellular radiobiological action

    International Nuclear Information System (INIS)

    Bond, V.P.; Varma, M.N.

    1983-01-01

    Hit theory is combined with microdosimetry in a stochastic approach that explains the observed responses of cell populations exposed in radiation fields of different qualities. The central thesis is that to expose a population of cells in a low-level radiation field is to subject the cells to the potential for interaction with charged particles in the vicinity of the cells, quantifiable in terms of the charged particle fluence theta. When such an interaction occurs there is a resulting stochastic transfer of energy to a critical volume (CV) of cross section sigma, within the cell(s). The severity of cell injury is dependent on the amount of energy thus imparted, or the hit size. If the severity is above some minimal level, there is a non-zero probability that the injury will result in a quantal effect (e.g., a mutational or carcinogenic initial event, cell transformation). A microdosimetric proportional counter, viewed here as a phantom cell CV that permits measurements not possible in the living cell, is used to determine the incidence of hit cells and the spectrum of hit sizes. Each hit is then weighted on the basis of an empirically-determined function that provides the fraction of cells responding quantally, as a function of hit size. The sum of the hits so weighted provides the incidence of quantally-responding cells, for any amount of exposure theta in a radiation field of any quality or mixture qualities. The hit size weighting function for pink mutations in Tradescantia is discussed, as are its implications in terms of a replacement for RBE and dose equivalent. 14 references, 9 figures

  18. Peptides, polypeptides and peptide-polymer hybrids as nucleic acid carriers.

    Science.gov (United States)

    Ahmed, Marya

    2017-10-24

    Cell penetrating peptides (CPPs), and protein transduction domains (PTDs) of viruses and other natural proteins serve as a template for the development of efficient peptide based gene delivery vectors. PTDs are sequences of acidic or basic amphipathic amino acids, with superior membrane trespassing efficacies. Gene delivery vectors derived from these natural, cationic and cationic amphipathic peptides, however, offer little flexibility in tailoring the physicochemical properties of single chain peptide based systems. Owing to significant advances in the field of peptide chemistry, synthetic mimics of natural peptides are often prepared and have been evaluated for their gene expression, as a function of amino acid functionalities, architecture and net cationic content of peptide chains. Moreover, chimeric single polypeptide chains are prepared by a combination of multiple small natural or synthetic peptides, which imparts distinct physiological properties to peptide based gene delivery therapeutics. In order to obtain multivalency and improve the gene delivery efficacies of low molecular weight cationic peptides, bioactive peptides are often incorporated into a polymeric architecture to obtain novel 'polymer-peptide hybrids' with improved gene delivery efficacies. Peptide modified polymers prepared by physical or chemical modifications exhibit enhanced endosomal escape, stimuli responsive degradation and targeting efficacies, as a function of physicochemical and biological activities of peptides attached onto a polymeric scaffold. The focus of this review is to provide comprehensive and step-wise progress in major natural and synthetic peptides, chimeric polypeptides, and peptide-polymer hybrids for nucleic acid delivery applications.

  19. Lack of Effects of a Single High-Fat Meal Enriched with Vegetable n-3 or a Combination of Vegetable and Marine n-3 Fatty Acids on Intestinal Peptide Release and Adipokines in Healthy Female Subjects.

    Science.gov (United States)

    Narverud, Ingunn; Myhrstad, Mari C W; Herzig, Karl-Heinz; Karhu, Toni; Dahl, Tuva B; Halvorsen, Bente; Ulven, Stine M; Holven, Kirsten B

    2016-01-01

    Peptides released from the small intestine and colon regulate short-term food intake by suppressing appetite and inducing satiety. Intake of marine omega-3 (n-3) fatty acids (FAs) from fish and fish oils is associated with beneficial health effects, whereas the relation between intake of the vegetable n-3 fatty acid α-linolenic acid and diseases is less clear. The aim of the present study was to investigate the postprandial effects of a single high-fat meal enriched with vegetable n-3 or a combination of vegetable and marine n-3 FAs with their different unsaturated fatty acid composition on intestinal peptide release and the adipose tissue. Fourteen healthy lean females consumed three test meals with different fat quality in a fixed order. The test meal consisted of three cakes enriched with coconut fat, linseed oil, and a combination of linseed and cod liver oil. The test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6 h after intake were analyzed. A significant postprandial effect was observed for cholecystokinin, peptide YY, glucose-dependent insulinotropic polypeptide, amylin and insulin, which increased, while leptin decreased postprandially independent of the fat composition in the high-fat meal. In conclusion, in healthy, young, lean females, an intake of a high-fat meal enriched with n-3 FAs from different origin stimulates intestinal peptide release without any difference between the different fat compositions.

  20. Lack of effects of a single high-fat meal enriched with vegetable n-3 or a combination of vegetable and marine n-3 fatty acids on intestinal peptide release and adipokines in healthy female subjects

    Directory of Open Access Journals (Sweden)

    Ingunn Naverud

    2016-08-01

    Full Text Available Peptides released from the small intestine and colon regulate short-term food intake by suppressing appetite and inducing satiety. Intake of marine omega-3 (n-3 fatty acids from fish and fish oils is associated with beneficial health effects, whereas the relation between intake of the vegetable n-3 fatty acid α-linolenic acid and diseases is less clear. The aim of the present study was to investigate the postprandial effects of a single high-fat meal enriched with vegetable n-3 or a combination of vegetable and marine n-3 fatty acids with their different unsaturated fatty acid composition on intestinal peptide release and the adipose tissue. Fourteen healthy lean females consumed three test meals with different fat quality in a fixed order. The test meal consisted of three cakes enriched with coconut fat, linseed oil and a combination of linseed and cod liver oil. The test days were separated by two weeks. Fasting and postprandial blood samples at three and six hours after intake were analysed. A significant postprandial effect was observed for cholecystokinin, peptide YY, glucose-dependent insulinotropic polypeptide, amylin and insulin which increased, while leptin decreased postprandially independent of the fat composition in the high-fat meal. In conclusion, in healthy, young, lean females, an intake of a high-fat meal enriched with n-3 fatty acids from different origin stimulates intestinal peptide release without any difference between the different fat compositions.

  1. Enhancing hit identification in Mycobacterium tuberculosis drug discovery using validated dual-event Bayesian models.

    Directory of Open Access Journals (Sweden)

    Sean Ekins

    Full Text Available High-throughput screening (HTS in whole cells is widely pursued to find compounds active against Mycobacterium tuberculosis (Mtb for further development towards new tuberculosis (TB drugs. Hit rates from these screens, usually conducted at 10 to 25 µM concentrations, typically range from less than 1% to the low single digits. New approaches to increase the efficiency of hit identification are urgently needed to learn from past screening data. The pharmaceutical industry has for many years taken advantage of computational approaches to optimize compound libraries for in vitro testing, a practice not fully embraced by academic laboratories in the search for new TB drugs. Adapting these proven approaches, we have recently built and validated Bayesian machine learning models for predicting compounds with activity against Mtb based on publicly available large-scale HTS data from the Tuberculosis Antimicrobial Acquisition Coordinating Facility. We now demonstrate the largest prospective validation to date in which we computationally screened 82,403 molecules with these Bayesian models, assayed a total of 550 molecules in vitro, and identified 124 actives against Mtb. Individual hit rates for the different datasets varied from 15-28%. We have identified several FDA approved and late stage clinical candidate kinase inhibitors with activity against Mtb which may represent starting points for further optimization. The computational models developed herein and the commercially available molecules derived from them are now available to any group pursuing Mtb drug discovery.

  2. Prediction of Potential Hit Song and Musical Genre Using Artificial Neural Networks

    Science.gov (United States)

    Monterola, Christopher; Abundo, Cheryl; Tugaff, Jeric; Venturina, Lorcel Ericka

    Accurately quantifying the goodness of music based on the seemingly subjective taste of the public is a multi-million industry. Recording companies can make sound decisions on which songs or artists to prioritize if accurate forecasting is achieved. We extract 56 single-valued musical features (e.g. pitch and tempo) from 380 Original Pilipino Music (OPM) songs (190 are hit songs) released from 2004 to 2006. Based on an effect size criterion which measures a variable's discriminating power, the 20 highest ranked features are fed to a classifier tasked to predict hit songs. We show that regardless of musical genre, a trained feed-forward neural network (NN) can predict potential hit songs with an average accuracy of ΦNN = 81%. The accuracy is about +20% higher than those of standard classifiers such as linear discriminant analysis (LDA, ΦLDA = 61%) and classification and regression trees (CART, ΦCART = 57%). Both LDA and CART are above the proportional chance criterion (PCC, ΦPCC = 50%) but are slightly below the suggested acceptable classifier requirement of 1.25*ΦPCC = 63%. Utilizing a similar procedure, we demonstrate that different genres (ballad, alternative rock or rock) of OPM songs can be automatically classified with near perfect accuracy using LDA or NN but only around 77% using CART.

  3. Video head-impulse test (vHIT) in dizzy children with normal caloric responses.

    Science.gov (United States)

    Khater, Ahmed Mohammed; Afifi, Pretty O

    2016-08-01

    The caloric test and the video head-impulse test are diagnostic tools to examine dizzy patients through assessing the function of the semicircular canals. There are major differences between the two tests as regards stimulus characteristics, methodology, and function examined. The aim of this study is to evaluate the results of vHIT in children and adolescents with normal caloric test. This work was performed on 63 patients, but 14 were excluded because of technical problems in the caloric test. So, this is a prospective work in 49 patients (27 females and 22 males) with different types of vestibular disease seen because of vertigo in which both procedures were performed the same day. The caloric test was performed with air at two different temperatures in which both ears were irrigated alternately. Then, the video head-impulse test was carried out. Main outcome measures were the gain of vestibulo-ocular reflex, gain asymmetry, and refixation saccades in the vHIT. in all studied cases, caloric test was normal. The mean age of patients was 16 years. By vHIT, in 8 patients (16%) no abnormality was detected, while abnormal findings were found in 41 patients. Single canal affection was seen in 29 patients whereas 12 patients had combined canal affection. The right side was affected in 27 and left side in 22 patients. In single canal affection, isolated horizontal canals were affected in 4, anterior canals in 5 and posterior canals in 20 patients. While in combined canal affection, the affection is seen in the same ear. Moreover the most common pattern seen is affection of left anterior and left posterior canals. The caloric and vHIT is very important tests in diagnosis of dizzy patients. The information from both methods is redundant in some cases but complementary in most. vHIT is a "child friendly," relatively easy-to-use, and simple tool to evaluate each of the 6 semicircular canals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Experience with Video Head Impulse Testing (vHIT

    Directory of Open Access Journals (Sweden)

    Carmen ÁLVAREZ-SANTACRUZ

    2017-03-01

    Full Text Available Introduction and objective: The diagnosis and study of vestibular pathology has been always guided by the medical history, exploration and caloric test. The caloric test has some limitations because it only allows the study of horizontal semicircular canal and it is also poorly tolerated by patients. Alternatively, the vHIT (Video Head Impulse Test, allows the analysis of all semicircular channels being quicker to perform and less obtrusive. The objective of the following study is to reflect our initial experience with the vHIT and compare it with another diagnosis tests. Method: This is a observational, prospective and descriptive study, of one year of observation in our Healthcare center for all patients who described symptoms of dizziness, unsteadiness or vertigo. Results: A total of 155 patients were included. There was a clear predominance of females, being Meniere's disease the most frequently diagnosed entity. The diagnosis was reached by vHIT. Caloric test was also performed in patients without definite or doubt in the diagnosis. With the data, the statistical relationships were established, being significant between sex with vestibular neuritis and vestibular migraine. There was a statistically significant relationship between vestibule-ocular reflex and caloric test associated with the previous pathologies. Discussion: The head impulse assisted video is a quick, simple and well tolerated technique without adverse symptoms like the caloric test. The disparities of results are due to differences in the stimulated frequencies, being the vHIT more physiological. Conclusions: vHIT facilitates the complementary diagnosis of acute pathology, being a well-tolerated technique. However, in pathologies with central compensation the results by vHIT may be normal, requiring the caloric test for better diagnostic approach.

  5. The Light Green Cells of Lymnaea: a neuroendocrine model system for stimulus-induced expression of multiple peptide genes in a single cell type

    NARCIS (Netherlands)

    Geraerts, W. P.; Smit, A. B.; Li, K. W.; Hordijk, P. L.

    1992-01-01

    We review recent experiments showing that the cerebral neuroendocrine Light Green Cells (LGCs) of the freshwater snail, Lymnaea stagnalis, express a family of distinct though related molluscan insulin-related peptide (MIP) genes. The LGCs are involved in the regulation of a wide range of

  6. Identification of bradykinin: related peptides from Phyllomedusa nordestina skin secretion using electrospray ionization tandem mass spectrometry after a single-step liquid chromatography

    Directory of Open Access Journals (Sweden)

    K Conceição

    2009-01-01

    Full Text Available Amphibian skin secretions are a source of potential new drugs with medical and biotechnological applications. Rich in peptides produced by holocrine-type serous glands in the integument, these secretions play different roles, either in the regulation of physiological skin functions or in the defense against predators or microorganisms. The aim of the present work was to identify novel peptides with bradykinin-like structure and/or activity present in the skin of Phyllomedusa nordestina. In order to achieve this goal, the crude skin secretion of this frog was pre-fractionated by solid phase extraction and separated by reversed-phase chromatography. The fractions were screened for low-molecular-mass peptides and sequenced by mass spectrometry. It was possible to identify three novel bradykinin-related peptides, namely: KPLWRL-NH2 (Pnor 3, RPLSWLPK (Pnor 5 and VPPKGVSM (Pnor 7 presenting vascular activities as assessed by intravital microscopy. Pnor 3 and Pnor 7 were able to induce vasodilation. On the other hand, Pnor 5 was a potent vasoconstrictor. These effects were reproduced by their synthetic analogues.

  7. Integrated dataset of screening hits against multiple neglected disease pathogens.

    Directory of Open Access Journals (Sweden)

    Solomon Nwaka

    2011-12-01

    Full Text Available New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.

  8. First hitting probabilities for semi markov chains and estimation

    DEFF Research Database (Denmark)

    Georgiadis, Stylianos

    2017-01-01

    . In the latter case, a nonparametric estimator for the first hitting probability is proposed and the asymptotic properties of strong consistency and asymptotic normality are proven. Finally, a numerical application on a five-state system is presented to illustrate the performance of this estimator.......We first consider a stochastic system described by an absorbing semi-Markov chain with finite state space and we introduce the absorption probability to a class of recurrent states. Afterwards, we study the first hitting probability to a subset of states for an irreducible semi-Markov chain...

  9. Possilibity of estimating payoff matrix from model for hit phenomena

    International Nuclear Information System (INIS)

    Ishii, Akira; Sakaidani, Shota; Iwanaga, Saori

    2016-01-01

    The conflicts of topics on social media is considered using an extended mathematical model based on the mathematical model for hit phenomena that has been used to analyze entertainment hits. The social media platform used in this study was blog. The calculation results shows examples of strong conflict, weak conflict, and no conflict cases. Since the conflict of two topics can be considered in the framework of game theory, the results can be used to determine each matrix element of the payoff matrix of game theory.

  10. Does ′heparin-induced thrombocytopenia′ hit our minds?

    Directory of Open Access Journals (Sweden)

    Arun R Thangavel

    2016-01-01

    Full Text Available Unfractionated heparin is a widely used drug to prevent deep vein thrombosis and pulmonary emboli in patients at risk. With the advent of newer anticoagulants having lesser side effects, its use has diminished but not out of service. Here, we report a case of deep venous thrombosis, in a patient on prophylactic dose of heparin, which was later found to be a manifestation of heparin-induced thrombocytopenia (HIT. Thrombosis in the presence of heparin prophylaxis should be considered as HIT rather than a failure of anticoagulation.

  11. A hit and run approach to inducible direct reprogramming of astrocytes to neural stem cells

    Directory of Open Access Journals (Sweden)

    Maria ePoulou

    2016-04-01

    Full Text Available Temporal and spatial control of gene expression can be achieved using an inducible system as a fundamental tool for regulated transcription in basic, applied and eventually in clinical research. We describe a novel hit and run inducible direct reprogramming approach. In a single step, two days post-transfection, transiently transfected Sox2FLAG under the Leu3p-αIPM inducible control (iSox2 triggers the activation of endogenous Sox2, redirecting primary astrocytes into abundant distinct nestin-positive radial glia cells. This technique introduces a unique novel tool for safe, rapid and efficient reprogramming amendable to regenerative medicine.

  12. Soft Play Detection in Shooter Games Using Hit Matrix Analysis

    Directory of Open Access Journals (Sweden)

    Jussi Laasonen

    2015-08-01

    Full Text Available Soft play is a form of cheating where players deliberately play easy against each other. We evaluate different methods for detecting the players engaging in soft play in shooter games using data generated with synthetic players. These methods are used when analysing the hit matrix of the game.

  13. Madoff Debacle Hits Colleges and Raises Questions about Trustee Conflicts

    Science.gov (United States)

    Fain, Paul

    2009-01-01

    Several colleges and universities lost millions in the alleged $50-billion Ponzi scheme run by the Wall Street trader Bernard L. Madoff. The losses include institutions' endowment holdings in hedge funds that were invested with Madoff as well as hits taken by supporting foundations and donors. Several foundations that have been active in higher…

  14. Derandomizing Arthur-Merlin Games using Hitting Sets

    DEFF Research Database (Denmark)

    Miltersen, Peter Bro; Vinodchandran, N. V.

    2005-01-01

    assumptions. The previous results on derandomizing AM were based on pseudorandom generators. In contrast, our approach is based on a strengthening of Andreev, Clementi and Rolim’s hitting set approach to derandomization. As a spin-off, we show that this approach is strong enough to give an easy proof...

  15. The probability of a tornado missile hitting a target

    International Nuclear Information System (INIS)

    Goodman, J.; Koch, J.E.

    1983-01-01

    It is shown that tornado missile transportation is a diffusion Markovian process. Therefore, the Green's function method is applied for the estimation of the probability of hitting a unit target area. This propability is expressed through a joint density of tornado intensity and path area, a probability of tornado missile injection and a tornado missile height distribution. (orig.)

  16. COPD: A stepwise or a hit hard approach?

    Directory of Open Access Journals (Sweden)

    A.J. Ferreira

    2016-07-01

    Full Text Available Current guidelines differ slightly on the recommendations for treatment of Chronic Obstructive Pulmonary Disease (COPD patients, and although there are some undisputed recommendations, there is still debate regarding the management of COPD. One of the hindrances to deciding which therapeutic approach to choose is late diagnosis or misdiagnosis of COPD. After a proper diagnosis is achieved and severity assessed, the choice between a stepwise or “hit hard” approach has to be made. For GOLD A patients the stepwise approach is recommended, whilst for B, C and D patients this remains debatable. Moreover, in patients for whom inhaled corticosteroids (ICS are recommended, a step-up or “hit hard” approach with triple therapy will depend on the patient's characteristics and, for patients who are being over-treated with ICS, ICS withdrawal should be performed, in order to optimize therapy and reduce excessive medications.This paper discusses and proposes stepwise, “hit hard”, step-up and ICS withdrawal therapeutic approaches for COPD patients based on their GOLD group. We conclude that all approaches have benefits, and only a careful patient selection will determine which approach is better, and which patients will benefit the most from each approach. Keywords: COPD, Stepwise, Hit hard, Step-up, ICS withdrawal, Bronchodilators, ICS

  17. Moonlighting peptides with emerging function.

    Directory of Open Access Journals (Sweden)

    Jonathan G Rodríguez Plaza

    Full Text Available Hunter-killer peptides combine two activities in a single polypeptide that work in an independent fashion like many other multi-functional, multi-domain proteins. We hypothesize that emergent functions may result from the combination of two or more activities in a single protein domain and that could be a mechanism selected in nature to form moonlighting proteins. We designed moonlighting peptides using the two mechanisms proposed to be involved in the evolution of such molecules (i.e., to mutate non-functional residues and the use of natively unfolded peptides. We observed that our moonlighting peptides exhibited two activities that together rendered a new function that induces cell death in yeast. Thus, we propose that moonlighting in proteins promotes emergent properties providing a further level of complexity in living organisms so far unappreciated.

  18. Peptide aldehyde inhibitors of bacterial peptide deformylases.

    Science.gov (United States)

    Durand, D J; Gordon Green, B; O'Connell, J F; Grant, S K

    1999-07-15

    Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity. Copyright 1999 Academic Press.

  19. Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection

    Energy Technology Data Exchange (ETDEWEB)

    Ely, Lauren K.; Green, Katherine J.; Beddoe, Travis; Clements, Craig S.; Miles, John J.; Bottomley, Stephen P.; Zernich, Danielle; Kjer-Nielsen, Lars; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R. (Monash)

    2010-06-30

    Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801{sup +} individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801{sup FLRGRAYGL}. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 {micro}M, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

  20. Substrate Capture Assay Using Inactive Oligopeptidases to Identify Novel Peptides.

    Science.gov (United States)

    Rioli, Vanessa; Ferro, Emer S

    2018-01-01

    Researchers are always searching for novel biologically active molecules including peptides. With the improvement of equipment for electrospray mass spectrometry, it is now possible to identify hundreds of novel peptides in a single run. However, after identifying the peptide sequences it is expensive to synthesize all the peptides to perform biological activity assays. Here, we describe a substrate capture assay that uses inactive oligopeptidases to identify putative biologically active peptides in complexes peptide mixtures. This methodology can use any crude extracts of biological tissues or cells, with the advantage to introduce a filter (i.e., binding to an inactive oligopeptidase) as a prior step in screening to bioactive peptides.

  1. Business Model and Replication Study of BIG HIT

    DEFF Research Database (Denmark)

    Zhao, Guangling; Ravn Nielsen, Eva

    . The BIG HIT project is creating a replicable hydrogen territory in Orkney (An island archipelago six miles offshore from North of Mainland Scotland.) by implementing a fully integrated model of hydrogen production, storage, distribution of the hydrogen across Orkney and utilised for mobility, heat...... and power. The BIG HIT project will use otherwise curtailed electricity from one wind turbine on Shapinsay and one wind turbine and a tidal test sites on Eday, and use 1.5 MW of Polymer Electrolyte Membrane (PEM) electrolyser to convert it into ~50 t pa of hydrogen. This will be used to provide heat...... and infrastructure investment and operation cost of electricity and water consumption. The functional unit is 1 kg hydrogen produced and consumed. The data collected from the project patterns and suppliers. The current analysis is based on the estimation of hydrogen production and consumption on both Shapinsay...

  2. Synthetic peptide vaccines: palmitoylation of peptide antigens by a thioester bond increases immunogenicity

    DEFF Research Database (Denmark)

    Beekman, N.J.C.M.; Schaaper, W.M.M.; Tesser, G.I.

    1997-01-01

    Synthetic peptides have frequently been used to immunize animals. However, peptides less than about 20 to 30 amino acids long are poor immunogens. In general, to increase its immunogenicity, the presentation of the peptide should be improved, and molecular weight needs to be increased. Many...... attempts have been made to couple peptide immunogens to different carrier proteins [e.g. keyhole limper haemocyanin (KLH) or ovalbumin]. This leads to very complex structures, however. We used a controlled conjugation of a peptide to a single long-chain fatty acid like palmitic acid by a thioester...... or an amide bond. It was found that these S-palmitoylated peptides were much more immunogenic than N-palmitoylated peptides and at least similar to KLH-conjugated peptides with respect to appearance and magnitude of induced antibodies (canine parvovirus) or immunocastration effect (gonadotropin...

  3. Looking for a new HIT. Sanyo's patents for the HIT technology has expired, and competitors hope for new profits; Suche nach dem neuen HIT. Sanyos Patente fuer die HIT-Technologie sind ausgelaufen, die Konkurrenz frohlockt

    Energy Technology Data Exchange (ETDEWEB)

    Chunduri, Shravan K.; Haase, Christian

    2010-11-15

    With their hybrid cells, Sanyo Electric Co. Ltd. had covered a solar niche market. The HIT technology offers high efficiency at low production cost. Now, however, the most relevant patents of the Japanese producer have expired, and competitors working on similar concepts are out for their chance. For example, Swiss manufacturer Roth and Rau have been taking orders for turnkey hybrid cell production from January 2011. (orig.)

  4. [Biosynthesis of opioid peptides].

    Science.gov (United States)

    Rossier, J

    1988-01-01

    The endogenous opioid peptides all contain the enkephalin sequence Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu at their aminoterminus. Three distinct families of these peptides (endorphins, enkephalins and dynorphins) are present in different neuronal pathways within the central nervous system. Molecular genetics have shown that these three families of opioid peptides are derived from three distinct precursors. Pro-opiomelanocortin gives rise to the endorphins, as well as adrenocorticotropic hormone (ACTH) and the melanotropic hormones (MSH's). [Met] enkephalin, [Leu] enkephalin and the related heptapeptide [Met] enkephalin-Arg6-Phe7 and octapeptide [Met] enkephalin-Arg6-Gly7-Leu8 are derived from proenkephalin. The third family is derived from prodynorphin and includes dynorphin A, dynorphin B (also known as rimorphin) and alpha- and beta-neo-endorphin. The structure of the genes coding for these precursors are similar, suggesting the possibility of one common ancestral gene. The most common scheme for enzymatic maturation of precursors proposes the action of a trypsin-like endopeptidase followed by a carboxypeptidase B-like exopeptidase. However, we have provided evidence that this combination of trypsin-like and carboxypeptidase B-like enzymes may not be the only mechanism for liberating enkephalin from low molecular weight enkephalin-containing peptides. Indeed, endo-oligopeptidase A, an enzyme, known to hydrolyze the Phe5-Ser6 bond of bradykinin and the Arg8-Arg9 bond of neurotensin, has been shown to produce, by a single cleavage, [Leu] enkephalin or [Met] enkephalin from small enkephalin-containing peptides, (Camargo et al., 1987, J. Neurochem. 48, 1258-1263).(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Antimicrobial Peptides

    Directory of Open Access Journals (Sweden)

    Ali Adem Bahar

    2013-11-01

    Full Text Available The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs, a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics.

  6. Reconstruction of hit time and hit position of annihilation quanta in the J-PET detector using the Mahalanobis distance

    Directory of Open Access Journals (Sweden)

    Sharma Neha Gupta

    2015-12-01

    Full Text Available The J-PET detector being developed at the Jagiellonian University is a positron emission tomograph composed of the long strips of polymer scintillators. At the same time, it is a detector system that will be used for studies of the decays of positronium atoms. The shape of photomultiplier signals depends on the hit time and hit position of the gamma quantum. In order to take advantage of this fact, a dedicated sampling front-end electronics that enables to sample signals in voltage domain with the time precision of about 20 ps and novel reconstruction method based on the comparison of examined signal with the model signals stored in the library has been developed. As a measure of the similarity, we use the Mahalanobis distance. The achievable position and time resolution depend on the number and values of the threshold levels at which the signal is sampled. A reconstruction method as well as preliminary results are presented and discussed.

  7. Teachers' Perspectives on Hitting Back in School: Between Inexcusable Violence and Self-Defense

    Science.gov (United States)

    Fleischmann, Amos

    2015-01-01

    Israeli schools expressly forbid a student to hit back after being attacked. In semistructured interviews, 71 Israeli educators were asked for their views on the hitting-back tactic. The interviews compared their attitude toward hitting back as teachers with their take on the matter as parents. The results, analyzed using grounded theory, show…

  8. Imaging exocytosis of single glucagon-like peptide-1 containing granules in a murine enteroendocrine cell line with total internal reflection fluorescent microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Ohara-Imaizumi, Mica; Aoyagi, Kyota [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Akimoto, Yoshihiro [Department of Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Nakamichi, Yoko; Nishiwaki, Chiyono [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Kawakami, Hayato [Department of Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan)

    2009-12-04

    To analyze the exocytosis of glucagon-like peptide-1 (GLP-1) granules, we imaged the motion of GLP-1 granules labeled with enhanced yellow fluorescent protein (Venus) fused to human growth hormone (hGH-Venus) in an enteroendocrine cell line, STC-1 cells, by total internal reflection fluorescent (TIRF) microscopy. We found glucose stimulation caused biphasic GLP-1 granule exocytosis: during the first phase, fusion events occurred from two types of granules (previously docked granules and newcomers), and thereafter continuous fusion was observed mostly from newcomers during the second phase. Closely similar to the insulin granule fusion from pancreatic {beta} cells, the regulated biphasic exocytosis from two types of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.

  9. Comparison of Document Index Graph Using TextRank and HITS Weighting Method in Automatic Text Summarization

    Science.gov (United States)

    Hadyan, Fadhlil; Shaufiah; Arif Bijaksana, Moch.

    2017-01-01

    Automatic summarization is a system that can help someone to take the core information of a long text instantly. The system can help by summarizing text automatically. there’s Already many summarization systems that have been developed at this time but there are still many problems in those system. In this final task proposed summarization method using document index graph. This method utilizes the PageRank and HITS formula used to assess the web page, adapted to make an assessment of words in the sentences in a text document. The expected outcome of this final task is a system that can do summarization of a single document, by utilizing document index graph with TextRank and HITS to improve the quality of the summary results automatically.

  10. Spreading of amyotrophic lateral sclerosis lesions--multifocal hits and local propagation?

    Science.gov (United States)

    Sekiguchi, Teruhiko; Kanouchi, Tadashi; Shibuya, Kazumoto; Noto, Yu-ichi; Yagi, Yohsuke; Inaba, Akira; Abe, Keisuke; Misawa, Sonoko; Orimo, Satoshi; Kobayashi, Takayoshi; Kamata, Tomoyuki; Nakagawa, Masanori; Kuwabara, Satoshi; Mizusawa, Hidehiro; Yokota, Takanori

    2014-01-01

    To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the 'single seed and simple propagation' hypothesis). Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Abnormal spontaneous activities in needle electromyography (nEMG)-that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs)-were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. The non-contiguously affected lumbosacral lesions involved motoneuron columns horizontally or radially proximate to one another, appearing to form a cluster in four of the eight patients. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5, suggesting that 2nd hits occur at L5 and then spread to other lumbosacral segments. In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the 'single seed and simple propagation' hypothesis alone. We propose a 'multifocal hits and local propagation' hypothesis instead.

  11. Analysis of indirect evidence in hit-and-run cases

    Directory of Open Access Journals (Sweden)

    Zhefeng Xu

    2017-01-01

    Full Text Available For personnel handling cases in public security bodies, evaluation of evidence is key to discover the fact and then to settle disputes. The process of evaluation shall be confirmed to rules of logic. Rules of logic are a set of judgment rules for people to reflect, induce, and deduce the development of law worldwide. Thus, evaluation of evidence shall be built on objective and rational logic deduction. Rules of logic applied in the investigation and judgment of evidence can help in finding a direct or indirect link between the evidence and the facts of an accident, thereby providing support and assistance for accident identification. It is particularly necessary to apply rules of logic to evaluate the indirect evidence chain in the investigation of hit-and-run traffic accident cases. This article demonstrates the specific application of such rules in the investigation of a serious hit-and-run traffic accident case. In the investigation process through the comprehensive analysis of and logical thinking around all indirect evidence, such as site inspection data, video monitoring data, witness testimony, and expert conclusions, and the combining of this with the direct evidence of the parties' statements, a complete chain of evidence for identifying a suspect's vehicle and the accident facts can be formed. The effective application of rules of logic in the evaluation of the indirect evidence chain in hit-and-run traffic accident cases provides more clues and narrows the scope of an investigation, improving its efficiency and accuracy, thereby helping to identify the facts of an accident.

  12. Recent Improvements in the SHIELD-HIT Code

    DEFF Research Database (Denmark)

    Hansen, David Christoffer; Lühr, Armin Christian; Herrmann, Rochus

    2012-01-01

    concentrating on three objectives, namely: Enhanced functionality, improved efficiency, and a modification of employed physical models. Methodological developments: SHIELD-HIT (currently at version ‘10A’) is now equipped with an independent detector geometry, ripple filter implementations, and it is capable...... of using accelerator control files as a basis for the primaries. Furthermore, the code has been parallelized and efficiency is improved. The physical description of inelastic ion collisions has been modified. Results: The simulation of an experimental depth-dose distribution including a ripple filter...

  13. Liquid Argon TPC Signal Formation, Signal Processing and Hit Reconstruction

    Energy Technology Data Exchange (ETDEWEB)

    Baller, Bruce [Fermilab

    2017-03-11

    This document describes the early stage of the reconstruction chain that was developed for the ArgoNeuT and MicroBooNE experiments at Fermilab. These experiments study accelerator neutrino interactions that occur in a Liquid Argon Time Projection Chamber. Reconstructing the properties of particles produced in these interactions requires knowledge of the micro-physics processes that affect the creation and transport of ionization electrons to the readout system. A wire signal deconvolution technique was developed to convert wire signals to a standard form for hit reconstruction, to remove artifacts in the electronics chain and to remove coherent noise.

  14. The Holistic Integrity Test (HIT - quantified resilience analysis

    Directory of Open Access Journals (Sweden)

    Dobson Mike

    2016-01-01

    Full Text Available The Holistic Integrity Test (HIT - Quantified Resilience Analysis. Rising sea levels and wider climate change mean we face an increasing risk from flooding and other natural hazards. Tough economic times make it difficult to economically justify or afford the desired level of engineered risk reduction. Add to this significant uncertainty from a range of future predictions, constantly updated with new science. We therefore need to understand not just how to reduce the risk, but what could happen should above design standard events occur. In flood terms this includes not only the direct impacts (damage and loss of life, but the wider cascade impacts to infrastructure systems and the longer term impacts on the economy and society. However, understanding the “what if” is only the first part of the equation; a range of improvement measures to mitigate such effects need to be identified and implemented. These measures should consider reducing the risk, lessening the consequences, aiding the response, and speeding up the recovery. However, they need to be objectively assessed through quantitative analysis, which underpins them technically and economically. Without such analysis, it cannot be predicted how measures will perform if the extreme events occur. It is also vital to consider all possible hazards as measures for one hazard may hinder the response to another. The Holistic Integrity Test (HIT, uses quantitative system analysis and “HITs” the site, its infrastructure, contained dangers and wider regional system to determine how it copes with a range of severe shock events, Before, During and After the event, whilst also accounting for uncertainty (as illustrated in figure 1. First explained at the TINCE 2014 Nuclear Conference in Paris, it was explained in terms of a Nuclear Facility needing to analyse the site in response to post Fukushima needs; the hit is however universally applicable. The HIT has three key risk reduction goals: The

  15. Synthetic antifreeze peptide

    OpenAIRE

    1991-01-01

    A synthetic antifreeze peptide and a synthetic gene coding for the antifreeze peptide have been produced. The antifreeze peptide has a greater number of repeating amino acid sequences than is present in the native antifreeze peptides from winter flounder upon which the synthetic antifreeze peptide was modeled. Each repeating amino acid sequence has two polar amino acid residues which are spaced a controlled distance apart so that the antifreeze peptide may inhibit ice formation. The synthetic...

  16. Segmental neurofibromatosis type 2: discriminating two hit from four hit in a patient presenting multiple schwannomas confined to one limb.

    Science.gov (United States)

    Castellanos, Elisabeth; Bielsa, Isabel; Carrato, Cristina; Rosas, Imma; Solanes, Ares; Hostalot, Cristina; Amilibia, Emilio; Prades, José; Roca-Ribas, Francesc; Lázaro, Conxi; Blanco, Ignacio; Serra, Eduard

    2015-01-24

    A clinical overlap exists between mosaic Neurofibromatosis Type 2 and sporadic Schwannomatosis conditions. In these cases a molecular analysis of tumors is recommended for a proper genetic diagnostics. This analysis is challenged by the fact that schwannomas in both conditions bear a somatic double inactivation of the NF2 gene. However, SMARCB1-associated schwannomas follow a four-hit, three-step model, in which both alleles of SMARCB1 and NF2 genes are inactivated in the tumor, with one of the steps being always the loss of a big part of chromosome 22 involving both loci. Here we report a 36-year-old woman who only presented multiple subcutaneous schwannomas on her right leg. To help discriminate between both possible diagnoses, an exhaustive molecular genetic and genomic analysis was performed on two schwannomas of the patient, consisting in cDNA and DNA sequencing, MLPA, microsatellite multiplex PCR and SNP-array analyses. The loss of a big part of chromosome 22 (22q12.1q13.33) was identified in both tumors. However, this loss involved the NF2 but not the SMARCB1 locus. SNP-array analysis revealed the presence of the same deletion breakpoint in both schwannomas, indicating that this alteration was actually the first NF2 inactivating hit. In addition, a distinct NF2 point mutation in each tumor was identified, representing independent second hits. In accordance with these results, no deletions or point mutations in the SMARCB1 gene were identified. None of the mutations were present in the blood. Two of the patient's children inherited chromosome 22 deleted in schwannomas of the mother, but in its wild type form. These results conclusively confirm the segmental mosaic NF2 nature of the clinical phenotype presented.

  17. Decision tree models for data mining in hit discovery.

    Science.gov (United States)

    Hammann, Felix; Drewe, Juergen

    2012-04-01

    Decision tree induction (DTI) is a powerful means of modeling data without much prior preparation. Models are readable by humans, robust and easily applied in real-world applications, features that are mutually exclusive in other commonly used machine learning paradigms. While DTI is widely used in disciplines ranging from economics to medicine, they are an intriguing option in pharmaceutical research, especially when dealing with large data stores. This review covers the automated technologies available for creating decision trees and other rules efficiently, even from large datasets such as chemical libraries. The authors discuss the need for properly documented and validated models. Lastly, the authors cover several case studies in hit discovery, drug metabolism and toxicology, and drug surveillance, and compare them with other established techniques. DTI is a competitive and easy-to-use tool in basic research as well as in hit and drug discovery. Its strengths lie in its ability to handle all sorts of different data formats, the visual nature of the models, and the small computational effort needed for implementation in real-world systems. Limitations include lack of robustness and over-fitted models for certain types of data. As with any modeling technique, proper validation and quality measures are of utmost importance. © 2012 Informa UK, Ltd.

  18. Capture orbits around asteroids by hitting zero-velocity curves

    Science.gov (United States)

    Wang, Wei; Yang, Hongwei; Zhang, Wei; Ma, Guangfu

    2017-12-01

    The problem of capturing a spacecraft from a heliocentric orbit into a high parking orbit around binary asteroids is investigated in the current study. To reduce the braking Δ V, a new capture strategy takes advantage of the three-body gravity of the binary asteroid to lower the inertial energy before applying the Δ V. The framework of the circular restricted three-body problem (CR3BP) is employed for the binary asteroid system. The proposed capture strategy is based on the mechanism by which inertial energy can be decreased sharply near zero-velocity curves (ZVCs). The strategy has two steps, namely, hitting the target ZVC and raising the periapsis by a small Δ V at the apoapsis. By hitting the target ZVC, the positive inertial energy decreases and becomes negative. Using a small Δ V, the spacecraft inserts into a bounded orbit around the asteroid. In addition, a rotating mass dipole model is employed for elongated asteroids, which leads to dynamics similar to that of the CR3BP. With this approach, the proposed capture strategy can be applied to elongated asteroids. Numerical simulations validate that the proposed capture strategy is applicable for the binary asteroid 90 Antiope and the elongated asteroid 216 Kleopatra.

  19. Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens

    DEFF Research Database (Denmark)

    Wallny, Hans-Joachim; Avila, David; Hunt, Lawrence G.

    2006-01-01

    Compared with the MHC of typical mammals, the chicken MHC is smaller and simpler, with only two class I genes found in the B12 haplotype. We make five points to show that there is a single-dominantly expressed class I molecule that can have a strong effect on MHC function. First, we find only one...

  20. Probing the role of metal cations on the aggregation behavior of amyloid β-peptide at a single molecule level by AFM

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yang; Wang, Jianhua, E-mail: wjh@cqu.edu.cn; Liu, Chundong [Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering (China)

    2016-09-15

    With the development of nanotechnology, understanding of intermolecular interactions on a single molecule level by atomic force spectroscopy (AFM) has played an important role in molecular biology and biomedical science. In recent years, some research suggested that the presence of metal cations is an important regulator in the processes of misfolding and aggregation of the amyloid β-protein (Aβ), which may be an important etiological factor of Alzheimer’s disease. However, the knowledge on the principle of interactions between Aβ and metal cations at the single molecule level is still poor understood. In this paper, the amyloid β-protein (Aβ) was fabricated on substrate of mixed thiol-modified gold nanoparticles using self-assembled monolayer method and the adhesion force in the longitudinal direction between metal cations and Aβ42 were investigated by AFM. The role of metal ions on Aβ aggregation is discussed from the perspective of single molecular force. The force results showed that the specific adhesion force F{sub i} and the nonspecific force F{sub 0} between a single Aβ–Aβ pair in control experiment were calculated as 42 ± 3 and 80 pN, respectively. However, F{sub i} between a single Aβ–Aβ pair in the presence of Cu{sup 2+}, Zn{sup 2+}, Ca{sup 2+} and Al{sup 3+} increased dramatically to 84 ± 6, 89 ± 3, 73 ± 5, 95 ± 5 pN successively, which indicated that unbinding between Aβ proteins is accelerated in the presence of metal cations. What is more, the imaging results showed that substoichiometric copper cations accelerate the formation of fibrils within 3 days. The combined atomic force spectroscopy and imaging analysis indicate that metal cations play a role in promoting the aggregating behavior of Aβ42.

  1. Probing the role of metal cations on the aggregation behavior of amyloid β-peptide at a single molecule level by AFM

    Science.gov (United States)

    Xie, Yang; Wang, Jianhua; Liu, Chundong

    2016-09-01

    With the development of nanotechnology, understanding of intermolecular interactions on a single molecule level by atomic force spectroscopy (AFM) has played an important role in molecular biology and biomedical science. In recent years, some research suggested that the presence of metal cations is an important regulator in the processes of misfolding and aggregation of the amyloid β-protein (Aβ), which may be an important etiological factor of Alzheimer's disease. However, the knowledge on the principle of interactions between Aβ and metal cations at the single molecule level is still poor understood. In this paper, the amyloid β-protein (Aβ) was fabricated on substrate of mixed thiol-modified gold nanoparticles using self-assembled monolayer method and the adhesion force in the longitudinal direction between metal cations and Aβ42 were investigated by AFM. The role of metal ions on Aβ aggregation is discussed from the perspective of single molecular force. The force results showed that the specific adhesion force F i and the nonspecific force F 0 between a single Aβ-Aβ pair in control experiment were calculated as 42 ± 3 and 80 pN, respectively. However, F i between a single Aβ-Aβ pair in the presence of Cu2+, Zn2+, Ca2+ and Al3+ increased dramatically to 84 ± 6, 89 ± 3, 73 ± 5, 95 ± 5 pN successively, which indicated that unbinding between Aβ proteins is accelerated in the presence of metal cations. What is more, the imaging results showed that substoichiometric copper cations accelerate the formation of fibrils within 3 days. The combined atomic force spectroscopy and imaging analysis indicate that metal cations play a role in promoting the aggregating behavior of Aβ42.

  2. Peptide fibrils with altered stability, activity, and cell selectivity

    OpenAIRE

    Chen, Long; Liang, Jun F.

    2013-01-01

    Peptides have some unique and superior features compared to proteins. However, the use of peptides as therapeutics is hampered by their low stability and cell selectivity. In this study, a new lytic peptide (CL-1, FLGALFRALSRLL) was constructed. Under the physiological condition, peptide CL-1 self-assembled into dynamically stable aggregates with fibrils-like structures. Aggregated CL-1 demonstrated dramatically altered activity and stability in comparison with single molecule CL-1 and other ...

  3. Prenatal cannabis exposure - The "first hit" to the endocannabinoid system.

    Science.gov (United States)

    Richardson, Kimberlei A; Hester, Allison K; McLemore, Gabrielle L

    As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, and workforce concerns. Unlike fetal alcohol spectrum disorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction. However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain from smoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this system is important in the regulation of cardiovascular processes. Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry. In this review, we discuss the Double-Hit Hypothesis as it relates to PCE. We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS, which is compromised in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the

  4. Single-Dose Metformin Enhances Bile Acid-Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2017-01-01

    -controlled, and double-blinded crossover study. Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Patients: Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study. Interventions: Four experimental study days in randomized order...... with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline. Main Outcome Measure: Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve. Results: Single-dose metformin further enhanced bile acid...

  5. Human peptide transporters

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Brodin, Birger; Jørgensen, Flemming Steen

    2002-01-01

    Peptide transporters are epithelial solute carriers. Their functional role has been characterised in the small intestine and proximal tubules, where they are involved in absorption of dietary peptides and peptide reabsorption, respectively. Currently, two peptide transporters, PepT1 and PepT2, wh...

  6. [SYNTHETIC PEPTIDE VACCINES].

    Science.gov (United States)

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested.

  7. Where Does HIT Fit? An Examination of the Affective Response to High-Intensity Intervals in Comparison to Continuous Moderate- and Continuous Vigorous-Intensity Exercise in the Exercise Intensity-Affect Continuum

    Science.gov (United States)

    Jung, Mary E.; Bourne, Jessica E.; Little, Jonathan P.

    2014-01-01

    Affect experienced during an exercise session is purported to predict future exercise behaviour. Compared to continuous moderate-intensity exercise (CMI), the affective response to continuous vigorous-intensity exercise (CVI) has consistently been shown to be more aversive. The affective response, and overall tolerability to high-intensity interval training (HIT), is less studied. To date, there has yet to be a comparison between HIT, CVI, and CMI. The purpose of this study was to compare the tolerability and affective responses during HIT to CVI and CMI. This study utilized a repeated measures, randomized, counter-balanced design. Forty-four participants visited the laboratory on four occasions. Baseline fitness testing was conducted to establish peak power output in Watts (Wpeak). Three subsequent visits involved a single bout of a) HIT, corresponding to 1-minute at ∼100% Wpeak and 1-minute at ∼20% Wpeak for 20 minutes, b) CMI, corresponding to ∼40% Wpeak for 40 minutes, and c) CVI, corresponding to ∼80% Wpeak for 20 minutes. The order of the sessions was randomized. Affective responses were measured before, during and after each session. Task self-efficacy, intentions, enjoyment and preference were measured after sessions. Participants reported greater enjoyment of HIT as compared to CMI and CVI, with over 50% of participants reporting a preference to engage in HIT as opposed to either CMI or CVI. HIT was considered more pleasurable than CVI after exercise, but less pleasurable than CMI at these times. Despite this participants reported being just as confident to engage in HIT as they were CMI, but less confident to engage in CVI. This study highlights the utility of HIT in inactive individuals, and suggests that it may be a viable alternative to traditionally prescribed continuous modalities of exercise for promoting self-efficacy and enjoyment of exercise. PMID:25486273

  8. Where does HIT fit? An examination of the affective response to high-intensity intervals in comparison to continuous moderate- and continuous vigorous-intensity exercise in the exercise intensity-affect continuum.

    Directory of Open Access Journals (Sweden)

    Mary E Jung

    Full Text Available Affect experienced during an exercise session is purported to predict future exercise behaviour. Compared to continuous moderate-intensity exercise (CMI, the affective response to continuous vigorous-intensity exercise (CVI has consistently been shown to be more aversive. The affective response, and overall tolerability to high-intensity interval training (HIT, is less studied. To date, there has yet to be a comparison between HIT, CVI, and CMI. The purpose of this study was to compare the tolerability and affective responses during HIT to CVI and CMI. This study utilized a repeated measures, randomized, counter-balanced design. Forty-four participants visited the laboratory on four occasions. Baseline fitness testing was conducted to establish peak power output in Watts (W peak. Three subsequent visits involved a single bout of a HIT, corresponding to 1-minute at ∼ 100% W peak and 1-minute at ∼ 20% W peak for 20 minutes, b CMI, corresponding to ∼ 40% W peak for 40 minutes, and c CVI, corresponding to ∼ 80% W peak for 20 minutes. The order of the sessions was randomized. Affective responses were measured before, during and after each session. Task self-efficacy, intentions, enjoyment and preference were measured after sessions. Participants reported greater enjoyment of HIT as compared to CMI and CVI, with over 50% of participants reporting a preference to engage in HIT as opposed to either CMI or CVI. HIT was considered more pleasurable than CVI after exercise, but less pleasurable than CMI at these times. Despite this participants reported being just as confident to engage in HIT as they were CMI, but less confident to engage in CVI. This study highlights the utility of HIT in inactive individuals, and suggests that it may be a viable alternative to traditionally prescribed continuous modalities of exercise for promoting self-efficacy and enjoyment of exercise.

  9. Inflammation and the Two-Hit Hypothesis of Schizophrenia

    Science.gov (United States)

    Feigenson, Keith A.; Kusnecov, Alex W.; Silverstein, Steven M.

    2014-01-01

    The high societal and individual cost of schizophrenia necessitates finding better, more effective treatment, diagnosis, and prevention strategies. One of the obstacles in this endeavor is the diverse set of etiologies that comprises schizophrenia. A substantial body of evidence has grown over the last few decades to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and etiologies. At the same time, an increasing number of clinical, epidemiological, and experimental studies have shown links between schizophrenia and inflammatory conditions. In this review, we analyze the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults. We then identify several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis. Lastly, we note the relevance of these findings to clinical applications in the diagnosis, prevention, and treatment of schizophrenia. PMID:24247023

  10. Pathomechanisms Underlying X-Adrenoleukodystrophy: A Three-Hit Hypothesis

    Science.gov (United States)

    Singh, Inderjit; Pujol, Aurora

    2011-01-01

    X-adrenoleukodystrophy (X-ALD) is a complex disease where inactivation of ABCD1 gene results in clinically diverse phenotypes, the fatal disorder of cerebral ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). Loss of ABCD1 function results in defective beta oxidation of very long chain fatty acids (VLCFA) resulting in excessive accumulation of VLCFA, the biochemical “hall mark” of X-ALD. At present, the ABCD1-mediated mechanisms that determine the different phenotype of X-ALD are not well understood. The studies reviewed here suggest for a “three-hit hypothesis” for neuropathology of cALD. An improved understanding of the molecular mechanisms associated with these three phases of cALD disease should facilitate the development of effective pharmacological therapeutics for X-ALD. PMID:20626745

  11. Tracking, aiming, and hitting the UAV with ordinary assault rifle

    Science.gov (United States)

    Racek, František; Baláž, Teodor; Krejčí, Jaroslav; Procházka, Stanislav; Macko, Martin

    2017-10-01

    The usage small-unmanned aerial vehicles (UAVs) is significantly increasing nowadays. They are being used as a carrier of military spy and reconnaissance devices (taking photos, live video streaming and so on), or as a carrier of potentially dangerous cargo (intended for destruction and killing). Both ways of utilizing the UAV cause the necessity to disable it. From the military point of view, to disable the UAV means to bring it down by a weapon of an ordinary soldier that is the assault rifle. This task can be challenging for the soldier because he needs visually detect and identify the target, track the target visually and aim on the target. The final success of the soldier's mission depends not only on the said visual tasks, but also on the properties of the weapon and ammunition. The paper deals with possible methods of prediction of probability of hitting the UAV targets.

  12. The application of strand invasion phenomenon, directed by peptide nucleic acid (PNA) and single-stranded DNA binding protein (SSB) for the recognition of specific sequences of human endogenous retroviral HERV-W family.

    Science.gov (United States)

    Machnik, Grzegorz; Bułdak, Łukasz; Ruczyński, Jarosław; Gąsior, Tomasz; Huzarska, Małgorzata; Belowski, Dariusz; Alenowicz, Magdalena; Mucha, Piotr; Rekowski, Piotr; Okopień, Bogusław

    2017-05-01

    The HERV-W family of human endogenous retroviruses represents a group of numerous sequences that show close similarity in genetic composition. It has been documented that some members of HERV-W-derived expression products are supposed to play significant role in humans' pathology, such as multiple sclerosis or schizophrenia. Other members of the family are necessary to orchestrate physiological processes (eg, ERVWE1 coding syncytin-1 that is engaged in syncytiotrophoblast formation). Therefore, an assay that would allow the recognition of particular form of HERV-W members is highly desirable. A peptide nucleic acid (PNA)-mediated technique for the discrimination between multiple sclerosis-associated retrovirus and ERVWE1 sequence has been developed. The assay uses a PNA probe that, being fully complementary to the ERVWE1 but not to multiple sclerosis-associated retrovirus (MSRV) template, shows high selective potential. Single-stranded DNA binding protein facilitates the PNA-mediated, sequence-specific formation of strand invasion complex and, consequently, local DNA unwinding. The target DNA may be then excluded from further analysis in any downstream process such as single-stranded DNA-specific exonuclease action. Finally, the reaction conditions have been optimized, and several PNA probes that are targeted toward distinct loci along whole HERV-W env sequences have been evaluated. We believe that PNA/single-stranded DNA binding protein-based application has the potential to selectively discriminate particular HERV-W molecules as they are at least suspected to play pathogenic role in a broad range of medical conditions, from psycho-neurologic disorders (multiple sclerosis and schizophrenia) and cancers (breast cancer) to that of an auto-immunologic background (psoriasis and lupus erythematosus). Copyright © 2016 John Wiley & Sons, Ltd.

  13. Novel 1:1 labeling and purification process for C-terminal thioester and single cysteine recombinant proteins using generic peptidic toolbox reagents.

    Science.gov (United States)

    Portal, Christophe F; Seifert, Jan-Marcus; Buehler, Christof; Meisner-Kober, Nicole-Claudia; Auer, Manfred

    2014-07-16

    We developed a versatile set of chemical labeling reagents which allow dye ligation to the C-terminus of a protein or a single internal cysteine and target purification in a simple two-step process. This simple process results in a fully 1:1 labeled conjugate suitable for all quantitative fluorescence spectroscopy and imaging experiments. We refer to a "generic labeling toolbox" because of the flexibility to choose one of many available dyes, spacers of different lengths and compositions which increase the target solubility, a variety of affinity purification tags, and different cleavage chemistries to release the 1:1 labeled proteins. Studying protein function in vitro or in the context of live cells and organisms is of vital importance in biological research. Although label free detection technologies gain increasing interest in molecular recognition science, fluorescence spectroscopy is still the most often used detection technique for assays and screens both in academic as well as in industrial groups. For generations, fluorescence spectroscopists have labeled their proteins of interest with small fluorescent dyes by random chemical linking on the proteins' exposed lysines and cysteines. Chemical reactions with a certain excess of activated esters or maleimides of longer wavelength dyes hardly ever result in quantitative labeling of the target protein. Most of the time, more than one exposed amino acid side chain reacts. This results in a mixture of dye-protein complexes of different labeling stoichiometries and labeling sites. Only mass spectrometry allows resolving the precise chemical composition of the conjugates. In "classical" ensemble averaging fluorescent experiments, these labeled proteins are still useful, and quantification of, e.g., ligand binding experiments, is achieved via knowledge of the overall protein concentration and a fluorescent signal change which is proportional to the amount of complex formed. With the development of fluorescence

  14. A monodisperse transmembrane α-helical peptide barrel

    Science.gov (United States)

    Mahendran, Kozhinjampara R.; Niitsu, Ai; Kong, Lingbing; Thomson, Andrew R.; Sessions, Richard B.; Woolfson, Derek N.; Bayley, Hagan

    2017-05-01

    The fabrication of monodisperse transmembrane barrels formed from short synthetic peptides has not been demonstrated previously. This is in part because of the complexity of the interactions between peptides and lipids within the hydrophobic environment of a membrane. Here we report the formation of a transmembrane pore through the self-assembly of 35 amino acid α-helical peptides. The design of the peptides is based on the C-terminal D4 domain of the Escherichia coli polysaccharide transporter Wza. By using single-channel current recording, we define discrete assembly intermediates and show that the pore is most probably a helix barrel that contains eight D4 peptides arranged in parallel. We also show that the peptide pore is functional and capable of conducting ions and binding blockers. Such α-helix barrels engineered from peptides could find applications in nanopore technologies such as single-molecule sensing and nucleic-acid sequencing.

  15. Conformation effects of CpG methylation on single-stranded DNA oligonucleotides: analysis of the opioid peptide dynorphin-coding sequences.

    Directory of Open Access Journals (Sweden)

    Malik Mumtaz Taqi

    Full Text Available Single-stranded DNA (ssDNA is characterized by high conformational flexibility that allows these molecules to adopt a variety of conformations. Here we used native polyacrylamide gel electrophoresis (PAGE, circular dichroism (CD spectroscopy and nuclear magnetic resonance (NMR spectroscopy to show that cytosine methylation at CpG sites affects the conformational flexibility of short ssDNA molecules. The CpG containing 37-nucleotide PDYN (prodynorphin fragments were used as model molecules. The presence of secondary DNA structures was evident from differences in oligonucleotide mobilities on PAGE, from CD spectra, and from formation of A-T, G-C, and non-canonical G-T base pairs observed by NMR spectroscopy. The oligonucleotides displayed secondary structures at 4°C, and some also at 37°C. Methylation at CpG sites prompted sequence-dependent formation of novel conformations, or shifted the equilibrium between different existing ssDNA conformations. The effects of methylation on gel mobility and base pairing were comparable in strength to the effects induced by point mutations in the DNA sequences. The conformational effects of methylation may be relevant for epigenetic regulatory events in a chromatin context, including DNA-protein or DNA-DNA recognition in the course of gene transcription, and DNA replication and recombination when double-stranded DNA is unwinded to ssDNA.

  16. Single Intramammary Infusion of Recombinant Bovine Interleukin-8 at Dry-Off Induces the Prolonged Secretion of Leukocyte Elastase, Inflammatory Lactoferrin-Derived Peptides, and Interleukin-8 in Dairy Cows

    Directory of Open Access Journals (Sweden)

    Atsushi Watanabe

    2012-01-01

    Full Text Available A single intramammary infusion of recombinant bovine interleukin-8 (IL-8 at 50 μg/quarter/head, but not 10 μg/quarter/head, induced clinical mastitis in three of four cows during the dry-off period, resulting in an elevated rectal temperature, redness and swelling of the mammary gland, extensive polymorphonuclear leukocyte (PMNL infiltration, and milk clot formation from 1 to 28 days post infusion (PI. In the mammary secretions of the mastitic glands, high levels of IL-8 were sustained from 8 hours to 28 days PI, peaking at 1–3 days PI. The levels of leukocyte-derived elastase and inflammatory 22 and 23 kDa lactoferrin derived peptides (LDP were also increased in the mammary secretions from the mastitic glands. In addition to the experimentally induced mastitis, the mammary secretions from the glands of cattle with spontaneous Staphylococcus aureus dry-period mastitis displayed milk clot formations and significant increases in their levels of PMNL counts, elastase, LDP, and IL-8, compared with those of the mammary secretions from the uninfected glands. These results suggest that after an intramammary infusion of IL-8 has elicited inflammatory responses, it induces the prolonged secretion of elastase, inflammatory LDP, and IL-8, and that long-lasting IL-8-induced inflammatory reactions are involved in the pathogenesis of S. aureus dry-period mastitis.

  17. Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Nik-Ahd, Farnoosh; Bertoni, Carmen

    2014-07-01

    Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single-stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients. © 2014 AlphaMed Press.

  18. Phage display of peptide / major histocompatibility class I complexes

    DEFF Research Database (Denmark)

    Vest Hansen, N; Ostergaard Pedersen, L; Stryhn, A

    2001-01-01

    and subsequently that ot the T cell receptor for peptide-MHC-I complex), we have fused a single chain peptide-MHC-I complex to the phage minor coat protein, gpIII, and displayed it on filamentous phage. Expression of peptide-MHC-I complexes was shown with relevant conformation-specific monoclonal antibodies and......, more importantly, with a unique "T cell receptor-like" (i. e. peptide-specific, MHC-I-restricted) antibody. Thus, properly assembled and folded peptide-MHC-I complexes can be displayed on filamentous phage. Despite the successful display, interaction with T cells could not be demonstrated....

  19. Low sensitivity but high specificity of ParaHIT-f in diagnosing malaria ...

    African Journals Online (AJOL)

    Low sensitivity but high specificity of ParaHIT-f in diagnosing malaria among children attending outpatient department in Butimba District Hospital, Mwanza, Tanzania. ... on the sensitivity and specificity are needed. A good quality control system on the performance of ParaHIT-f and other RDTs is highly recommended.

  20. Designing Antibacterial Peptides with Enhanced Killing Kinetics

    Directory of Open Access Journals (Sweden)

    Faiza H. Waghu

    2018-02-01

    Full Text Available Antimicrobial peptides (AMPs are gaining attention as substitutes for antibiotics in order to combat the risk posed by multi-drug resistant pathogens. Several research groups are engaged in design of potent anti-infective agents using natural AMPs as templates. In this study, a library of peptides with high sequence similarity to Myeloid Antimicrobial Peptide (MAP family were screened using popular online prediction algorithms. These peptide variants were designed in a manner to retain the conserved residues within the MAP family. The prediction algorithms were found to effectively classify peptides based on their antimicrobial nature. In order to improve the activity of the identified peptides, molecular dynamics (MD simulations, using bilayer and micellar systems could be used to design and predict effect of residue substitution on membranes of microbial and mammalian cells. The inference from MD simulation studies well corroborated with the wet-lab observations indicating that MD-guided rational design could lead to discovery of potent AMPs. The effect of the residue substitution on membrane activity was studied in greater detail using killing kinetic analysis. Killing kinetics studies on Gram-positive, negative and human erythrocytes indicated that a single residue change has a drastic effect on the potency of AMPs. An interesting outcome was a switch from monophasic to biphasic death rate constant of Staphylococcus aureus due to a single residue mutation in the peptide.

  1. Scientific impact: the story of your big hit

    Science.gov (United States)

    Sinatra, Roberta; Wang, Dashun; Deville, Pierre; Song, Chaoming; Barabasi, Albert-Laszlo

    2014-03-01

    A gradual increase in performance through learning and practice characterize most trades, from sport to music or engineering, and common sense suggests this to be true in science as well. This prompts us to ask: what are the precise patterns that lead to scientific excellence? Does performance indeed improve throughout a scientific career? Are there quantifiable signs of an impending scientific hit? Using citation-based measures as a proxy of impact, we show that (i) major discoveries are not preceded by works of increasing impact, nor are followed by work of higher impact, (ii) the precise time ranking of the highest impact work in a scientist's career is uniformly random, with the higher probability to have a major discovery in the middle of scientific careers being due only to changes in productivity, (iii) there is a strong correlation between the highest impact work and average impact of a scientist's work. These findings suggest that the impact of a paper is drawn randomly from an impact distribution that is unique for each scientist. We present a model which allows to reconstruct the individual impact distribution, making possible to create synthetic careers that exhibit the same properties of the real data and to define a ranking based on the overall impact of a scientist. RS acknowledges support from the James McDonnell Foundation.

  2. Anisotropic Membrane Curvature Sensing by Amphipathic Peptides

    OpenAIRE

    Gómez-Llobregat, Jordi; Elías-Wolff, Federico; Lindén, Martin

    2016-01-01

    Many proteins and peptides have an intrinsic capacity to sense and induce membrane curvature, and play crucial roles for organizing and remodelling cell membranes. However, the molecular driving forces behind these processes are not well understood. Here, we describe a new approach to study curvature sensing, by simulating the direction-dependent interactions of single molecules with a buckled lipid bilayer. We analyse three amphipathic antimicrobial peptides, a class of membrane-associated m...

  3. PageRank, HITS and a unified framework for link analysis

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Chris; He, Xiaofeng; Husbands, Parry; Zha, Hongyuan; Simon, Horst

    2001-10-01

    Two popular webpage ranking algorithms are HITS and PageRank. HITS emphasizes mutual reinforcement between authority and hub webpages, while PageRank emphasizes hyperlink weight normalization and web surfing based on random walk models. We systematically generalize/combine these concepts into a unified framework. The ranking framework contains a large algorithm space; HITS and PageRank are two extreme ends in this space. We study several normalized ranking algorithms which are intermediate between HITS and PageRank, and obtain closed-form solutions. We show that, to first order approximation, all ranking algorithms in this framework, including PageRank and HITS, lead to same ranking which is highly correlated with ranking by indegree. These results support the notion that in web resource ranking indegree and outdegree are of fundamental importance. Rankings of webgraphs of different sizes and queries are presented to illustrate our analysis.

  4. Annotating and Interpreting Linear and Cyclic Peptide Tandem Mass Spectra.

    Science.gov (United States)

    Niedermeyer, Timo Horst Johannes

    2016-01-01

    Nonribosomal peptides often possess pronounced bioactivity, and thus, they are often interesting hit compounds in natural product-based drug discovery programs. Their mass spectrometric characterization is difficult due to the predominant occurrence of non-proteinogenic monomers and, especially in the case of cyclic peptides, the complex fragmentation patterns observed. This makes nonribosomal peptide tandem mass spectra annotation challenging and time-consuming. To meet this challenge, software tools for this task have been developed. In this chapter, the workflow for using the software mMass for the annotation of experimentally obtained peptide tandem mass spectra is described. mMass is freely available (http://www.mmass.org), open-source, and the most advanced and user-friendly software tool for this purpose. The software enables the analyst to concisely annotate and interpret tandem mass spectra of linear and cyclic peptides. Thus, it is highly useful for accelerating the structure confirmation and elucidation of cyclic as well as linear peptides and depsipeptides.

  5. PeptideAtlas

    Data.gov (United States)

    U.S. Department of Health & Human Services — PeptideAtlas is a multi-organism, publicly accessible compendium of peptides identified in a large set of tandem mass spectrometry proteomics experiments. Mass...

  6. A Case Study of a Combat Aircraft’s Single Hit Vulnerability

    Science.gov (United States)

    1986-09-01

    The DMEA also identifies any secondary damage caused by the primary damage mechanism. For example, a secondary fire caused by the detonation of an...k/d), the "probability of kill given a detonation envelope" if the weapons system is expected to encounter HE warheads in its mission profile. Another...o » 3 CJ 01—1 U_l X3 ^ CO 01 0) Uu-i c c C 3 —i oi c ~* _ tr cn-rt 10 to j£ JCz u u o 1 JJ 1 jj jj 10 01 u u u CO u o u o O t— t 01 oj BO 1 0) 0

  7. Designer Natriuretic Peptides

    Science.gov (United States)

    Lee, Candace Y. W.; Lieu, Hsiao; Burnett, John C.

    2011-01-01

    Designer natriuretic peptides (NPs) are novel hybrid peptides that are engineered from the native NPs through addition, deletion, or substitution of amino acid(s) with a goal toward optimization of pharmacological actions while minimizing undesirable effects. In this article, selected peptides that were designed in our laboratory are reviewed, and future directions for research and development of designer NPs are discussed. PMID:19158603

  8. PH dependent adhesive peptides

    Science.gov (United States)

    Tomich, John; Iwamoto, Takeo; Shen, Xinchun; Sun, Xiuzhi Susan

    2010-06-29

    A novel peptide adhesive motif is described that requires no receptor or cross-links to achieve maximal adhesive strength. Several peptides with different degrees of adhesive strength have been designed and synthesized using solid phase chemistries. All peptides contain a common hydrophobic core sequence flanked by positively or negatively charged amino acids sequences.

  9. Peptide Nucleic Acid Synthons

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  10. Peptide-Carrier Conjugation

    DEFF Research Database (Denmark)

    Hansen, Paul Robert

    2015-01-01

    To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined....

  11. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2003-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  12. Peptide Nucleic Acids (PNA)

    DEFF Research Database (Denmark)

    2002-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  13. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    1998-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  14. Accurate MALDI-TOF/TOF Sequencing of One-Bead−One-Compound Peptide Libraries with Application to the Identification of Multiligand Protein Affinity Agents Using in Situ Click Chemistry Screening

    OpenAIRE

    Lee, Su Seong; Lim, Jaehong; Tan, Sylvia; Cha, Junhoe; Yeo, Shi Yun; Agnew, Heather D.; Heath, James R.

    2010-01-01

    Combinatorial one-bead-one-compound (OBOC) peptide libraries are widely used for affinity screening, and the sequencing of peptides from hit beads is a key step in the process. For rapid sequencing, CNBr cleavage of the peptides from the beads, followed by de novo sequencing by MALDI-TOF/TOF is explored. We report on a semi-automated sequencing algorithm, and validate it through comparison against Edman degradation sequencing. The initial 44% sequencing success rate of the standard de novo se...

  15. Phage display of peptide / major histocompatibility class I complexes

    DEFF Research Database (Denmark)

    Vest Hansen, N; Ostergaard Pedersen, L; Stryhn, A

    2001-01-01

    Major histocompatibility complex class I (MHC-I) molecules sample peptides from the intracellular environment and present them to cytotoxic T cells (CTL). To establish a selection system, and, thereby, enable a library approach to identify the specificities involved (that of the MHC-I for peptides...... and subsequently that ot the T cell receptor for peptide-MHC-I complex), we have fused a single chain peptide-MHC-I complex to the phage minor coat protein, gpIII, and displayed it on filamentous phage. Expression of peptide-MHC-I complexes was shown with relevant conformation-specific monoclonal antibodies and......, more importantly, with a unique "T cell receptor-like" (i. e. peptide-specific, MHC-I-restricted) antibody. Thus, properly assembled and folded peptide-MHC-I complexes can be displayed on filamentous phage. Despite the successful display, interaction with T cells could not be demonstrated....

  16. Frequency and Distribution of Single-Nucleotide Polymorphisms within mprF in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides.

    Science.gov (United States)

    Bayer, Arnold S; Mishra, Nagendra N; Chen, Liang; Kreiswirth, Barry N; Rubio, Aileen; Yang, Soo-Jin

    2015-08-01

    MprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance in Staphylococcus aureus. (Note that although the official term is daptomycin nonsusceptibility, we use the term daptomycin resistance in this paper for ease of presentation.) Using 22 daptomycin-susceptible (DAP(s))/daptomycin-resistant (DAP(r)) clinical methicillin-resistant S. aureus (MRSA) strain pairs, we assessed (i) the frequencies and distribution of putative mprF gain-in-function SNPs, (ii) the relationships of the SNPs to both daptomycin resistance and cross-resistance to the prototypical endovascular host defense peptide (HDP) thrombin-induced platelet microbicidal protein (tPMP), and (iii) the impact of mprF SNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of the mprF SNPs identified in our DAP(r) strains were clustered within the two MprF loci, (i) the central bifunctional domain and (ii) the C-terminal synthase domain. Moreover, we were able to correlate the presence and location of mprF SNPs in DAP(r) strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAP(r) strains with mprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAP(r) strains with SNPs in the synthase domain, this relationship was not observed in positive surface charge assays. These results demonstrated that both charge-mediated and -unrelated mechanisms are involved in DAP resistance and HDP cross-resistance in S. aureus. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  17. Multimodal Imaging of Integrin Receptor-Positive Tumors by Bioluminescence, Fluorescence, Gamma Scintigraphy, and Single-Photon Emission Computed Tomography Using a Cyclic RGD Peptide Labeled with a Near-Infrared Fluorescent Dye and a Radionuclide

    Directory of Open Access Journals (Sweden)

    W. Barry Edwards

    2009-03-01

    Full Text Available Integrins, particularly the αvβ3 heterodimers, play important roles in tumor-induced angiogenesis and invasiveness. To image the expression pattern of the αvβ3 integrin in tumors through a multimodality imaging paradigm, we prepared a cyclic RGDyK peptide analogue (LS308 bearing a tetraazamacrocycle 1,4,7,10-tetraazacyclododecane-N, N′, N″, N‴-tetraacetic acid (DOTA and a lipophilic near-infrared (NIR fluorescent dye cypate. The αvβ3 integrin binding affinity and the internalization properties of LS308 mediated by the αvβ3 integrin in 4t1luc cells were investigated by receptor binding assay and fluorescence microscopy, respectively. The in vivo distribution of 111In-labeled LS308 in a 4t1luc tumor-bearing mouse model was studied by fluorescence, bioluminescence, planar gamma, and single-photon emission computed tomography (SPECT. The results show that LS308 has high affinity for αvβ3 integrin and internalized preferentially via the αvβ3 integrin-mediated endocytosis in 4t1luc cells. We also found that LS308 selectively accumulated in αvβ3-positve tumors in a receptor-specific manner and was visualized by the four imaging methods. Whereas the endogenous bioluminescence imaging identified the ensemble of the tumor tissue, the fluorescence and SPECT methods with the exogenous contrast agent LS308 reported the local expression of αvβ3 integrin. Thus, the multimodal imaging approach could provide important complementary diagnostic information for monitoring the efficacy of new antiangiogenic drugs.

  18. B-type natriuretic peptide as predictor of heart failure in patients with acute ST elevation myocardial infarction, single-vessel disease, and complete revascularization: follow-up study.

    LENUS (Irish Health Repository)

    Manola, Sime

    2012-01-31

    AIM: To assess the concentration of B-type natriuretic peptide (BNP) as a predictor of heart failure in patients with acute ST elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) with successful and complete revascularization. METHODS: Out of a total of 220 patients with acute STEMI admitted to the Sisters of Mercy University Hospital in the period January 1 to December 31, 2007, only patients with acute STEMI undergoing primary PCI who had single vessel disease and were successfully revascularized were included in the study. Selected patients had no history of myocardial infarction or heart failure and a normal or near-normal left ventricular ejection fraction (> or =50%) assessed by left ventriculography at admission. Only 58 patients met the inclusion criteria for the study. Out of those, 6 patients refused to participate in the study, and another 5 could not be followed up, so a total of 47 patients were evaluated. Blood samples were taken for measurement of BNP levels at admission, 24 hours later, and 7 days later. Patients were followed up for 1 year. The primary outcome was reduction in left ventricular ejection fraction (LVEF) to <50% after 1 year. RESULTS: Patients who developed echocardiographic signs of reduced systolic function defined as LVEF<50% had significantly higher values of BNP (> or =80 pg\\/mL) at 24 hours (P=0.001) and 7 days (P=0.020) after STEMI and successful reperfusion. Patients who had BNP levels > or =80 pg\\/mL after 7 days were 21 times more likely to develop LVEF<50 (odds ratio, 20.8; 95% confidence interval, 2.2-195.2; P=0.008). CONCLUSION: BNP can be used as a predictor of reduced systolic function in patients with STEMI who underwent successful reperfusion and had normal ejection fraction at admission.

  19. Jumping Hurdles: Peptides Able To Overcome Biological Barriers.

    Science.gov (United States)

    Sánchez-Navarro, Macarena; Teixidó, Meritxell; Giralt, Ernest

    2017-08-15

    diketoperazines (DKPs), (N-MePhe) n , or (PhPro) n . On the other hand, we have investigated BBB-shuttles that utilize active transport mechanisms such as SGV, THRre, or MiniAp-4. For the development of both groups, we have explored several approaches, such as the use of peptide libraries, both chemical and phage display, or hit-to-lead optimization processes. In this Account, we describe, in chronologic order, our contribution to the development of peptides able to overcome various biological barriers and our efforts to understand the mechanisms that they display. In addition, the potential use of both CPPs and BBB-shuttles to improve the transport of promising therapeutic compounds is described.

  20. Acylation of Therapeutic Peptides

    DEFF Research Database (Denmark)

    Trier, Sofie; Henriksen, Jonas Rosager; Jensen, Simon Bjerregaard

    to the harsh and selective gastrointestinal system, and development has lacked far behind injection therapy. Peptide acylation is a powerful tool to alter the pharmacokinetics, biophysical properties and chemical stability of injectable peptide drugs, primarily used to prolong blood circulation....... This work aims to characterize acylated analogues of two therapeutic peptides by systematically increasing acyl chain length in order to elucidate its influence on membrane interaction and intestinal cell translocation in vitro. The studied peptides are the 33 amino acid Glucagon-like peptide-2 (GLP-2...... peptides can increase in vitro intestinal permeability, modestly for GLP-2 and drastically for sCT, and might benefit oral delivery. GLP-2 results provide a well-founded predictive power for future peptide analogues, whereas sCT results hold great promise for future analogues, albeit with a larger...

  1. SHIELD-HIT12A - a Monte Carlo particle transport program for ion therapy research

    DEFF Research Database (Denmark)

    Bassler, Niels; Hansen, David Christoffer; Lühr, Armin

    2014-01-01

    . We experienced that new users quickly learn to use SHIELD-HIT12A and setup new geometries. Contrary to previous versions of SHIELD-HIT, the 12A distribution comes along with easy-to-use example files and an English manual. A new implementation of Vavilov straggling resulted in a massive reduction...... of computation time. Scheduled for later release are CT import and photon-electron transport. Conclusions: SHIELD-HIT12A is an interesting alternative ion transport engine. Apart from being a flexible particle therapy research tool, it can also serve as a back end for a MC ion treatment planning system. More...

  2. Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study.

    Science.gov (United States)

    Lamarre-Cliche, Maxime; Souich, Patrick du; Champlain, Jacques de; Larochelle, Pierre

    2008-09-01

    Midodrine is an alpha-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At Cmax, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL (P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm (P = 0.022). A significant correlation was found between DGM concentration and HR ( varphi -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous

  3. Cell Penetrating Peptides and Cationic Antibacterial Peptides

    Science.gov (United States)

    Rodriguez Plaza, Jonathan G.; Morales-Nava, Rosmarbel; Diener, Christian; Schreiber, Gabriele; Gonzalez, Zyanya D.; Lara Ortiz, Maria Teresa; Ortega Blake, Ivan; Pantoja, Omar; Volkmer, Rudolf; Klipp, Edda; Herrmann, Andreas; Del Rio, Gabriel

    2014-01-01

    Cell penetrating peptides (CPP) and cationic antibacterial peptides (CAP) have similar physicochemical properties and yet it is not understood how such similar peptides display different activities. To address this question, we used Iztli peptide 1 (IP-1) because it has both CPP and CAP activities. Combining experimental and computational modeling of the internalization of IP-1, we show it is not internalized by receptor-mediated endocytosis, yet it permeates into many different cell types, including fungi and human cells. We also show that IP-1 makes pores in the presence of high electrical potential at the membrane, such as those found in bacteria and mitochondria. These results provide the basis to understand the functional redundancy of CPPs and CAPs. PMID:24706763

  4. Radial junction solar cells based on heterojunction with intrinsic thin layer (HIT) structure

    Science.gov (United States)

    Shen, Haoting

    The radial junction wire array structure was previously proposed as a solar cell geometry to separate the direction of carrier collection from the direction of light absorption, thereby circumventing the need to use high quality but expensive single crystal silicon (c-Si) material that has long minority carrier diffusion lengths. The Si radial junction structure can be realized by forming radial p-n junctions on Si pillar/wire arrays that have a diameter comparable to the minority carrier diffusion length. With proper design, the Si pillar arrays are also able to enhance light trapping and thereby increase the light absorption. However, the larger junction area and surface area on the pillar arrays compared to traditional planar junction Si solar cells makes it challenging to fabricate high performance devices due an in increase in surface defects. Therefore, effective surface passivation strategies are essential for radial junction devices. Hydrogenated amorphous silicon (a-Si:H) deposited by plasma-enhanced chemical vapor deposition (PECVD) using a heterojunction with intrinsic thin layer (HIT) structure has previously been demonstrated as a very effective surface passivation layer for planar c-Si solar cells. It is therefore of interest to use a-Si:H in a HIT layer structure for radial p-n junction c-Si pillar array solar cells. This poses several challenges, however, including the need to fabricate ultra-thin a-Si:H layers conformally on high aspect ratio Si pillars, control the crystallinity at the a-Si:H/c-Si interface to yield a low interface state density and optimize the layer thicknesses, doping and contacts to yield high performance devices. This research in this thesis was aimed at developing the processing technology required to apply the HIT structure to radial junction Si pillar array solar cell devices and to evaluate the device characteristics. Initial studies focused on understanding the effects of process conditions on the growth rate and

  5. Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update.

    Science.gov (United States)

    Galanopoulou, Aristea S; Mowrey, Wenzhu B; Liu, Wei; Li, Qianyun; Shandra, Oleksii; Moshé, Solomon L

    2017-07-01

    Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide. On PN5 p-chlorophenylalanine was given intraperitoneally (i.p.). Daily monitoring of weights and developmental milestones was done and rats were intermittently video monitored. A blinded, randomized, vehicle-controlled study design was followed. The caspase 1 inhibitor VX-765 (50-200 mg/kg i.p.) and the GABA B receptor inhibitor CGP35348 (12.5-100 mg/kg i.p.) each was administered in different cohorts as single intraperitoneal injections on PN4, using a dose- and time-response design with intermittent monitoring till PN5. 17β-estradiol (40 ng/g/day subcutaneously) was given daily between PN3-10 and intermittent monitoring was done till PN12. None of the treatments demonstrated acute or delayed effects on spasms, yet all were well tolerated. We discuss the implications for therapy discovery and challenges of replication trials.

  6. Peptide pool immunization and CD8+ T cell reactivity

    DEFF Research Database (Denmark)

    Rasmussen, Susanne B; Harndahl, Mikkel N; Buus, Anette Stryhn

    2013-01-01

    Mice were immunized twice with a pool of five peptides selected among twenty 8-9-mer peptides for their ability to form stable complexes at 37°C with recombinant H-2K(b) (half-lives 10-15h). Vaccine-induced immunity of splenic CD8(+) T cells was studied in a 24h IFNγ Elispot assay. Surprisingly......, IFNγ spot-formation was observed without addition of peptide to the assay culture at 3 weeks and 3 months after immunization. To clarify if IFNγ spot formation in the absence of peptide exposure ex vivo is caused by the peptide-pool per se, mice were immunized with single peptides. Three of the five...... peptides induced normal peptide immunity i.e. the specific T cell reactivity in the Elispot culture was strictly dependent on exposure to the immunizing peptide ex vivo. However, immunization with two of the peptides, a VSV- and a Mycobacterium-derived peptide, resulted in IFNγ spot formation without...

  7. Peptide fibrils with altered stability, activity, and cell selectivity.

    Science.gov (United States)

    Chen, Long; Liang, Jun F

    2013-07-08

    Peptides have some unique and superior features compared to proteins. However, the use of peptides as therapeutics is hampered by their low stability and cell selectivity. In this study, a new lytic peptide (CL-1, FLGALFRALSRLL) was constructed. Under the physiological condition, peptide CL-1 self-assembled into dynamically stable aggregates with fibrils-like structures. Aggregated CL-1 demonstrated dramatically altered activity and stability in comparison with single molecule CL-1 and other lytic peptides: when incubated with cocultured bacteria and tissue cells, CL-1 aggregates killed bacteria selectively but spared cocultured human cells; CL-1 aggregates were kept intact in human serum for more than five hours. Peptide-cell interaction studies performed on lipid monolayers and live human tissue cells revealed that in comparison with monomeric CL-1, aggregated CL-1 had decreased cell affinity and membrane insertion capability on tissue cells. A dynamic process involving aggregate dissociation and rearrangement seemed to be an essential step for membrane bound CL-1 aggregates to realize its cytotoxicity to tissue cells. Our study suggests that peptide aggregation could be as important as the charge and secondary structure of a peptide in affecting peptide-cell interactions. Controlling peptide self-assembly represents a new way to increase the stability and cell selectivity of bioactive peptides for wide biomedical applications.

  8. Plant peptide hormone signalling.

    Science.gov (United States)

    Motomitsu, Ayane; Sawa, Shinichiro; Ishida, Takashi

    2015-01-01

    The ligand-receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone-receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions. © 2015 Authors; published by Portland Press Limited.

  9. Single administration of p2TA (AB103, a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice.

    Directory of Open Access Journals (Sweden)

    Salida Mirzoeva

    Full Text Available The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103 that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C, Peptide (P; 5 mg/kg of p2TA peptide, Radiation (R; total body irradiation with 8 Gy γ-rays, and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later. Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1 and inflammation (COX-2 markers, as well as the presence of macrophages (F4/80. Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.

  10. The T10 beam produces a few hits per event. In ALICE the SSD will have to cope with many hits per strip. In the three centimeters of aluminium the beam will produce many secondary particles. This increases the chance of multiple hits per strip, although not to the level in ALICE.

    CERN Multimedia

    Nooren, G.

    2004-01-01

    The T10 beam produces a few hits per event. In ALICE the SSD will have to cope with many hits per strip. In the three centimeters of aluminium the beam will produce many secondary particles. This increases the chance of multiple hits per strip, although not to the level in ALICE.

  11. HIT Solar Cells with N-Type Low-Cost Metallurgical Si

    Directory of Open Access Journals (Sweden)

    Xing Yang

    2018-01-01

    Full Text Available A conversion efficiency of 20.23% of heterojunction with intrinsic thin layer (HIT solar cell on 156 mm × 156 mm metallurgical Si wafer has been obtained. Applying AFORS-HET software simulation, HIT solar cell with metallurgical Si was investigated with regard to impurity concentration, compensation level, and their impacts on cell performance. It is known that a small amount of impurity in metallurgical Si materials is not harmful to solar cell properties.

  12. USER FRUSTRATION IN HIT INTERFACES: EXPLORING PAST HCI RESEARCH FOR A BETTER UNDERSTANDING OF CLINICIANS' EXPERIENCES.

    Science.gov (United States)

    Opoku-Boateng, Gloria A

    2015-01-01

    User frustration research has been one way of looking into clinicians' experience with health information technology use and interaction. In order to understand how clinician frustration with Health Information Technology (HIT) use occurs, there is the need to explore Human-Computer Interaction (HCI) literature that addresses both frustration and HIT use. In the past three decades, HCI frustration research has increased and expanded. Researchers have done a lot of work to understand emotions, end-user frustration and affect. This paper uses a historical literature review approach to review the origins of emotion and frustration research and explore the research question; Does HCI research on frustration provide insights on clinicians' frustration with HIT interfaces? From the literature review HCI research on emotion and frustration provides additional insights that can indeed help explain user frustration in HIT. Different approaches and HCI perspectives also help frame HIT user frustration research as well as inform HIT system design. The paper concludes with a suggested directions on how future design and research may take.

  13. USER FRUSTRATION IN HIT INTERFACES: EXPLORING PAST HCI RESEARCH FOR A BETTER UNDERSTANDING OF CLINICIANS’ EXPERIENCES

    Science.gov (United States)

    Opoku-Boateng, Gloria A.

    2015-01-01

    User frustration research has been one way of looking into clinicians’ experience with health information technology use and interaction. In order to understand how clinician frustration with Health Information Technology (HIT) use occurs, there is the need to explore Human-Computer Interaction (HCI) literature that addresses both frustration and HIT use. In the past three decades, HCI frustration research has increased and expanded. Researchers have done a lot of work to understand emotions, end-user frustration and affect. This paper uses a historical literature review approach to review the origins of emotion and frustration research and explore the research question; Does HCI research on frustration provide insights on clinicians’ frustration with HIT interfaces? From the literature review HCI research on emotion and frustration provides additional insights that can indeed help explain user frustration in HIT. Different approaches and HCI perspectives also help frame HIT user frustration research as well as inform HIT system design. The paper concludes with a suggested directions on how future design and research may take. PMID:26958238

  14. Are stripes beneficial? Dazzle camouflage influences perceived speed and hit rates.

    Directory of Open Access Journals (Sweden)

    Bettina von Helversen

    Full Text Available In the animal kingdom, camouflage refers to patterns that help potential prey avoid detection. Mostly camouflage is thought of as helping prey blend in with their background. In contrast, disruptive or dazzle patterns protect moving targets and have been suggested as an evolutionary force in shaping the dorsal patterns of animals. Dazzle patterns, such as stripes and zigzags, are thought to reduce the probability with which moving prey will be captured by impairing predators' perception of speed. We investigated how different patterns of stripes (longitudinal-i.e., parallel to movement direction-and vertical-i.e., perpendicular to movement direction affect the probability with which humans can hit moving objects and if differences in hitting probability are caused by a misperception of speed. A first experiment showed that longitudinally striped objects were hit more often than unicolored objects. However, vertically striped objects did not differ from unicolored objects. A second study examining the link between perceived speed and hitting probability showed that longitudinally and vertically striped objects were both perceived as moving faster and were hit more often than unicolored objects. In sum, our results provide evidence that striped patterns disrupt the perception of speed, which in turn influences how often objects are hit. However, the magnitude and the direction of the effects depend on additional factors such as speed and the task setup.

  15. The rationale and design of the national familial hypercholesterolemia registries in Turkey: A-HIT1 and A-HIT2 studies.

    Science.gov (United States)

    Kayıkçıoğlu, Meral; Tokgözoğlu, Lale

    2017-04-01

    Familial hypercholesterolemia (FH) is a genetic disease characterized by extremely high levels of cholesterol, leading to premature atherosclerosis. Although many countries have already addressed the burden of FH by means of national registries, Turkey has no national FH registry or national screening program to detect FH. Creation of a series of FH registries is planned as part of Turkish FH Initiative endorsed by the Turkish Society of Cardiology to meet this need. This article provides detailed information on the rationale and design of the first 2 FH registries (A-HIT1 and A-HIT2). A-HIT1 is a nationwide survey of adult homozygous FH (HoFH) patients undergoing low-density lipoprotein (LDL) apheresis (LA) in Turkey. A-HIT1 will provide insight into the clinical status of HoFH patients undergoing LA. Primary objective of this cross-sectional study is to identify how HoFH patients on LA are managed. Inclusion criteria are age >12 years, diagnosis of HoFH, and regular LA treatment. All available apheresis centers were electronically invited to participate in the study. The principal physicians of each center will respond to a questionnaire regarding their attitude toward LA. For each patient, another questionnaire will be used to collect data on clinical status, medication use, and disease data. In addition, patients will be asked to complete self-report questionnaires that provide information on quality of life, disease-related anxiety, and depression. A-HIT2 is a registry of adult FH patients presenting at outpatient clinics. At least 1000 FH patients will be recruited from 30 outpatient clinics representing the 12 statistical regions in Turkey based on the EU NUTS classification. Sites specializing in cardiology, internal medicine, and endocrinology were invited to participate. The primary objective of this cross-sectional study is to determine clinical status and management of patients in Turkey diagnosed with FH. Eligibility for screening was defined as having

  16. Characterization of a single peptide derived from cytochrome P4501B1 that elicits spontaneous human leukocyte antigen (HLA)-A1 as well as HLA-B35 restricted CD8 T-cell responses in cancer patients

    DEFF Research Database (Denmark)

    Kvistborg, P.; Hadrup, S.R.; Andersen, M.H.

    2008-01-01

    Cytochrome P450 1B1 (CYP1B1) is widely expressed in human malignancies, but silent in most normal tissues. Importantly, the protein is believed to play an important role in the survival and growth of cancer cells in a stressed environment, e.g., as a result of hypoxia or chemotherapy. Thus......, targeting of CYP1B1 represents a potentially successful strategy in the treatment of metastatic cancer, e.g., by therapeutic vaccination. Herein, we describe the characterization of a novel peptide from the CYP1B1 protein (CYP240), which is spontaneously recognized by CD8 T cells in cancer patients....... Rare but strong responses were detected in HLA-A1-positive patients, and more frequent responses were detected in HLA-B35-positive patients. No reactivity against the peptide could be detected in healthy donors. Furthermore, we demonstrated that peptide-specific T cells were able to lyze target cells...

  17. Antimicrobial Peptides in Reptiles

    Science.gov (United States)

    van Hoek, Monique L.

    2014-01-01

    Reptiles are among the oldest known amniotes and are highly diverse in their morphology and ecological niches. These animals have an evolutionarily ancient innate-immune system that is of great interest to scientists trying to identify new and useful antimicrobial peptides. Significant work in the last decade in the fields of biochemistry, proteomics and genomics has begun to reveal the complexity of reptilian antimicrobial peptides. Here, the current knowledge about antimicrobial peptides in reptiles is reviewed, with specific examples in each of the four orders: Testudines (turtles and tortosises), Sphenodontia (tuataras), Squamata (snakes and lizards), and Crocodilia (crocodilans). Examples are presented of the major classes of antimicrobial peptides expressed by reptiles including defensins, cathelicidins, liver-expressed peptides (hepcidin and LEAP-2), lysozyme, crotamine, and others. Some of these peptides have been identified and tested for their antibacterial or antiviral activity; others are only predicted as possible genes from genomic sequencing. Bioinformatic analysis of the reptile genomes is presented, revealing many predicted candidate antimicrobial peptides genes across this diverse class. The study of how these ancient creatures use antimicrobial peptides within their innate immune systems may reveal new understandings of our mammalian innate immune system and may also provide new and powerful antimicrobial peptides as scaffolds for potential therapeutic development. PMID:24918867

  18. Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Darrell R.

    2012-10-25

    The purpose of this project is to develop a new radiolabeled peptide for imaging and treating metastatic melanoma. The immunoconjugate consists of a receptor-specific peptide that targets melanoma cells. The beta-emitter lead-212 (half-life = 10.4 hours) is linked by coordination chemistry to the peptide. After injection, the peptide targets melanoma receptors on the surfaces of melanoma cells. Lead-212 decays to the alpha-emitter bismuth-212 (half-life = 60 minutes). Alpha-particles that hit melanoma cell nuclei are likely to kill the melanoma cell. For cancer cell imaging, the lead-212 is replaced by lead-203 (half-life = 52 hours). Lead-203 emits 279 keV photons (80.1% abundance) that can be imaged and measured for biodistribution analysis, cancer imaging, and quantitative dosimetry.

  19. Age-dependent values of N-terminal pro-B-type natriuretic peptide are superior to a single cut-point for ruling out suspected systolic dysfunction in primary care

    DEFF Research Database (Denmark)

    Hildebrandt, Per; Collinson, Paul O; Doughty, Robert N

    2010-01-01

    The study evaluated the use of age-related decision limits for N-terminal pro-B-type natriuretic peptide (NT-proBNP), for ruling out suspected systolic dysfunction in symptomatic patients in primary care, compared with the present standards.......The study evaluated the use of age-related decision limits for N-terminal pro-B-type natriuretic peptide (NT-proBNP), for ruling out suspected systolic dysfunction in symptomatic patients in primary care, compared with the present standards....

  20. Coffee, hunger, and peptide YY.

    Science.gov (United States)

    Greenberg, James A; Geliebter, Allan

    2012-06-01

    There is evidence from several empirical studies suggesting that coffee may help people control body weight. Our objective was to assess the effects of caffeine, caffeinated coffee, and decaffeinated coffee, both alone and in combination with 75 g of glucose, on perceived hunger and satiety and related peptides. We conducted a placebo-controlled single-blinded randomized 4-way crossover trial. Eleven healthy male volunteers (mean age, 23.5 ± 5.7 years; mean BMI, 23.6 ± 4.2 kg/m(2)) ingested 1 of 3 test beverages (caffeine in water, caffeinated coffee, or decaffeinated coffee) or placebo (water), and 60 minutes later they ingested the glucose. Eight times during each laboratory visit, hunger and satiety were assessed by visual analog scales, and blood samples were drawn to measure 3 endogenous peptides associated with hunger and satiety: ghrelin, peptide YY (PYY), and leptin. Compared to placebo, decaffeinated coffee yielded significantly lower hunger during the whole 180-minute study period and higher plasma PYY for the first 90 minutes (p hunger or PYY. Caffeinated coffee showed a pattern between that of decaffeinated coffee and caffeine in water. These findings suggest that one or more noncaffeine ingredients in coffee may have the potential to decrease body weight. Glucose ingestion did not change the effects of the beverages. Our randomized human trial showed that decaffeinated coffee can acutely decrease hunger and increase the satiety hormone PYY.

  1. An efficient method for isolating antibody fragments against small peptides by antibody phage display

    DEFF Research Database (Denmark)

    Duan, Zhi; Siegumfeldt, Henrik

    2010-01-01

    We generated monoclonal scFv (single chain variable fragment) antibodies from an antibody phage display library towards three small synthetic peptides derived from the sequence of s1-casein. Key difficulties for selection of scFv-phages against small peptides were addressed. Small peptides do...

  2. Comprehensive computational design of ordered peptide macrocycles

    Energy Technology Data Exchange (ETDEWEB)

    Hosseinzadeh, Parisa; Bhardwaj, Gaurav; Mulligan, Vikram K.; Shortridge, Matthew D.; Craven, Timothy W.; Pardo-Avila, Fatima; Rettie, Stephan A.; Kim, David E.; Silva, Daniel A.; Ibrahim, Yehia M.; Webb, Ian K.; Cort, John R.; Adkins, Joshua N.; Varani, Gabriele; Baker, David

    2017-12-14

    Mixed chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to-date, but there is currently no way to systematically search through the structural space spanned by such compounds for new drug candidates. Natural proteins do not provide a useful guide: peptide macrocycles lack regular secondary structures and hydrophobic cores and have different backbone torsional constraints. Hence the development of new peptide macrocycles has been approached by modifying natural products or using library selection methods; the former is limited by the small number of known structures, and the latter by the limited size and diversity accessible through library-based methods. To overcome these limitations, here we enumerate the stable structures that can be adopted by macrocyclic peptides composed of L and D amino acids. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. We synthesize and characterize by NMR twelve 7-10 residue macrocycles, 9 of which have structures very close to the design models in solution. NMR structures of three 11-14 residue bicyclic designs are also very close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide based macrocycles unparalleled for other molecular systems, and vastly increase the available starting scaffolds for both rational drug design and library selection methods.

  3. CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms.

    Science.gov (United States)

    Briggs, Stephen W; Mowrey, Wenzhu; Hall, Charles B; Galanopoulou, Aristea S

    2014-01-01

    Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a γ-aminobutyric acid (GABA) aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP-115; Catalyst Pharmaceutical Partners, Inc., Coral Gables, FL, U.S.A.) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP-115 in reducing spasms and its tolerability in the multiple-hit rat model of IS, in which daily vigabatrin reduced spasms for only one day, but was not well tolerated. Male rats were treated with the protocol of the multiple-hit model of IS on postnatal day 3 (PN3). Using a randomized, blinded, vehicle-controlled, dose-response study design, CPP-115 (0.1, 1, or 5 mg/kg intraperitoneally [i.p.]) or vehicle was given daily (PN4-12) or as a single injection (PN7) after spasm onset. Intermittent video- or video-electroencephalography (EEG) monitoring was done. Secondary end points included the following: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3-20), horizontal bar (PN13-20), and Barnes maze (PN16-19). Statistics used a linear mixed model of raw or normalized log-transformed data, taking into account the repeated observations on each animal. The lower CPP-115 doses (0.1-1 mg/kg/day, PN4-12) reduced spasms between PN6 and 7 without increasing mortality. CPP-115 at 5 mg/kg/day (PN4-12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP-115 injection (1 mg/kg, i.p.) decreased electroclinical spasms acutely but transiently. CPP-115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasm cessation. CPP-115 did not alter neurodevelopmental outcomes or visuospatial learning. We provide proof-of-concept evidence that CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of IS at considerably lower and better tolerated doses than vigabatrin

  4. Insulin C-peptide test

    Science.gov (United States)

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin the body produces and insulin someone injects ...

  5. A robotic object hitting task to quantify sensorimotor impairments in participants with stroke.

    Science.gov (United States)

    Tyryshkin, Kathrin; Coderre, Angela M; Glasgow, Janice I; Herter, Troy M; Bagg, Stephen D; Dukelow, Sean P; Scott, Stephen H

    2014-04-02

    Existing clinical scores of upper limb function often use observer-based ordinal scales that are subjective and commonly have floor and ceiling effects. The purpose of the present study was to develop an upper limb motor task to assess objectively the ability of participants to select and engage motor actions with both hands. A bilateral robotic system was used to quantify upper limb sensorimotor function of participants with stroke. Participants performed an object hit task that required them to hit virtual balls moving towards them in the workspace with virtual paddles attached to each hand. Task difficulty was initially low, but increased with time by increasing the speed and number of balls in the workspace. Data were collected from 262 control participants and 154 participants with recent stroke. Control participants hit ~60 to 90% of the 300 balls with relatively symmetric performance for the two arms. Participants with recent stroke performed the task with most participants hitting fewer balls than 95% of healthy controls (67% of right-affected and 87% of left-affected strokes). Additionally, nearly all participants (97%) identified with visuospatial neglect hit fewer balls than healthy controls. More detailed analyses demonstrated that most participants with stroke displayed asymmetric performance between their affected and non-affected limbs with regards to number of balls hit, workspace area covered by the limb and hand speed. Inter-rater reliability of task parameters was high with half of the correlations above 0.90. Significant correlations were observed between many of the task parameters and the Functional Independence Measure and/or the Behavioural Inattention Test. As this object hit task requires just over two minutes to complete, it provides an objective and easy approach to quantify upper limb motor function and visuospatial skills following stroke.

  6. Age-dependent values of N-terminal pro-B-type natriuretic peptide are superior to a single cut-point for ruling out suspected systolic dysfunction in primary care

    DEFF Research Database (Denmark)

    Hildebrandt, Per; Collinson, Paul O; Doughty, Robert N

    2010-01-01

    The study evaluated the use of age-related decision limits for N-terminal pro-B-type natriuretic peptide (NT-proBNP), for ruling out suspected systolic dysfunction in symptomatic patients in primary care, compared with the present standards....

  7. One For All? Hitting multiple Alzheimer’s Disease targets with one drug

    Directory of Open Access Journals (Sweden)

    Rebecca Ellen Hughes

    2016-04-01

    Full Text Available Alzheimer’s disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs. Intended as a introduction for non-experts, this review describes the key multi-target drug design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch and also the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer’s Disease are rasagiline, originally developed for the treatment of Parkinson’s Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

  8. Anticipating mismatches of HIT investments: Developing a viability-fit model for e-health services.

    Science.gov (United States)

    Mettler, Tobias

    2016-01-01

    Albeit massive investments in the recent years, the impact of health information technology (HIT) has been controversial and strongly disputed by both research and practice. While many studies are concerned with the development of new or the refinement of existing measurement models for assessing the impact of HIT adoption (ex post), this study presents an initial attempt to better understand the factors affecting viability and fit of HIT and thereby underscores the importance of also having instruments for managing expectations (ex ante). We extend prior research by undertaking a more granular investigation into the theoretical assumptions of viability and fit constructs. In doing so, we use a mixed-methods approach, conducting qualitative focus group discussions and a quantitative field study to improve and validate a viability-fit measurement instrument. Our findings suggest two issues for research and practice. First, the results indicate that different stakeholders perceive HIT viability and fit of the same e-health services very unequally. Second, the analysis also demonstrates that there can be a great discrepancy between the organizational viability and individual fit of a particular e-health service. The findings of this study have a number of important implications such as for health policy making, HIT portfolios, and stakeholder communication. Copyright © 2015. Published by Elsevier Ireland Ltd.

  9. Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach

    Directory of Open Access Journals (Sweden)

    Grace Mugumbate

    2017-09-01

    Full Text Available Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC50 below 50 μM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.

  10. Hit expansion approaches using multiple similarity methods and virtualized query structures.

    Science.gov (United States)

    Bergner, Andreas; Parel, Serge P

    2013-05-24

    Ligand-based virtual screening and computational hit expansion methods undoubtedly facilitate the finding of novel active chemical entities, utilizing already existing knowledge of active compounds. It has been demonstrated that the parallel execution of complementary similarity search methods enhances the performance of such virtual screening campaigns. In this article, we examine the use of virtualized template (query, seed) structures as an extension to common search methods, such as fingerprint and pharmacophore graph-based similarity searches. We demonstrate that template virtualization by bioisosteric enumeration and other rule-based methods, in combination with standard similarity search techniques, represents a powerful approach for hit expansion following high-throughput screening campaigns. The reliability of the methods is demonstrated by four different test data sets representing different target classes and two hit finding case studies on the epigenetic targets G9a and LSD1.

  11. Reviewing hit discovery literature for difficult targets: glutathione transferase omega-1 as an example.

    Science.gov (United States)

    Xie, Yiyue; Dahlin, Jayme L; Oakley, Aaron J; Casarotto, Marco G; Board, Philip G; Baell, Jonathan B

    2018-04-13

    Early-stage drug discovery reporting on relatively new or difficult targets is often associated with insufficient hit triage. Literature reviews of such targets seldom delve into the detail required to critically analyze the associated screening hits reported. Here we take the enzyme GSTO1-1 as an example of a relatively difficult target and review the associated literature involving small-molecule inhibitors. As part of this process we deliberately play closer-than-usual attention to assay interference and hit quality aspects. We believe this Perspective will be a useful guide for future development of GSTO1-1 inhibitors, as well serving as a template for future review formats of new or difficult targets.

  12. #MaybeHeDoesntHitYou: Social Media Underscore the Realities of Intimate Partner Violence.

    Science.gov (United States)

    McCauley, Heather L; Bonomi, Amy E; Maas, Megan K; Bogen, Katherine W; O'Malley, Teagen L

    2018-03-22

    Public intimate partner violence (IPV) discourse emphasizes physical violence. In May 2016, the Twitter hashtag #MaybeHeDoesntHitYou generated a public conversation about abuse beyond physical IPV. Because of the often-disconnect between IPV research and what survivors struggle to name as abuse in their daily lives, we sought to understand how IPV discourse was unfolding as a result of the #MaybeHeDoesntHitYou hashtag. NCapture was used to collect publically available Twitter data containing the hashtag "#MaybeHeDoesntHitYou" from May 10, 2016 to May 17, 2016. Using the Duluth Power and Control Wheel (a range of tactics used by abusers to control and harm their partners) and the Women's Experience with Battering (WEB) framework (emotional and behavioral responses to being abused), we analyzed 1,229 original content tweets using qualitative content analysis. All dimensions of the Power and Control Wheel and five of six dimensions of the WEB framework were expressed via #MaybeHeDoesntHitYou; users did not express yearning for intimacy with their abusive partners. Users described one form of IPV not currently represented within the Power and Control Wheel-reproductive coercion (e.g., "#MaybeHeDoesntHitYou but he refuses to use condoms and forces you not to use contraception so you try to do it behind his back"). Two additional themes emerged; users challenged the gender pronoun of the hashtag, highlighting that abuse may happen with partners of all genders, and users provided social support for others (e.g., "#MaybeHeDoesntHitYou is real. Bruises and scars aren't the only measure of abuse! If this is you, help is there…"). Results from our study underscore the potential for social media platforms to be powerful agents for engaging public dialogue about the realities of IPV, as well as a space for seeking and providing social support about this critical women's health issue.

  13. Descriptors for antimicrobial peptides

    DEFF Research Database (Denmark)

    Jenssen, Håvard

    2011-01-01

    Introduction: A frightening increase in the number of isolated multidrug resistant bacterial strains linked to the decline in novel antimicrobial drugs entering the market is a great cause for concern. Cationic antimicrobial peptides (AMPs) have lately been introduced as a potential new class...... of antimicrobial drugs, and computational methods utilizing molecular descriptors can significantly accelerate the development of new peptide drug candidates. Areas covered: This paper gives a broad overview of peptide and amino-acid scale descriptors available for AMP modeling and highlights which...

  14. On hitting children: a review of corporal punishment in the United States.

    Science.gov (United States)

    Knox, Michele

    2010-01-01

    Research has clearly demonstrated associations between corporal punishment of children and maladaptive behavior patterns such as aggression and delinquency. Hitting children is an act of violence and a clear violation of children's human rights. In this article, the position of the United States on corporal punishment of children is discussed. Professional and international progress on ending corporal punishment is explained, and the relationship between corporal punishment and child abuse is discussed. An appeal is made for prevention efforts such as parent education and removal of social sanctions for hitting children that may hold significant promise for preventing child maltreatment.

  15. Improvements to the ion Doppler spectrometer diagnostic on the HIT-SI experiments

    Science.gov (United States)

    Hossack, Aaron; Chandra, Rian; Everson, Chris; Jarboe, Tom

    2018-03-01

    An ion Doppler spectrometer diagnostic system measuring impurity ion temperature and velocity on the HIT-SI and HIT-SI3 spheromak devices has been improved with higher spatiotemporal resolution and lower error than previously described devices. Hardware and software improvements to the established technique have resulted in a record of 6.9 μs temporal and ≤2.8 cm spatial resolution in the midplane of each device. These allow Ciii and Oii flow, displacement, and temperature profiles to be observed simultaneously. With 72 fused-silica fiber channels in two independent bundles, and an f/8.5 Czerny-Turner spectrometer coupled to a video camera, frame rates of up to ten times the imposed magnetic perturbation frequency of 14.5 kHz were achieved in HIT-SI, viewing the upper half of the midplane. In HIT-SI3, frame rates of up to eight times the perturbation frequency were achieved viewing both halves of the midplane. Biorthogonal decomposition is used as a novel filtering tool, reducing uncertainty in ion temperature from ≲13 to ≲5 eV (with an instrument temperature of 8-16 eV) and uncertainty in velocity from ≲2 to ≲1 km/s. Doppler shift and broadening are calculated via the Levenberg-Marquardt algorithm, after which the errors in velocity and temperature are uniquely specified. Axisymmetric temperature profiles on HIT-SI3 for Ciii peaked near the inboard current separatrix at ≈40 eV are observed. Axisymmetric plasma displacement profiles have been measured on HIT-SI3, peaking at ≈6 cm at the outboard separatrix. Both profiles agree with the upper half of the midplane observable by HIT-SI. With its complete midplane view, HIT-SI3 has unambiguously extracted axisymmetric, toroidal current dependent rotation of up to 3 km/s. Analysis of the temporal phase of the displacement uncovers a coherent structure, locked to the applied perturbation. Previously described diagnostic systems could not achieve such results.

  16. Numerical Simulations of Tungsten Targets Hit by LHC Proton Beam

    CERN Document Server

    Peroni, L; Bertarelli, A; Dallocchio, A

    2011-01-01

    The unprecedented energy intensities of modern hadron accelerators yield special problems with the materials that are placed close to or into the high intensity beams. The energy stored in a single beam of LHC particle accelerator is equivalent to about 80 kg of TNT explosive, stored in a transverse beam area with a typical value of 0.2 mm×0.2 mm. The materials placed close to the beam are used at, or even beyond, their damage limits. However, it is very difficult to predict structural efficiency and robustness accurately: beam-induced damage for high energy and high intensity occurs in a regime where practical experience does not exist. The interaction between high energy particle beams and metals induces a sudden non uniform temperature increase. This provokes a dynamic response of the structure entailing thermal stress waves and thermally induced vibrations or even the failure of the component. This study is performed in order to estimate the damage on a tungsten component due to the impact with a proton ...

  17. Anisotropic Membrane Curvature Sensing by Amphipathic Peptides.

    Science.gov (United States)

    Gómez-Llobregat, Jordi; Elías-Wolff, Federico; Lindén, Martin

    2016-01-05

    Many proteins and peptides have an intrinsic capacity to sense and induce membrane curvature, and play crucial roles for organizing and remodeling cell membranes. However, the molecular driving forces behind these processes are not well understood. Here, we describe an approach to study curvature sensing by simulating the interactions of single molecules with a buckled lipid bilayer. We analyze three amphipathic antimicrobial peptides, a class of membrane-associated molecules that specifically target and destabilize bacterial membranes, and find qualitatively different sensing characteristics that would be difficult to resolve with other methods. Our findings provide evidence for direction-dependent curvature sensing mechanisms in amphipathic peptides and challenge existing theories of hydrophobic insertion. The buckling approach is generally applicable to a wide range of curvature-sensing molecules, and our results provide strong motivation to develop new experimental methods to track position and orientation of membrane proteins. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  18. Viral O-GalNAc peptide epitopes

    DEFF Research Database (Denmark)

    Olofsson, Sigvard; Blixt, Klas Ola; Bergström, Tomas

    2016-01-01

    meningitis patients, CSF antibodies are focussed to only one single glycoform peptide of a major viral glycoprotein. Thus, dependent on the viral disease, the serological response may be variable or constant with respect to the number of targeted peptide glycoforms. Mapping of these epitopes relies......Viral envelope glycoproteins are major targets for antibodies that bind to and inactivate viral particles. The capacity of a viral vaccine to induce virus-neutralizing antibodies is often used as a marker for vaccine efficacy. Yet the number of known neutralization target epitopes is restricted...... owing to various viral escape mechanisms. We expand the range of possible viral glycoprotein targets, by presenting a previously unknown type of viral glycoprotein epitope based on a short peptide stretch modified with small O-linked glycans. Besides being immunologically active, these epitopes have...

  19. RAId_DbS: Peptide Identification using Database Searches with Realistic Statistics

    Directory of Open Access Journals (Sweden)

    Ogurtsov Aleksey Y

    2007-10-01

    Full Text Available Abstract Background The key to mass-spectrometry-based proteomics is peptide identification. A major challenge in peptide identification is to obtain realistic E-values when assigning statistical significance to candidate peptides. Results Using a simple scoring scheme, we propose a database search method with theoretically characterized statistics. Taking into account possible skewness in the random variable distribution and the effect of finite sampling, we provide a theoretical derivation for the tail of the score distribution. For every experimental spectrum examined, we collect the scores of peptides in the database, and find good agreement between the collected score statistics and our theoretical distribution. Using Student's t-tests, we quantify the degree of agreement between the theoretical distribution and the score statistics collected. The T-tests may be used to measure the reliability of reported statistics. When combined with reported P-value for a peptide hit using a score distribution model, this new measure prevents exaggerated statistics. Another feature of RAId_DbS is its capability of detecting multiple co-eluted peptides. The peptide identification performance and statistical accuracy of RAId_DbS are assessed and compared with several other search tools. The executables and data related to RAId_DbS are freely available upon request.

  20. Boosting with intranasal dendrimeric Aβ1–15 but not Aβ1–15 peptide leads to an effective immune response following a single injection of Aβ1–40/42 in APP-tg mice

    Directory of Open Access Journals (Sweden)

    Thomas Katelyn

    2006-06-01

    Full Text Available Abstract Background Immunotherapy for Alzheimer's disease (AD is emerging as a potential treatment. However, a clinical trial (AN1792 was halted after adverse effects occurred in a small subset of subjects, which may have been caused by a T cell-mediated immunological response. In general, aging limits the humoral immune response, therefore, immunogens and vaccination regimes are required that induce a strong antibody response with less potential for an adverse immune response. Method In the current study, we immunized both wildtype and J20 APP-tg mice with a priming injection of Aβ1–40/42, followed by multiple intranasal boosts with the novel immunogen dAβ1–15 (16 copies of Aβ1–15 on a lysine tree, Aβ1–15 peptide or Aβ1–40/42 full length peptide. Results J20 APP-tg mice primed with Aβ1–40/42 subcutaneously and subsequently boosted intranasally with Aβ1–15 peptide did not generate a cellular or humoral immune response. In contrast, J20 APP-tg mice boosted intranasally with dAβ1–15 or full length Aβ1–40/42 produced high levels of anti-Aβ antibodies. Splenocyte proliferation was minimal in mice immunized with dAβ1–15. Wildtype littermates of the J20 APP-tg mice produced higher amounts of anti-Aβ antibodies compared to APP-tg mice but also had low T cell proliferation. The anti-Aβ antibodies were mainly composed of IgG2b and directed to an epitope within the Aβ1–7 region, regardless of the immunogen. Examination of the brain showed a significant reduction in Aβ plaque burden in the J20 APP-tg mice producing antibodies compared to controls. Biochemically, Aβ40 or Aβ42 were also reduced in brain homogenates and elevated in plasma but the changes did not reach significance. Conclusion Our results demonstrate that priming with full length Aβ40/42 followed by boosting with dAβ1–15 but not Aβ1–15 peptide led to a robust humoral immune response with a minimal T cell response in J20 APP-tg mice. In addition, A

  1. Number of Waste Package Hit by Igneous Intrusion

    International Nuclear Information System (INIS)

    M. Wallace

    2004-01-01

    The purpose of this scientific analysis report is to document calculations of the number of waste packages that could be damaged in a potential future igneous event through a repository at Yucca Mountain. The analyses include disruption from an intrusive igneous event and from an extrusive volcanic event. This analysis supports the evaluation of the potential consequences of future igneous activity as part of the total system performance assessment for the license application (TSPA-LA) for the Yucca Mountain Project (YMP). Igneous activity is a disruptive event that is included in the TSPA-LA analyses. Two igneous activity scenarios are considered: (1) The igneous intrusion groundwater release scenario (also called the igneous intrusion scenario) considers the in situ damage to waste packages or failure of waste packages that occurs if they are engulfed or otherwise affected by magma as a result of an igneous intrusion. (2) The volcanic eruption scenario depicts the direct release of radioactive waste due to an intrusion that intersects the repository followed by a volcanic eruption at the surface. An igneous intrusion is defined as the ascent of a basaltic dike or dike system (i.e., a set or swarm of multiple dikes comprising a single intrusive event) to repository level, where it intersects drifts. Magma that does reach the surface from igneous activity is an eruption (or extrusive activity) (Jackson 1997 [DIRS 109119], pp. 224, 333). The objective of this analysis is to develop a probabilistic measure of the number of waste packages that could be affected by each of the two scenarios

  2. Tumor penetrating peptides

    Directory of Open Access Journals (Sweden)

    Tambet eTeesalu

    2013-08-01

    Full Text Available Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC, contains the integrin-binding RGD motif. RGD mediates tumor homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular zip code of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is

  3. Tumor-Penetrating Peptides

    Science.gov (United States)

    Teesalu, Tambet; Sugahara, Kazuki N.; Ruoslahti, Erkki

    2013-01-01

    Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC), contains the integrin-binding RGD motif. RGD mediates tumor-homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR) motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular “zip code” of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies, and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is present in the

  4. Novel Endogenous Antimicrobial Peptides

    OpenAIRE

    Nordahl, Emma

    2009-01-01

    Antimicrobial peptides serve as a first line of defence against invading microorganisms and are an essential part of our fast innate immune system. They are ancient molecules found in all classes of life. Antimicrobial peptides rapidly kill a broad spectrum of microbes and are immunomodulatory, i.e. having additional actions influencing inflammation and other innate immune responses. Results presented in this thesis demonstrate that proteases of common human pathogens degrade and inactivate t...

  5. Self-assembly of fibronectin mimetic peptide-amphiphile nanofibers

    Science.gov (United States)

    Rexeisen, Emilie Lynn

    umbilical vein endothelial cells and alpha5beta1 integrins immobilized on an AFM tip preferred binding to a fibronectin mimetic peptide that contained both hydrophilic and hydrophobic residues in the linker and a medium length spacer. Most cells require a three-dimensional scaffold in order to thrive. To incorporate the fibronectin mimetic peptide into a three-dimensional structure, a single hydrocarbon tail was attached to form a peptideamphiphile. Single-tailed peptide-amphiphiles have been shown to form nanofibers in solution and gel after screening of the electrostatic charges in the headgroup. These gels show promise as scaffolds for tissue engineering. A fibronectin mimetic peptide-amphiphile containing a linker with alternating hydrophobic and hydrophilic residues was designed to form nanofibers in solution. The critical micelle concentration of the peptide-amphiphile was determined to be 38 muM, and all subsequent experiments were performed above this concentration. Circular dichroism (CD) spectroscopy indicated that the peptide headgroup of the peptide-amphiphile forms an alpha+beta secondary structure; whereas, the free peptide forms a random secondary structure. Cryogenic-transmission electron microscopy (cryo-TEM) and small angle neutron scattering showed that the peptide-amphiphile self-assembled into nanofibers. The cryo-TEM images showed single nanofibers with a diameter of 10 nm and lengths on the order of microns. Images of higher peptideamphiphile concentrations showed evidence of bundling between individual nanofibers, which could give rise to gelation behavior at higher concentrations. The peptide-amphiphile formed a gel at concentrations above 6 mM. A 10 mM sample was analyzed with oscillating plate rheometry and was found to have an elastic modulus within the range of living tissue, showing potential as a possible scaffold for tissue engineering.

  6. Comprehensive computational design of ordered peptide macrocycles

    Science.gov (United States)

    Hosseinzadeh, Parisa; Bhardwaj, Gaurav; Mulligan, Vikram Khipple; Shortridge, Matthew D.; Craven, Timothy W.; Pardo-Avila, Fátima; Rettie, Stephen A.; Kim, David E.; Silva, Daniel-Adriano; Ibrahim, Yehia M.; Webb, Ian K.; Cort, John R.; Adkins, Joshua N.; Varani, Gabriele; Baker, David

    2018-01-01

    Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with L-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of L- and D-amino acids by near-exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods. PMID:29242347

  7. Hitting the Pulsar Jackpot in Terzan 5 with the GBT

    Science.gov (United States)

    Ransom, S. M.; Hessels, J. W. T.; Stairs, I. H.; Freire, P. C.; Kaspi, V. M.; Camilo, F.; Kaplan, D. L.

    2004-12-01

    We report the discovery of at least 17 new pulsars in the rich globular cluster Terzan 5 using the GBT at 2 GHz. This cluster, located near the galactic center, has long been suspected of harboring many millisecond pulsars (MSPs) due both to its large predicted stellar interaction rate and the steep-spectrum radio emission observed in its core. However, earlier pulsar searches using the Parkes radio-telescope had only uncovered 3 pulsars, due primarily to the deleterious effects of the ISM towards the cluster. Our single 6-hr observation of Terzan 5 taken in July 2004, resulted in 14 new millisecond and/or binary pulsars, while follow-up observations provided (at least) 3 others. These discoveries imply that the 20+ known pulsars in the cluster are but the tip of the iceberg, and in fact much searching remains to be done with our current data. These discoveries confirm that Terzan 5 is one of the largest producers of MSPs among the Galactic globular clusters. At least 9 of the new pulsars are members of binary systems. There are two or more eclipsing systems, the 3rd and 4th fastest known rotators, a rare long orbital period (Porb ˜60 days) binary, and two highly eccentric binaries. Timing of these latter systems over the next year will provide their total masses and may (after several years) allow us to separate out the pulsar and companion masses. Two or three of the binaries may have main sequence companions, implying they were formed during exchange encounters after the MSPs were recycled and making them amenable to detection in the near-IR. Timing observations of the ensemble of pulsars will allow us to probe the mass-to-light ratio of the cluster core (and provide evidence for or against a black hole residing there), the mass distribution of the cluster as projected on the sky, and other aspects of globular cluster dynamics. In addition, extended monitoring may show that one or more of the pulsars are members of long-period binary systems.

  8. Visual strategies underpinning the development of visual-motor expertise when hitting a ball

    NARCIS (Netherlands)

    Sarpeshkar, Vishnu; Abernethy, B.; Mann, D.L.

    2017-01-01

    It is well known that skilled batters in fast-ball sports do not align their gaze with the ball throughout ball-flight, but instead adopt a unique sequence of eye and head movements that contribute toward their skill. However, much of what we know about visual-motor behavior in hitting is based on

  9. Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1

    DEFF Research Database (Denmark)

    Rist, Oystein; Grimstrup, Marie; Receveur, Jean-Marie

    2009-01-01

    Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists...

  10. Bi-phasic hitting with constraints on impact velocity and temporal precision

    NARCIS (Netherlands)

    Caljouw, S.R.; van der Kamp, J.; Savelsbergh, G.J.P.

    2005-01-01

    The aim of the experiment was to investigate how bi-phasic hitting movements are organized to comply with both impact and temporal precision constraints. 'Bi-phasic' refers to a sequential movement with a preparatory movement away from the interception location followed by a strike phase. The

  11. FedWeb Greatest Hits: Presenting the New Test Collection for Federated Web Search

    NARCIS (Netherlands)

    Demeester, Thomas; Trieschnigg, Rudolf Berend; Zhou, Ke; Nguyen, Dong-Phuong; Hiemstra, Djoerd

    This paper presents 'FedWeb Greatest Hits', a large new test collection for research in web information retrieval. As a combination and extension of the datasets used in the TREC Federated Web Search Track, this collection opens up new research possibilities on federated web search challenges, as

  12. Predictability of Harmonic Complexity Across 75 Years of Popular Music Hits

    DEFF Research Database (Denmark)

    Jensen, Karl Kristoffer; Hebert, David

    2015-01-01

    This study applies a novel computational strategy––Jensen Chroma Complexity (JCC)––to develop robust harmonic profiles of music recordings. This feature has been calculated on all US Billboard Top 100 hits across a 75-year period (n=6,394). Results indicate a clear historical trajectory of harmonic...

  13. Influence of ITO deposition and post annealing on HIT solar cell structures

    NARCIS (Netherlands)

    Zhang, D.; Tavakoliyaraki, A.; Wu, Y.; Van Swaaij, R.A.C.M.M.; Zeman, M.

    2011-01-01

    Heterojunction silicon with intrinsic thin layer (HIT) solar cells that combine advanced thin-film hydrogenated amorphous silicon (a-Si:H) and crystalline silicon (c-Si) technologies are promising because of the high performance at low cost. Due to the low conductivity of a-Si:H, indium tin oxide

  14. Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification

    Science.gov (United States)

    Ballester, Pedro J.; Mangold, Martina; Howard, Nigel I.; Robinson, Richard L. Marchese; Abell, Chris; Blumberger, Jochen; Mitchell, John B. O.

    2012-01-01

    One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated Ki ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification. PMID:22933186

  15. Interactive football training based on rebounders with hit position sensing and audio/light feedback

    DEFF Research Database (Denmark)

    Jensen, Mads Møller; Grønbæk, Kaj; Rasmussen, Majken Kirkegård

    position sensing. The rebounders are equipped with loudspeakers and lights being used to call for the ball. Here we discuss one game “Pass ­and ­Turn”, which is meant to train speed in controlling a returned ball, reaction to a call for the ball and turning to hit rebounders to the left, right, behind...

  16. Hitting moving targets : A dissociation between the use of the target's speed and direction of motion

    NARCIS (Netherlands)

    Brouwer, Anne Marie; Middelburg, Tom; Smeets, Jeroen B J; Brenner, Eli

    2003-01-01

    Previous work has indicated that people do not use their judgment of a target's speed to determine where to hit it. Instead, they use their judgment of the target's changing position and an expected speed (based on the speed of previous targets). In the present study we investigate whether people

  17. Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI

    Directory of Open Access Journals (Sweden)

    Madeleine L. Barnett

    2018-01-01

    Conclusion: This study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury.

  18. Temporal scales for nearshore hits of current-driven pollution in the Gulf of Finland.

    Science.gov (United States)

    Viikmäe, Bert; Soomere, Tarmo

    2016-05-15

    Lagrangian trajectories of water parcels reconstructed using the TRACMASS model from three-dimensional velocity fields by the RCO model for 1965-2004 are used to analyse the temporal scales and the probability for the hits to the nearshore by pollution originating from a major fairway in the Gulf of Finland and transported by surface currents. Increasing the simulation length from 10 to 20days induces a linear increase in particle age, but the pattern of nearshore hits remains the same. A reasonable benefit can be reached by relatively small shifts of certain parts of the present fairway in a few locations. The overall probabilities do not reveal any trend for 1965-2004. The largest changes in the nearshore hits are revealed for the proportion of hits to the opposite nearshore areas. This feature probably reflects an abrupt turn of the geostrophic air-flow over the southern Baltic Sea by ~40° since 1987. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Our Young People and Hard Hit Communities: Recovery Has Passed Them By. A First Friday Report.

    Science.gov (United States)

    Full Employment Action Council, Washington, DC.

    Although the joblessness and underemployment that characterize the labor market status of American youth are worst for Hispanic and Black youth, they also reflect the absence of job opportunities, irrespective of race, in depressed rural areas and urban communities hard hit by sustained high levels of unemployment. In December 1984, teenagers had…

  20. SURGICAL MANAGEMENT OF AN ARROW HIT DOMESTIC BULL (BOS INDICUS - A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Deepak Sharma

    2017-12-01

    Full Text Available A free range bull was hit by an arrow. It was brought to the Veterinary Centre of Buxa Tiger Reserve Forest, Alipurduar, West Bengal, India. Immediate surgical intervention was started and the arrow was operated out. The animal was cured uneventfully.

  1. Generalized Continuous-Time Random Walks (CTRW), Subordination by Hitting Times and Fractional Dynamics

    OpenAIRE

    Kolokoltsov, Vassili N.

    2007-01-01

    Functional limit theorem for continuous-time random walks (CTRW) are found in general case of dependent waiting times and jump sizes that are also position dependent. The limiting anomalous diffusion is described in terms of fractional dynamics. Probabilistic interpretation of generalized fractional evolution is given in terms of the random time change (subordination) by means of hitting times processes.

  2. 77 FR 2448 - Special Local Regulation; HITS Triathlon; Corpus Christi Bayfront, Corpus Christi, TX

    Science.gov (United States)

    2012-01-18

    ...-AA08 Special Local Regulation; HITS Triathlon; Corpus Christi Bayfront, Corpus Christi, TX AGENCY... Special Local Regulation in the Corpus Christi Bayfront area within the Corpus Christi, TX Captain of the Port Zone. This Special Local Regulation will restrict vessels from portions of the Corpus Christi...

  3. An orthogonal-polynomial approach to first-hitting times of birth-death processes

    NARCIS (Netherlands)

    van Doorn, Erik A.

    In a recent paper in this journal, Gong, Mao and Zhang, using the theory of Dirichlet forms, extended Karlin and McGregor’s classical results on first-hitting times of a birth–death process on the nonnegative integers by establishing a representation for the Laplace transform E[exp(sTij)] of the

  4. An orthogonal-polynomial approach to first-hitting times of birth-death processes

    NARCIS (Netherlands)

    van Doorn, Erik A.

    In a recent paper [J. Theor. Probab. 25 (2012) 950-980] Gong, Mao and Zhang, using the theory of Dirichlet forms, extended Karlin and McGregor's classical results on first-hitting times of a birth-death process on the nonnegative integers by establishing a representation for the Laplace transform

  5. 77 FR 66617 - HIT Policy and Standards Committees; Workgroup Application Database

    Science.gov (United States)

    2012-11-06

    ... Database AGENCY: Office of the National Coordinator for Health Information Technology, HHS. ACTION: Notice of New ONC HIT FACA Workgroup Application Database. The Office of the National Coordinator (ONC) has launched a new Health Information Technology Federal Advisory Committee Workgroup Application Database...

  6. LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes.

    Directory of Open Access Journals (Sweden)

    Hanqian L Carlson

    2015-12-01

    Full Text Available Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA, LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA-HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage.

  7. Selective 'in synthesis' labeling of peptides with biotin and rhodamine.

    Science.gov (United States)

    Chersi, A; Giommi, S; Rosanò, L

    2000-04-06

    A new method is described for the selective 'in synthesis' labeling of peptides by rhodamine or biotin at a single, predetermined epsilon-amino group of a lysine residue. The alpha-amino group and other lysyl residues of the peptide remain unmodified. Peptides are assembled by the Fmoc approach, which requires mild operative conditions for the final deprotection and cleavage, and ensures little damage of the reporter group. The labeling technique involves the previous preparation of a suitable Lysine derivative, easily obtained from commercially-available protected amino acids. This new derivative, where the reporter group (biotin, or rhodamine) acts now as permanent protection of lysyl side chain functions, is then inserted into the synthesis program as a conventional protected amino acid, and linked to the preceding residue by aid of carbodiimide. A simpler, alternative method is also described for the selective 'in synthesis' labeling of peptides with N-terminal lysyl residues. Several applications of labeled peptides are reported.

  8. Application of synthetic peptides for detection of anti-citrullinated peptide antibodies.

    Science.gov (United States)

    Trier, Nicole Hartwig; Holm, Bettina Eide; Slot, Ole; Locht, Henning; Lindegaard, Hanne; Svendsen, Anders; Nielsen, Christoffer Tandrup; Jacobsen, Søren; Theander, Elke; Houen, Gunnar

    2016-02-01

    Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and represent an important tool for the serological diagnosis of RA. In this study, we describe ACPA reactivity to overlapping citrullinated Epstein-Barr virus nuclear antigen-1 (EBNA-1)-derived peptides and analyze their potential as substrates for ACPA detection by streptavidin capture enzyme-linked immunosorbent assay. Using systematically overlapping peptides, containing a 10 amino acid overlap, labelled with biotin C-terminally or N-terminally, sera from 160 individuals (RA sera (n=60), healthy controls (n=40), systemic lupus erythematosus (n=20), Sjögren's syndrome (n=40)) were screened for antibody reactivity. Antibodies to a panel of five citrullinated EBNA-1 peptides were found in 67% of RA sera, exclusively of the IgG isotype, while 53% of the patient sera reacted with a single peptide, ARGGSRERARGRGRG-Cit-GEKR, accounting for more than half of the ACPA reactivity alone. Moreover, these antibodies were detected in 10% of CCP2-negative RA sera. In addition, 47% of the RA sera reacted with two or three citrullinated EBNA-1 peptides from the selected peptide panel. Furthermore, a negative correlation between the biotin attachment site and the location of citrulline in the peptides was found, i.e. the closer the citrulline was located to biotin, the lower the antibody reactivity. Our data suggest that citrullinated EBNA-1 peptides may be considered a substrate for the detection of ACPAs and that the presence of Epstein-Barr virus may play a role in the induction of these autoantibodies. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Granin-derived peptides.

    Science.gov (United States)

    Troger, Josef; Theurl, Markus; Kirchmair, Rudolf; Pasqua, Teresa; Tota, Bruno; Angelone, Tommaso; Cerra, Maria C; Nowosielski, Yvonne; Mätzler, Raphaela; Troger, Jasmin; Gayen, Jaur R; Trudeau, Vance; Corti, Angelo; Helle, Karen B

    2017-07-01

    The granin family comprises altogether 7 different proteins originating from the diffuse neuroendocrine system and elements of the central and peripheral nervous systems. The family is dominated by three uniquely acidic members, namely chromogranin A (CgA), chromogranin B (CgB) and secretogranin II (SgII). Since the late 1980s it has become evident that these proteins are proteolytically processed, intragranularly and/or extracellularly into a range of biologically active peptides; a number of them with regulatory properties of physiological and/or pathophysiological significance. The aim of this comprehensive overview is to provide an up-to-date insight into the distribution and properties of the well established granin-derived peptides and their putative roles in homeostatic regulations. Hence, focus is directed to peptides derived from the three main granins, e.g. to the chromogranin A derived vasostatins, betagranins, pancreastatin and catestatins, the chromogranin B-derived secretolytin and the secretogranin II-derived secretoneurin (SN). In addition, the distribution and properties of the chromogranin A-derived peptides prochromacin, chromofungin, WE14, parastatin, GE-25 and serpinins, the CgB-peptide PE-11 and the SgII-peptides EM66 and manserin will also be commented on. Finally, the opposing effects of the CgA-derived vasostatin-I and catestatin and the SgII-derived peptide SN on the integrity of the vasculature, myocardial contractility, angiogenesis in wound healing, inflammatory conditions and tumors will be discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Peptide Optical waveguides.

    Science.gov (United States)

    Handelman, Amir; Apter, Boris; Shostak, Tamar; Rosenman, Gil

    2017-02-01

    Small-scale optical devices, designed and fabricated onto one dielectric substrate, create integrated optical chip like their microelectronic analogues. These photonic circuits, based on diverse physical phenomena such as light-matter interaction, propagation of electromagnetic waves in a thin dielectric material, nonlinear and electro-optical effects, allow transmission, distribution, modulation, and processing of optical signals in optical communication systems, chemical and biological sensors, and more. The key component of these optical circuits providing both optical processing and photonic interconnections is light waveguides. Optical confinement and transmitting of the optical waves inside the waveguide material are possible due to the higher refractive index of the waveguides in comparison with their surroundings. In this work, we propose a novel field of bionanophotonics based on a new concept of optical waveguiding in synthetic elongated peptide nanostructures composed of ordered peptide dipole biomolecules. New technology of controllable deposition of peptide optical waveguiding structures by nanofountain pen technique is developed. Experimental studies of refractive index, optical transparency, and linear and nonlinear waveguiding in out-of-plane and in-plane diphenylalanine peptide nanotubes have been conducted. Optical waveguiding phenomena in peptide structures are simulated by the finite difference time domain method. The advantages of this new class of bio-optical waveguides are high refractive index contrast, wide spectral range of optical transparency, large optical nonlinearity, and electro-optical effect, making them promising for new applications in integrated multifunctional photonic circuits. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  11. Novel method for hit-position reconstruction using voltage signals in plastic scintillators and its application to Positron Emission Tomography

    Science.gov (United States)

    Raczyński, L.; Moskal, P.; Kowalski, P.; Wiślicki, W.; Bednarski, T.; Białas, P.; Czerwiński, E.; Kapłon, Ł.; Kochanowski, A.; Korcyl, G.; Kowal, J.; Kozik, T.; Krzemień, W.; Kubicz, E.; Molenda, M.; Moskal, I.; Niedźwiecki, Sz.; Pałka, M.; Pawlik-Niedźwiecka, M.; Rudy, Z.; Salabura, P.; Sharma, N. G.; Silarski, M.; Słomski, A.; Smyrski, J.; Strzelecki, A.; Wieczorek, A.; Zieliński, M.; Zoń, N.

    2014-11-01

    Currently inorganic scintillator detectors are used in all commercial Time of Flight Positron Emission Tomograph (TOF-PET) devices. The J-PET collaboration investigates a possibility of construction of a PET scanner from plastic scintillators which would allow for single bed imaging of the whole human body. This paper describes a novel method of hit-position reconstruction based on sampled signals and an example of an application of the method for a single module with a 30 cm long plastic strip, read out on both ends by Hamamatsu R4998 photomultipliers. The sampling scheme to generate a vector with samples of a PET event waveform with respect to four user-defined amplitudes is introduced. The experimental setup provides irradiation of a chosen position in the plastic scintillator strip with an annihilation gamma quanta of energy 511 keV. The statistical test for a multivariate normal (MVN) distribution of measured vectors at a given position is developed, and it is shown that signals sampled at four thresholds in a voltage domain are approximately normally distributed variables. With the presented method of a vector analysis made out of waveform samples acquired with four thresholds, we obtain a spatial resolution of about 1 cm and a timing resolution of about 80 ps (σ).

  12. Novel method for hit-position reconstruction using voltage signals in plastic scintillators and its application to Positron Emission Tomography

    International Nuclear Information System (INIS)

    Raczyński, L.; Moskal, P.; Kowalski, P.; Wiślicki, W.; Bednarski, T.; Białas, P.; Czerwiński, E.; Kapłon, Ł.; Kochanowski, A.; Korcyl, G.; Kowal, J.; Kozik, T.; Krzemień, W.; Kubicz, E.; Molenda, M.; Moskal, I.; Niedźwiecki, Sz.; Pałka, M.; Pawlik-Niedźwiecka, M.; Rudy, Z.

    2014-01-01

    Currently inorganic scintillator detectors are used in all commercial Time of Flight Positron Emission Tomograph (TOF-PET) devices. The J-PET collaboration investigates a possibility of construction of a PET scanner from plastic scintillators which would allow for single bed imaging of the whole human body. This paper describes a novel method of hit-position reconstruction based on sampled signals and an example of an application of the method for a single module with a 30 cm long plastic strip, read out on both ends by Hamamatsu R4998 photomultipliers. The sampling scheme to generate a vector with samples of a PET event waveform with respect to four user-defined amplitudes is introduced. The experimental setup provides irradiation of a chosen position in the plastic scintillator strip with an annihilation gamma quanta of energy 511 keV. The statistical test for a multivariate normal (MVN) distribution of measured vectors at a given position is developed, and it is shown that signals sampled at four thresholds in a voltage domain are approximately normally distributed variables. With the presented method of a vector analysis made out of waveform samples acquired with four thresholds, we obtain a spatial resolution of about 1 cm and a timing resolution of about 80 ps (σ)

  13. Novel method for hit-position reconstruction using voltage signals in plastic scintillators and its application to Positron Emission Tomography

    Energy Technology Data Exchange (ETDEWEB)

    Raczyński, L., E-mail: lech.raczynski@ncbj.gov.pl [Świerk Computing Centre, National Centre for Nuclear Research, 05-400 Otwock-Świerk (Poland); Moskal, P. [Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-059 Cracow (Poland); Kowalski, P.; Wiślicki, W. [Świerk Computing Centre, National Centre for Nuclear Research, 05-400 Otwock-Świerk (Poland); Bednarski, T.; Białas, P.; Czerwiński, E. [Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-059 Cracow (Poland); Kapłon, Ł. [Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-059 Cracow (Poland); Institute of Metallurgy and Materials Science of Polish Academy of Sciences, Cracow (Poland); Kochanowski, A. [Faculty of Chemistry, Jagiellonian University, 30-060 Cracow (Poland); Korcyl, G.; Kowal, J.; Kozik, T.; Krzemień, W.; Kubicz, E. [Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-059 Cracow (Poland); Molenda, M. [Faculty of Chemistry, Jagiellonian University, 30-060 Cracow (Poland); Moskal, I.; Niedźwiecki, Sz.; Pałka, M.; Pawlik-Niedźwiecka, M.; Rudy, Z. [Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-059 Cracow (Poland); and others

    2014-11-11

    Currently inorganic scintillator detectors are used in all commercial Time of Flight Positron Emission Tomograph (TOF-PET) devices. The J-PET collaboration investigates a possibility of construction of a PET scanner from plastic scintillators which would allow for single bed imaging of the whole human body. This paper describes a novel method of hit-position reconstruction based on sampled signals and an example of an application of the method for a single module with a 30 cm long plastic strip, read out on both ends by Hamamatsu R4998 photomultipliers. The sampling scheme to generate a vector with samples of a PET event waveform with respect to four user-defined amplitudes is introduced. The experimental setup provides irradiation of a chosen position in the plastic scintillator strip with an annihilation gamma quanta of energy 511 keV. The statistical test for a multivariate normal (MVN) distribution of measured vectors at a given position is developed, and it is shown that signals sampled at four thresholds in a voltage domain are approximately normally distributed variables. With the presented method of a vector analysis made out of waveform samples acquired with four thresholds, we obtain a spatial resolution of about 1 cm and a timing resolution of about 80 ps (σ)

  14. Computing Principal Eigenvectors of Large Web Graphs: Algorithms and Accelerations Related to PageRank and HITS

    Science.gov (United States)

    Nagasinghe, Iranga

    2010-01-01

    This thesis investigates and develops a few acceleration techniques for the search engine algorithms used in PageRank and HITS computations. PageRank and HITS methods are two highly successful applications of modern Linear Algebra in computer science and engineering. They constitute the essential technologies accounted for the immense growth and…

  15. Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms.

    Science.gov (United States)

    Jequier Gygax, Marine; Klein, Brian D; White, H Steve; Kim, Mimi; Galanopoulou, Aristea S

    2014-01-01

    Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4mg/kg) or vehicle. Video monitoring for spasms included a 1h pre-injection period, followed by 5h of recording post-injection, and two 2h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4h after injection. The relative expression of GalR1 and GalR2 mRNA over β-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n=11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and

  16. Peptide Integrated Optics.

    Science.gov (United States)

    Handelman, Amir; Lapshina, Nadezda; Apter, Boris; Rosenman, Gil

    2018-02-01

    Bio-nanophotonics is a wide field in which advanced optical materials, biomedicine, fundamental optics, and nanotechnology are combined and result in the development of biomedical optical chips. Silk fibers or synthetic bioabsorbable polymers are the main light-guiding components. In this work, an advanced concept of integrated bio-optics is proposed, which is based on bioinspired peptide optical materials exhibiting wide optical transparency, nonlinear and electrooptical properties, and effective passive and active waveguiding. Developed new technology combining bottom-up controlled deposition of peptide planar wafers of a large area and top-down focus ion beam lithography provides direct fabrication of peptide optical integrated circuits. Finding a deep modification of peptide optical properties by reconformation of biological secondary structure from native phase to β-sheet architecture is followed by the appearance of visible fluorescence and unexpected transition from a native passive optical waveguiding to an active one. Original biocompatibility, switchable regimes of waveguiding, and multifunctional nonlinear optical properties make these new peptide planar optical materials attractive for application in emerging technology of lab-on-biochips, combining biomedical photonic and electronic circuits toward medical diagnosis, light-activated therapy, and health monitoring. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Maximizing the sensitivity and reliability of peptide identification in large-scale proteomic experiments by harnessing multiple search engines.

    Science.gov (United States)

    Yu, Wen; Taylor, J Alex; Davis, Michael T; Bonilla, Leo E; Lee, Kimberly A; Auger, Paul L; Farnsworth, Chris C; Welcher, Andrew A; Patterson, Scott D

    2010-03-01

    Despite recent advances in qualitative proteomics, the automatic identification of peptides with optimal sensitivity and accuracy remains a difficult goal. To address this deficiency, a novel algorithm, Multiple Search Engines, Normalization and Consensus is described. The method employs six search engines and a re-scoring engine to search MS/MS spectra against protein and decoy sequences. After the peptide hits from each engine are normalized to error rates estimated from the decoy hits, peptide assignments are then deduced using a minimum consensus model. These assignments are produced in a series of progressively relaxed false-discovery rates, thus enabling a comprehensive interpretation of the data set. Additionally, the estimated false-discovery rate was found to have good concordance with the observed false-positive rate calculated from known identities. Benchmarking against standard proteins data sets (ISBv1, sPRG2006) and their published analysis, demonstrated that the Multiple Search Engines, Normalization and Consensus algorithm consistently achieved significantly higher sensitivity in peptide identifications, which led to increased or more robust protein identifications in all data sets compared with prior methods. The sensitivity and the false-positive rate of peptide identification exhibit an inverse-proportional and linear relationship with the number of participating search engines.

  18. Peptide-microgel interactions in the strong coupling regime.

    Science.gov (United States)

    Hansson, Per; Bysell, Helena; Månsson, Ronja; Malmsten, Martin

    2012-09-06

    The interaction between lightly cross-linked poly(acrylic acid) microgels and oppositely charged peptides was investigated as a function of peptide length, charge density, pH, and salt concentration, with emphasis on the strong coupling regime at high charge contrast. By micromanipulator-assisted light microscopy, the equilibrium volume response of single microgel particles upon oligolysine and oligo(lysine/alanine) absorption could be monitored in a controlled fashion. Results show that microgel deswelling, caused by peptide binding and network neutralization, increases with peptide length (3 attraction between the network chains is described using an exponential force law, and the network elasticity by the inverse Langevin theory. The model was used to calculate the composition of microgels in contact with reservoir solutions of peptides and simple electrolytes. At high electrostatic coupling, the calculated swelling curves were found to display first-order phase transition behavior. The model was demonstrated to capture pH- and electrolyte-dependent microgel swelling, as well as effects of peptide length and charge density on microgel deswelling. The analysis demonstrated that the peptide charge (length), rather than the peptide charge density, determines microgel deswelling. Furthermore, a transition between continuous and discrete network collapse was identified, consistent with experimental results in the present investigations, as well as with results from the literature on microgel deswelling caused by multivalent cations.

  19. Zooming into the binding groove of HLA molecules : which positions and which substitutions change peptide binding most?

    NARCIS (Netherlands)

    van Deutekom, Hanneke W M; Kesmir, C.

    Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA

  20. A functional mimic of natural peroxidases : synthesis and catalytic activity of a non-heme iron peptide hydroperoxide complex

    NARCIS (Netherlands)

    Choma, CT; Schudde, EP; Kellogg, RM; Robillard, GT; Feringa, BL

    1998-01-01

    Site-selective attachment of unprotected peptides to a non-heme iron complex is achieved by displacing two halides on the catalyst by peptide caesium thiolates, This coupling approach should be compatible with any peptide sequence provided there is only a single reduced cysteine. The oxidation

  1. Synthetic antibiofilm peptides.

    Science.gov (United States)

    de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete; Franco, Octavio Luiz; Hancock, Robert E W

    2016-05-01

    Bacteria predominantly exist as multicellular aggregates known as biofilms that are associated with at least two thirds of all infections and exhibit increased adaptive resistance to conventional antibiotic therapies. Therefore, biofilms are major contributors to the global health problem of antibiotic resistance, and novel approaches to counter them are urgently needed. Small molecules of the innate immune system called host defense peptides (HDPs) have emerged as promising templates for the design of potent, broad-spectrum antibiofilm agents. Here, we review recent developments in the new field of synthetic antibiofilm peptides, including mechanistic insights, synergistic interactions with available antibiotics, and their potential as novel antimicrobials against persistent infections caused by biofilms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. PepBank - a database of peptides based on sequence text mining and public peptide data sources

    Directory of Open Access Journals (Sweden)

    Pivovarov Misha

    2007-08-01

    Full Text Available Abstract Background Peptides are important molecules with diverse biological functions and biomedical uses. To date, there does not exist a single, searchable archive for peptide sequences or associated biological data. Rather, peptide sequences still have to be mined from abstracts and full-length articles, and/or obtained from the fragmented public sources. Description We have constructed a new database (PepBank, which at the time of writing contains a total of 19,792 individual peptide entries. The database has a web-based user interface with a simple, Google-like search function, advanced text search, and BLAST and Smith-Waterman search capabilities. The major source of peptide sequence data comes from text mining of MEDLINE abstracts. Another component of the database is the peptide sequence data from public sources (ASPD and UniProt. An additional, smaller part of the database is manually curated from sets of full text articles and text mining results. We show the utility of the database in different examples of affinity ligand discovery. Conclusion We have created and maintain a database of peptide sequences. The database has biological and medical applications, for example, to predict the binding partners of biologically interesting peptides, to develop peptide based therapeutic or diagnostic agents, or to predict molecular targets or binding specificities of peptides resulting from phage display selection. The database is freely available on http://pepbank.mgh.harvard.edu/, and the text mining source code (Peptide::Pubmed is freely available above as well as on CPAN (http://www.cpan.org/.

  3. Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum.

    Science.gov (United States)

    Avery, Vicky M; Bashyam, Sridevi; Burrows, Jeremy N; Duffy, Sandra; Papadatos, George; Puthukkuti, Shyni; Sambandan, Yuvaraj; Singh, Shivendra; Spangenberg, Thomas; Waterson, David; Willis, Paul

    2014-05-27

    In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as 'signposts' in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay. This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC₅₀  10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series. A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical

  4. Transfer, loss and physical processing of water in hit-and-run collisions of planetary embryos

    Science.gov (United States)

    Burger, C.; Maindl, T. I.; Schäfer, C. M.

    2018-01-01

    Collisions between large, similar-sized bodies are believed to shape the final characteristics and composition of terrestrial planets. Their inventories of volatiles such as water are either delivered or at least significantly modified by such events. Besides the transition from accretion to erosion with increasing impact velocity, similar-sized collisions can also result in hit-and-run outcomes for sufficiently oblique impact angles and large enough projectile-to-target mass ratios. We study volatile transfer and loss focusing on hit-and-run encounters by means of smooth particle hydrodynamics simulations, including all main parameters: impact velocity, impact angle, mass ratio and also the total colliding mass. We find a broad range of overall water losses, up to 75% in the most energetic hit-and-run events, and confirm the much more severe consequences for the smaller body also for stripping of volatile layers. Transfer of water between projectile and target inventories is found to be mostly rather inefficient, and final water contents are dominated by pre-collision inventories reduced by impact losses, for similar pre-collision water mass fractions. Comparison with our numerical results shows that current collision outcome models are not accurate enough to reliably predict these composition changes in hit-and-run events. To also account for non-mechanical losses, we estimate the amount of collisionally vaporized water over a broad range of masses and find that these contributions are particularly important in collisions of ˜ Mars-sized bodies, with sufficiently high impact energies, but still relatively low gravity. Our results clearly indicate that the cumulative effect of several (hit-and-run) collisions can efficiently strip protoplanets of their volatile layers, especially the smaller body, as it might be common, e.g., for Earth-mass planets in systems with Super-Earths. An accurate model for stripping of volatiles that can be included in future planet

  5. Therapeutic HIV Peptide Vaccine

    DEFF Research Database (Denmark)

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

  6. Peptide Vaccine Against Paracoccidioidomycosis.

    Science.gov (United States)

    Taborda, Carlos P; Travassos, Luiz R

    2017-01-01

    The chapter reviews methods utilized for the isolation and characterization of a promising immunogen candidate, aiming at a human vaccine against paracoccidioidomycosis. Peptide P10 carries a T-CD4+ epitope and was identified as an internal sequence of the major diagnostic antigen known as gp43 glycoprotein. It successfully treated massive intratracheal infections by virulent Paracoccidioides brasiliensis in combination with chemotherapy.An introduction about the systemic mycosis was found essential to understand the various options that were considered to design prophylactic and therapeutic vaccine protocols using peptide P10.

  7. The Niśvāsamukha, the Introductory book of the Niśvāsatattvasaṃhitā : critical edition, with an introduction and annotated translation appended by Śivadharmasaṅgraha 5–9

    NARCIS (Netherlands)

    Kafle, Nirajan

    2015-01-01

    A single 9th-century Nepalese palm-leaf manuscript transmits what appears to be the oldest surviving Śaiva tantra, called the Niśvāsatattvasaṃhitā. The manuscript consists of five separate books: Niśvāsamukha, Mūlasūtra, Nayasūtra, Uttarasūtra and Guhyasūtra. The Niśvāsamukha, which is divided into

  8. Multifunctional hybrid networks based on self assembling peptide sequences

    Science.gov (United States)

    Sathaye, Sameer

    The overall aim of this dissertation is to achieve a comprehensive correlation between the molecular level changes in primary amino acid sequences of amphiphilic beta-hairpin peptides and their consequent solution-assembly properties and bulk network hydrogel behavior. This has been accomplished using two broad approaches. In the first approach, amino acid substitutions were made to peptide sequence MAX1 such that the hydrophobic surfaces of the folded beta-hairpins from the peptides demonstrate shape specificity in hydrophobic interactions with other beta-hairpins during the assembly process, thereby causing changes to the peptide nanostructure and bulk rheological properties of hydrogels formed from the peptides. Steric lock and key complementary hydrophobic interactions were designed to occur between two beta-hairpin molecules of a single molecule, LNK1 during beta-sheet fibrillar assembly of LNK1. Experimental results from circular dichroism, transmission electron microscopy and oscillatory rheology collectively indicate that the molecular design of the LNK1 peptide can be assigned the cause of the drastically different behavior of the networks relative to MAX1. The results indicate elimination or significant reduction of fibrillar branching due to steric complementarity in LNK1 that does not exist in MAX1, thus supporting the original hypothesis. As an extension of the designed steric lock and key complementarity between two beta-hairpin molecules of the same peptide molecule. LNK1, three new pairs of peptide molecules LP1-KP1, LP2-KP2 and LP3-KP3 that resemble complementary 'wedge' and 'trough' shapes when folded into beta-hairpins were designed and studied. All six peptides individually and when blended with their corresponding shape complement formed fibrillar nanostructures with non-uniform thickness values. Loose packing in the assembled structures was observed in all the new peptides as compared to the uniform tight packing in MAX1 by SANS analysis. This

  9. Organizations disseminating health messages: the roles of organizational identification and HITs.

    Science.gov (United States)

    Stephens, Keri K; Goins, Elizabeth S; Dailey, Stephanie L

    2014-01-01

    Research into the dissemination of health information now includes more focus on how various organizations (e.g., beauty shops, schools, workplaces, and churches) and health information technologies (HITs) reach and affect audiences. One relational feature of organizations is identification--the feeling of belongingness. Our study explores how it influences audiences, especially in combination with HITs such as e-mail, websites, and social media. We use social identity theory to predict how organizational identification and social media might function in health communication. Using a 3 × 2 experimental design, we find that people's identification with a message source mediates the effect of social media on outcomes. These findings improve our understanding of when organizations might be most helpful for disseminating health information.

  10. Sleeping beauties in psychology: comparisons of "hits" and "missed signals" in psychological journals.

    Science.gov (United States)

    Lange, Lydia L

    2005-05-01

    Scientific publications tend to be forgotten quickly. A few works, however, are still cited 100 years and more after their publication. The author used bibliometric methods to compare "hits" (works noticed by the scientific community soon after their publication) with "missed signals" (works that went unnoticed until much later) by investigating 2 psychological journals founded in the 1890s: Zeitschrift für Psychologie and Psychological Review. All articles that were published in either of these journals up to 1920 and cited more than 25 times in the Web of Science up to the year 2000 were considered for inclusion in the analysis. It emerged that hits corresponded more closely to the focus of scientific attention at the time of the publications than missed signals.

  11. Sharp error terms and neccesary conditions for exponential hitting times in mixing processes

    CERN Document Server

    Abadi, M G

    2001-01-01

    We prove an upper bound for the error in the exponential approximation of the hitting time law of a rare event in $\\alpha$-mixing processes with exponential decay, $\\phi$-mixing processes with a summable function $\\phi$ and for general $\\psi$-mixing processes with a finite alphabet. In the first case the bound is uniform as a function of the measure of the event. In the last two cases the bound depends also on the time scale $t$. This allow us to get further statistical properties as the ratio convergence of the expected hitting time and the expected return time. A uniform bound is a consequence. We present an example that shows that this bound is sharp. We also prove that second moments are not necessary for having the exponential law. Moreover, we prove a necessary condition for having the exponential limit law.

  12. Hit and lead criteria in drug discovery for infectious diseases of the developing world.

    Science.gov (United States)

    Katsuno, Kei; Burrows, Jeremy N; Duncan, Ken; Hooft van Huijsduijnen, Rob; Kaneko, Takushi; Kita, Kiyoshi; Mowbray, Charles E; Schmatz, Dennis; Warner, Peter; Slingsby, B T

    2015-11-01

    Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

  13. "Hits" emerge through self-organized coordination in collective response of free agents

    Science.gov (United States)

    Chakrabarti, Anindya S.; Sinha, Sitabhra

    2016-10-01

    Individuals in free societies frequently exhibit striking coordination when making independent decisions en masse. Examples include the regular appearance of hit products or memes with substantially higher popularity compared to their otherwise equivalent competitors or extreme polarization in public opinion. Such segregation of events manifests as bimodality in the distribution of collective choices. Here we quantify how apparently independent choices made by individuals result in a significantly polarized but stable distribution of success in the context of the box-office performance of movies and show that it is an emergent feature of a system of noninteracting agents who respond to sequentially arriving signals. The aggregate response exhibits extreme variability amplifying much smaller differences in individual cost of adoption. Due to self-organization of the competitive landscape, most events elicit only a muted response but a few stimulate widespread adoption, emerging as "hits".

  14. Novel current drive experiments on the CDX-U, HIT, and DIII-D Tokamaks

    International Nuclear Information System (INIS)

    Ono, M.; Forest, C.B.; Hwang, Y.S.; Armstrong, R.J.; Choe, W.; Darrow, D.S.; Greene, G.; Jones, T.; Schaffer, M.J.; Hyatt, A.W.; Pinsker, R.I.; Staebler, G.M.; Stambaugh, R.D.; Strait, E.J.; Greene, K.L.; Leuer, J.A.; Lohr, J.M.

    1992-01-01

    Two types of novel, non-inductive current drive concepts for starting-up and maintaining tokamak discharges have been developed on the CDX-U, HIT, and DIII-D Tokamaks. On CDX-U, a new, non-inductive current drive technique utilizing fully internally generated pressure driven currents has been demonstrated. The measured current density profile shows a non-hollow profile which agrees with a modeling calculation including helicity conserving non-classical current transport providing the ''seed current''. Another current drive concept, dc-helicity injection, has been investigated on, CDX-U, HIT and DIII-D. This method utilizes injection of magnetic helicity via low energy electron currents, maintaining the plasma current through helicity conserving relaxiation. In these experiments, non-ohmic tokamak plasmas were formed and maintained in the tens of kA range

  15. Variation in number of hits for complex searches in Google Scholar

    Directory of Open Access Journals (Sweden)

    Wichor Matthijs Bramer, BSc

    2016-11-01

    Full Text Available Objective: Google Scholar is often used to search for medical literature. Numbers of results reported by Google Scholar outperform the numbers reported by traditional databases. How reliable are these numbers? Why are often not all available 1,000 references shown? Methods: For several complex search strategies used in systematic review projects, the number of citations and the total number of versions were calculated. Several search strategies were followed over a two-year period, registering fluctuations in reported search results. Results: Changes in numbers of reported search results varied enormously between search strategies and dates. Theories for calculations of the reported and shown number of hits were not proved. Conclusions: The number of hits reported in Google Scholar is an unreliable measure. Therefore, its repeatability is problematic, at least when equal results are needed.

  16. B-HIT - A Tool for Harvesting and Indexing Biodiversity Data.

    Directory of Open Access Journals (Sweden)

    Patricia Kelbert

    Full Text Available With the rapidly growing number of data publishers, the process of harvesting and indexing information to offer advanced search and discovery becomes a critical bottleneck in globally distributed primary biodiversity data infrastructures. The Global Biodiversity Information Facility (GBIF implemented a Harvesting and Indexing Toolkit (HIT, which largely automates data harvesting activities for hundreds of collection and observational data providers. The team of the Botanic Garden and Botanical Museum Berlin-Dahlem has extended this well-established system with a range of additional functions, including improved processing of multiple taxon identifications, the ability to represent associations between specimen and observation units, new data quality control and new reporting capabilities. The open source software B-HIT can be freely installed and used for setting up thematic networks serving the demands of particular user groups.

  17. Hitting the nursing faculty shortage head on: strategies to recruit, retain, and develop nursing faculty.

    Science.gov (United States)

    Feldman, Harriet R; Greenberg, Martha J; Jaffe-Ruiz, Marilyn; Kaufman, Sophie Revillard; Cignarale, Stacie

    2015-01-01

    More than ever before, schools of nursing are challenged with finding qualified faculty to teach growing numbers of undergraduate and graduate students. Qualified applicants by the thousands are being turned away, in large part because of an insufficient pipeline of faculty. This article describes how one school hit the shortage head on by creating alternate models for employing and growing new faculty, and then instituting a variety of strategies to develop and keep them. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Development and formative evaluation of the e-Health Implementation Toolkit (e-HIT).

    Science.gov (United States)

    Murray, Elizabeth; May, Carl; Mair, Frances

    2010-10-18

    The use of Information and Communication Technology (ICT) or e-Health is seen as essential for a modern, cost-effective health service. However, there are well documented problems with implementation of e-Health initiatives, despite the existence of a great deal of research into how best to implement e-Health (an example of the gap between research and practice). This paper reports on the development and formative evaluation of an e-Health Implementation Toolkit (e-HIT) which aims to summarise and synthesise new and existing research on implementation of e-Health initiatives, and present it to senior managers in a user-friendly format. The content of the e-HIT was derived by combining data from a systematic review of reviews of barriers and facilitators to implementation of e-Health initiatives with qualitative data derived from interviews of "implementers", that is people who had been charged with implementing an e-Health initiative. These data were summarised, synthesised and combined with the constructs from the Normalisation Process Model. The software for the toolkit was developed by a commercial company (RocketScience). Formative evaluation was undertaken by obtaining user feedback. There are three components to the toolkit--a section on background and instructions for use aimed at novice users; the toolkit itself; and the report generated by completing the toolkit. It is available to download from http://www.ucl.ac.uk/pcph/research/ehealth/documents/e-HIT.xls. The e-HIT shows potential as a tool for enhancing future e-Health implementations. Further work is needed to make it fully web-enabled, and to determine its predictive potential for future implementations.

  19. The hit principle and the mutagenic effect of ionizing radiations of different quality on bacterial cells

    International Nuclear Information System (INIS)

    Krasavin, E.A.; Kozubek, S.; Amirtaev, K.G.; Tokarova, B.

    1988-01-01

    The role of the most important methodological principle - the hit principle, worked out by N.V. Timofeeff-Ressovsky, in recent understanding of the mutagenic effect of ionizing radiation of different quality on bacterial cells has been discussed. Experimentaol results are presented which allow that mutagenic effect of ionizing radiation is determined by the influence of factors of both physical nature (the parameters of radiation and the geometry of a target) and biological nature (repair systems in cells)

  20. Network brokers or hit makers? Analyzing the influence of incubation on start-up investments

    OpenAIRE

    Van Rijnsoever, Frank J.; Van Weele, Marijn A.; Eveleens, Chris P.

    2017-01-01

    Incubators are a prominent way to support technology based start-ups. Yet, it remains unclear to what extent these incubators enhance start-up performance, nor is it known through which mechanisms this would occur. In this paper we test two mechanisms to explain the relationship between incubation and the amount of investments raised by early stage start-ups as performance measure. The ‘hit maker’ mechanism refers to beneficial effects of the direct transfer of resources and organizational or...

  1. BASE MOVEMENT INFLUENCE OF HITTING BALL USING HAD AND FOOT IN FOOTBALL GAME

    Directory of Open Access Journals (Sweden)

    Midhat Mekić

    2006-06-01

    Full Text Available We had analyzed movements abilities influence on situation movement abilities applied on evaluation of strenght of hitting ball using foot and had football game, played by 13 years old boys. In aim of that we had choose 24 movement facts and 3 situations tests of football game. In those examples we had got rezults which are proof that these about influence of movement element s on rezults in analiyzed test.

  2. NCAM Mimetic Peptides: An Update

    DEFF Research Database (Denmark)

    Berezin, Vladimir; Bock, Elisabeth

    2008-01-01

    of combinatorial peptide libraries. The C3 and NBP10 peptides target the first Ig module whereas the ENFIN2 and ENFIN11 peptides target fibronectin type III (FN3) modules of NCAM. A number of NCAM mimetics can induce neurite outgrowth and exhibit neuroprotective and synaptic plasticity modulating properties...

  3. brain natriuretic peptide

    African Journals Online (AJOL)

    Background: Recently brain natriuretic peptide (BNP) level has been introduced as a screening test for congestive heart failure (CHF) in children. The current CHF assessment scores are not satisfactory as they use a large number of variables. Objective: To evaluate two CHF scores: a modified clinical score and an echo-.

  4. Brain Peptides and Psychopharmacology

    Science.gov (United States)

    Arehart-Treichel, Joan

    1976-01-01

    Proteins isolated from the brain and used as drugs can improve and apparently even transfer mental states and behavior. Much of the pioneering work and recent research with humans and animals is reviewed and crucial questions that are being posed about the psychologically active peptides are related. (BT)

  5. Imidazolidinone adducts of peptides and hemoglobin

    International Nuclear Information System (INIS)

    San George, R.C.; Hoberman, H.D.

    1986-01-01

    Acetaldehyde reacts selectively with the terminal amino groups of the α and β chains of hemoglobin to form stable adducts, the structures of which, based on 13 C NMR studies, are proposed to be diastereomeric 2-methyl imidazolidin-4-ones. In this scheme, acetaldelhyde forms a reversible Schiff base with the α-amino groups of the polypeptide chains which cyclize with the amide nitrogen of the first peptide bond to form the stable imidazolidinone adducts. In support of this mechanism, the authors found that in following the reaction of the peptide val-gly-gly with [1,2- 13 C] acetaldehyde, 13 C NMR resonances attributed to a Schiff base (δ = 170 ppm) were observed which slowly disappeared prior to appearance of resonances from a pair of stable adducts (δ = 70 and 71 ppm) believed to be the diastereomeric imidazolidinones. Schiff base formation appeared to limit the overall rate. Tetraglycine reacted in a similar manner but with a resonance from a single stable adduct observed representing the enantiomeric imidazolidinone adducts of this peptide. Peptides with proline in position 2 should be incapable of forming imidazolidinones, and the authors found that ala-pro-gly did in fact fail to form a stable adduct with acetaldehyde. The 2-methyl imidazolidin-4-one adducts of hemoglobin may be useful in determining the contribution of the amino terminal groups to the structure and functional properties of hemoglobins

  6. Real time tracker based upon local hit correlation circuit for silicon strip sensors

    Energy Technology Data Exchange (ETDEWEB)

    Lehmann, Niklaus, E-mail: niklaus.lehmann@cern.ch [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States); Pirrami, Lorenzo [University of Applied Sciences Western Switzerland, Boulevard de Pérolles 80 – CP 32, CH-1705 Fribourg (Switzerland); Blue, Andrew [SUPA School of Physics and Astronomy, University of Glasgow, G12 8QQ (United Kingdom); Diez, Sergio [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States); Deutsches Elektronen-Synchrotron, Notkestraße 85, 22607 Hamburg (Germany); Dressnandt, Nandor [University of Pennsylvania, Philadelphia, PA 19104 (United States); Duner, Silvan [University of Applied Sciences Western Switzerland, Boulevard de Pérolles 80 – CP 32, CH-1705 Fribourg (Switzerland); Garcia-Sciveres, Maurice; Haber, Carl [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States); Halgeri, Amogh; Keener, Paul [University of Pennsylvania, Philadelphia, PA 19104 (United States); Keller, John [Deutsches Elektronen-Synchrotron, Notkestraße 85, 22607 Hamburg (Germany); Newcomer, Mitchell [University of Pennsylvania, Philadelphia, PA 19104 (United States); Pasner, Jacob [University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064 (United States); Peschke, Richard [Deutsches Elektronen-Synchrotron, Notkestraße 85, 22607 Hamburg (Germany); Risbud, Amar [University of California Berkeley, Berkeley, CA 94720 (United States); Ropraz, Eric; Stalder, Jonas [University of Applied Sciences Western Switzerland, Boulevard de Pérolles 80 – CP 32, CH-1705 Fribourg (Switzerland); Wang, Haichen [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States)

    2016-01-11

    For the planned high luminosity upgrade of the Large Hadron Collider (LHC), a significant performance improvement of the detectors is required, including new tracker and trigger systems that makes use of charged track information early on. In this note we explore the principle of real time track reconstruction integrated in the readout electronics. A prototype was built using the silicon strip sensor for the ATLAS phase-II upgrade. The real time tracker is not the baseline for ATLAS but is nevertheless of interest, as the upgraded trigger design has not yet been finalized. For this, a new readout scheme in parallel with conventional readout, called the Fast Cluster Finder (FCF), was included in the latest prototype of the ATLAS strip detector readout chip (ABC130). The FCF is capable of finding hits within 6 ns and transmitting the found hit information synchronously every 25 ns. Using the FCF together with external correlation logic makes it possible to look for pairs of hits consistent with tracks from the interaction point above a transverse momentum threshold. A correlator logic finds correlations between two closely spaced parallel sensors, a “doublet”, and can generate information used as input to a lowest level trigger decision. Such a correlator logic was developed as part of a demonstrator and was successfully tested in an electron beam. The results of this test beam experiment proved the concept of the real time track vector processor with FCF.

  7. HitWalker2: visual analytics for precision medicine and beyond.

    Science.gov (United States)

    Bottomly, Daniel; McWeeney, Shannon K; Wilmot, Beth

    2016-04-15

    The lack of visualization frameworks to guide interpretation and facilitate discovery is a potential bottleneck for precision medicine, systems genetics and other studies. To address this we have developed an interactive, reproducible, web-based prioritization approach that builds on our earlier work. HitWalker2 is highly flexible and can utilize many data types and prioritization methods based upon available data and desired questions, allowing it to be utilized in a diverse range of studies such as cancer, infectious disease and psychiatric disorders. Source code is freely available at https://github.com/biodev/HitWalker2 and implemented using Python/Django, Neo4j and Javascript (D3.js and jQuery). We support major open source browsers (e.g. Firefox and Chromium/Chrome). wilmotb@ohsu.edu Supplementary data are available at Bioinformatics online. Additional information/instructions are available at https://github.com/biodev/HitWalker2/wiki. © The Author 2015. Published by Oxford University Press.

  8. Contribution of Visual Information about Ball Trajectory to Baseball Hitting Accuracy.

    Science.gov (United States)

    Higuchi, Takatoshi; Nagami, Tomoyuki; Nakata, Hiroki; Watanabe, Masakazu; Isaka, Tadao; Kanosue, Kazuyuki

    2016-01-01

    The contribution of visual information about a pitched ball to the accuracy of baseball-bat contact may vary depending on the part of trajectory seen. The purpose of the present study was to examine the relationship between hitting accuracy and the segment of the trajectory of the flying ball that can be seen by the batter. Ten college baseball field players participated in the study. The systematic error and standardized variability of ball-bat contact on the bat coordinate system and pitcher-to-catcher direction when hitting a ball launched from a pitching machine were measured with or without visual occlusion and analyzed using analysis of variance. The visual occlusion timing included occlusion from 150 milliseconds (ms) after the ball release (R+150), occlusion from 150 ms before the expected arrival of the launched ball at the home plate (A-150), and a condition with no occlusion (NO). Twelve trials in each condition were performed using two ball speeds (31.9 m·s-1 and 40.3 m·s-1). Visual occlusion did not affect the mean location of ball-bat contact in the bat's long axis, short axis, and pitcher-to-catcher directions. Although the magnitude of standardized variability was significantly smaller in the bat's short axis direction than in the bat's long axis and pitcher-to-catcher directions (p ball trajectory for improving hitting accuracy, which is likely due to visuo-motor delay.

  9. A business case for HIT adoption: effects of "meaningful use" EHR financial incentives on clinic revenue.

    Science.gov (United States)

    Behkami, Nima A; Dorr, David A; Morrice, Stuart

    2010-01-01

    The goal of this study is to describe a framework that allows decision makers to efficiently evaluate factors that affect Electronic Health Record (EHR) adoption and test suitable interventions; specifically financial incentives. The United States healthcare delivery system is experiencing a transformation to improve population health. There is strong agreement that "meaningful use" of Health Information Technology (HIT) is a major enabler in this effort. However it's also understood that the high cost of implementing an EHR is an obstacle for adoption. To help understand these complexities we developed a simulation model designed to capture the dynamic nature of policy interventions that affect the adoption of EHR. We found that "Effective" use of HIT approaches break-even-point and larger clinic revenue many times faster that "average" or "poor" use of HIT. This study uses a systems perspective to the evaluate EHR adoption process through the "meaningful use" redesign as proposed in the American Reinvestment and Recovery Act 2009 in the United States healthcare industry by utilizing the System Dynamics methodology and Scenario Analysis.

  10. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis.

    Science.gov (United States)

    Davis, Justin; Eyre, Harris; Jacka, Felice N; Dodd, Seetal; Dean, Olivia; McEwen, Sarah; Debnath, Monojit; McGrath, John; Maes, Michael; Amminger, Paul; McGorry, Patrick D; Pantelis, Christos; Berk, Michael

    2016-06-01

    Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Rapid and simple IgG specific test for the exclusion of heparin induced thrombocytopenia (HIT).

    Science.gov (United States)

    Kolde, Hans-Jürgen; Dostatni, Ralf; Mauracher, Susanne

    2011-08-29

    The exclusion of heparin induced thrombocytopenia (HIT) is required for selecting the most appropriate anticoagulation therapy in affected patients. It requires the combination of clinical data with the detection of antibodies directed against platelet factor 4 (PF4) in complex with polyanions (PA) such as heparin. We developed a lateral flow immunoassay (LFIA) for PF4/PA complex specific IgG antibodies based on gold nanoparticles. Unlike most other assays, the initial immune reaction takes place in the liquid phase. The sensitivity of the assay has been adjusted with clinical samples aiming in the reliable detection of sera which are positive in a functional platelet activation assay. Sera from 60 patients with suspected HIT were investigated. LFIA identified correctly all samples (n=20) which were positive in a functional assay (HIPA) and an IgG specific ELISA. It correlated with ELISA, but false positive results were less frequent (7 samples were negative with LFIA and HIPA but positive with ELISA). The LFIA may be a suitable tool for the rapid exclusion of HIT within 10 min.

  12. Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors.

    Science.gov (United States)

    Sahu, Niteshkumar U; Singh, Vinayak; Ferraris, Davide M; Rizzi, Menico; Kharkar, Prashant S

    2018-04-18

    Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data

    DEFF Research Database (Denmark)

    Jurtz, Vanessa Isabell; Paul, Sinu; Andreatta, Massimo

    2017-01-01

    Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway...

  14. Biochemical functionalization of peptide nanotubes with phage displayed peptides

    Science.gov (United States)

    Swaminathan, Swathi; Cui, Yue

    2016-09-01

    The development of a general approach for the biochemical functionalization of peptide nanotubes (PNTs) could open up existing opportunities in both fundamental studies as well as a variety of applications. PNTs are spontaneously assembled organic nanostructures made from peptides. Phage display has emerged as a powerful approach for identifying selective peptide binding motifs. Here, we demonstrate for the first time the biochemical functionalization of PNTs via peptides identified from a phage display peptide library. The phage-displayed peptides are shown to recognize PNTs. These advances further allow for the development of bifunctional peptides for the capture of bacteria and the self-assembly of silver particles onto PNTs. We anticipate that these results could provide significant opportunities for using PNTs in both fundamental studies and practical applications, including sensors and biosensors nanoelectronics, energy storage devices, drug delivery, and tissue engineering.

  15. Synthetic Medicinal Chemistry in Chagas' Disease: Compounds at The Final Stage of "Hit-To-Lead" Phase.

    Science.gov (United States)

    Cerecetto, Hugo; González, Mercedes

    2010-03-25

    Chagas' disease, or American trypanosomosiasis, has been the most relevant illness produced by protozoa in Latin America. Synthetic medicinal chemistry efforts have provided an extensive number of chemodiverse hits at the "active-to-hit" stage. However, only a more limited number of these have been studied in vivo in models of Chagas' disease. Herein, we survey some of the cantidates able to surpass the "hit-to-lead" stage discussing their limitations or merit to enter in clinical trials in the short term.

  16. A Novel Scheme of Fast-frequency Hopping Optical CDMA System with No-hit-zone Sequence

    Science.gov (United States)

    Ji, Jianhua; liu, Ling; Wang, Ke; Zhang, Zhipeng; Xu, Ming

    2013-09-01

    In traditional fast frequency-hopping OCDMA (FFH-OCDMA) system, beat noise and multiple-access interference are the main performance limitations, and complicated power control must be employed to eliminate the near-far effect. In this paper, a novel scheme of FFH-OCDMA with no-hit-zone sequence is proposed, which is named NHZ FFH-OCDMA. In NHZ FFH-OCDMA, the synchronization among users can be controlled within permissible time delay, and the code cross-correlation for different users equals zero. Therefore, near-far effect can be eliminated. Furthermore, beat noise and multiple-access interference also can be removed. Simulation of eight simultaneous users with dada rate 100 Mbit/s is demonstrated, where the fiber link consists of 50 km single-mode fiber, plus 5 km dispersion compensating fiber. Simulation results show that the near-far problem of NHZ FFH-OCDMA can be eliminated, and complicated power control can be removed. Therefore, this scheme is a good candidate for optical access network.

  17. Phase II Study of Personalized Peptide Vaccination with Both a Hepatitis C Virus-Derived Peptide and Peptides from Tumor-Associated Antigens for the Treatment of HCV-Positive Advanced Hepatocellular Carcinoma Patients

    Directory of Open Access Journals (Sweden)

    Shigeru Yutani

    2015-01-01

    Full Text Available Objective. To evaluate safety and immune responses of personalized peptide vaccination (PPV for hepatitis C virus- (HCV- positive advanced hepatocellular carcinoma (HCC. Patients and Methods. Patients diagnosed with HCV-positive advanced HCC were eligible for this study. A maximum of four HLA-matched peptides were selected based on the preexisting IgG responses specific to 32 different peptides, which consisted of a single HCV-derived peptide at core protein positions 35–44 (C-35 and 31 peptides derived from 15 different tumor-associated antigens (TAAs, followed by subcutaneous administration once per week for 8 weeks. Peptide-specific cytotoxic T lymphocyte (CTL and IgG responses were measured before and after vaccination. Results. Forty-two patients were enrolled. Grade 3 injection site skin reaction was observed in 2 patients, but no other PPV-related severe adverse events were noted. Peptide-specific CTL responses before vaccination were observed in only 3 of 42 patients, but they became detectable in 23 of 36 patients tested after vaccination. Peptide-specific IgG responses were also boosted in 19 of 36 patients. Peptide-specific IgG1 responses to both C-35 and TAA-derived peptides could be potentially prognostic for overall survival. Conclusion. Further clinical study of PPV would be warranted for HCV-positive advanced HCC, based on the safety and strong immune induction.

  18. A peptide-retrieval strategy enables significant improvement of quantitative performance without compromising confidence of identification.

    Science.gov (United States)

    Tu, Chengjian; Shen, Shichen; Sheng, Quanhu; Shyr, Yu; Qu, Jun

    2017-01-30

    Reliable quantification of low-abundance proteins in complex proteomes is challenging largely owing to the limited number of spectra/peptides identified. In this study we developed a straightforward method to improve the quantitative accuracy and precision of proteins by strategically retrieving the less confident peptides that were previously filtered out using the standard target-decoy search strategy. The filtered-out MS/MS spectra matched to confidently-identified proteins were recovered, and the peptide-spectrum-match FDR were re-calculated and controlled at a confident level of FDR≤1%, while protein FDR maintained at ~1%. We evaluated the performance of this strategy in both spectral count- and ion current-based methods. >60% increase of total quantified spectra/peptides was respectively achieved for analyzing a spike-in sample set and a public dataset from CPTAC. Incorporating the peptide retrieval strategy significantly improved the quantitative accuracy and precision, especially for low-abundance proteins (e.g. one-hit proteins). Moreover, the capacity of confidently discovering significantly-altered proteins was also enhanced substantially, as demonstrated with two spike-in datasets. In summary, improved quantitative performance was achieved by this peptide recovery strategy without compromising confidence of protein identification, which can be readily implemented in a broad range of quantitative proteomics techniques including label-free or labeling approaches. We hypothesize that more quantifiable spectra and peptides in a protein, even including less confident peptides, could help reduce variations and improve protein quantification. Hence the peptide retrieval strategy was developed and evaluated in two spike-in sample sets with different LC-MS/MS variations using both MS1- and MS2-based quantitative approach. The list of confidently identified proteins using the standard target-decoy search strategy was fixed and more spectra/peptides with less

  19. Antibody Production with Synthetic Peptides.

    Science.gov (United States)

    Lee, Bao-Shiang; Huang, Jin-Sheng; Jayathilaka, Lasanthi P; Lee, Jenny; Gupta, Shalini

    2016-01-01

    Peptides (usually 10-20 amino acid residues in length) can be used as effectively as proteins in raising antibodies producing both polyclonal and monoclonal antibodies routinely with titers higher than 20,000. Peptide antigens do not function as immunogens unless they are conjugated to proteins. Production of high quality antipeptide antibodies is dependent upon peptide sequence selection, the success of peptide synthesis, peptide-carrier protein conjugation, the humoral immune response in the host animal, the adjuvant used, the peptide dose administered, the injection method, and the purification of the antibody. Peptide sequence selection is probably the most critical step in the production of antipeptide antibodies. Although the process for designing peptide antigens is not exact, several guidelines and computational B-cell epitope prediction methods can help maximize the likelihood of producing antipeptide antibodies that recognize the protein. Antibodies raised by peptides have become essential tools in life science research. Virtually all phospho-specific antibodies are now produced using phosphopeptides as antigens. Typically, 5-20 mg of peptide is enough for antipeptide antibody production. It takes 3 months to produce a polyclonal antipeptide antibody in rabbits that yields ~100 mL of serum which corresponds to ~8-10 mg of the specific antibody after affinity purification using a peptide column.

  20. C-MYC-positive relapsed and refractory, diffuse large B-cell lymphoma: Impact of additional "hits" and outcomes with subsequent therapy.

    Science.gov (United States)

    Epperla, Narendranath; Maddocks, Kami J; Salhab, Mohammed; Chavez, Julio C; Reddy, Nishitha; Karmali, Reem; Umyarova, Elvira; Bachanova, Veronika; Costa, Cristiana; Glenn, Martha; Calzada, Oscar; Xavier, Ana C; Zhou, Zheng; Hossain, Nasheed M; Hernandez-Ilizaliturri, Francisco J; Al-Mansour, Zeina; Barta, Stefan K; Chhabra, Saurabh; Lansigan, Frederick; Mehta, Amitkumar; Jaglal, Michael V; Evans, Andrew; Flowers, Christopher R; Cohen, Jonathon B; Fenske, Timothy S; Hamadani, Mehdi; Costa, Luciano J

    2017-11-15

    The impact of MYC proto-oncogene, basic helix-loop-helix (MYC) translocations (with or without additional rearrangements involving the B-cell lymphoma 2 [BCL2] or BCL6 genes) on the response to salvage therapy and survival in patients with diffuse large B-cell lymphoma (DLBCL) who experience primary treatment failure is not well defined. This was a multicenter, retrospective study of the impact of MYC, BCL2, and BCL6 rearrangements in patients with DLBCL who failed to achieve complete remission or relapsed within 6 months after they completed upfront chemoimmunotherapy. The authors examined response to salvage therapy, receipt of hematopoietic cell transplantation (HCT), and survival outcomes in MYC-negative (n = 120), MYC-positive single hit (SH) (n = 20), and MYC-positive double hit/triple hit (DH/TH) (n = 35) cohorts. The overall response rate in these cohorts to first salvage therapy (51%, 50%, and 54%, respectively) and receipt of HCT (52%, 40%, and 43%, respectively) were comparable between the 3 cohorts. The 2-year overall survival rate was 29.9% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 9.9% in the MYC-positive DH/TH cohort (P MYC-positive SH DLBCL (hazard ratio, 1.70; 95% confidence interval, 0.98-2.96; P = .06) and those with MYC-positive DH/TH DLBCL (hazard ratio, 2.22; 95% confidence interval, 1.41-3.50; P = .001) persisted after adjusting for covariates. For patients who underwent autologous HCT, the 2-year overall survival rate was 55.4% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 19.4% in the MYC-positive DH/TH cohort (P MYC-positive patients who underwent allogeneic HCT relapsed in MYC-positive DLBCL who experience primary treatment failure have response rates to similar to those achieved by salvage therapy compared with their MYC-negative counterparts, but their survival is dismal irrespective of additional "hits" and HCT, representing an unmet medical need. Cancer 2017;123:4411-8. © 2017 American

  1. Selective 'in synthesis' labelling of peptides by fluorochromes.

    Science.gov (United States)

    Chersi, A; di Modugno, F; Rosanò, L

    1997-07-19

    A new method is described for producing fluorescently-tagged peptides containing specific internal derivatives of lysyl residues. The technique employs the base-labile Boc-Lys(Fmoc)-COOH derivative with base-catalyzed removal of the Fmoc protecting group during peptide synthesis and subsequent fluorescent derivatization of the deprotected epsilon-amino group of lysine. By this technique, other lysine residues and the alpha-amino group of the fragment remain unmodified, which could have some value in studies where it might be required to tag a single individual lysine residue within the peptide, but not the amino terminus. In spite of the fact that poly-substituted peptides are badly soluble and might seldom find a practical application, this technique also allows the introduction of different fluorochromes at different lysyl residues within the peptide, thus obtaining double fluorescence. The method, fast and easy, requires a limited number of manual operations during the automatic synthesis of peptides. Although peptide synthesizers provided with an oscillating glass reactor are more suitable for the manual interventions described, this technique might be also adapted to the newer instruments utilizing continuous-flow columns.

  2. Combinatorially selected peptides for protection of soybean against Phakopsora pachyrhizi.

    Science.gov (United States)

    Fang, Zhiwei D; Marois, James J; Stacey, Gary; Schoelz, James E; English, James T; Schmidt, Francis J

    2010-10-01

    Phakopsora pachyrhizi, the fungal pathogen that causes Asian soybean rust, has the potential to cause significant losses in soybean yield in many production regions of the United States. Germplasm with durable, single-gene resistance is lacking, and control of rust depends on timely application of fungicides. To assist the development of new modes of soybean resistance, we identified peptides from combinatorial phage-display peptide libraries that inhibit germ tube growth from urediniospores of P. pachyrhizi. Two peptides, Sp2 and Sp39, were identified that inhibit germ tube development when displayed as fusions with the coat protein of M13 phage or as fusions with maize cytokinin oxidase/dehydrogenase (ZmCKX1). In either display format, the inhibitory effect of the peptides on germ tube growth was concentration dependent. In addition, when peptides Sp2 or Sp39 in either format were mixed with urediniospores and inoculated to soybean leaves with an 8-h wetness period, rust lesion development was reduced. Peptides Sp2 and Sp39, displayed on ZmCKX1, were found to interact with a 20-kDa protein derived from germinated urediniospores. Incorporating peptides that inhibit pathogen development and pathogenesis into breeding programs may contribute to the development of soybean cultivars with improved, durable rust tolerance.

  3. X-hitting: A new algorithm for novelty detection and dereplication by UV spectra of complex mixtures of natural products

    DEFF Research Database (Denmark)

    Hansen, Michael Edberg; Smedsgaard, Jørn; Larsen, Thomas Ostenfeld

    2005-01-01

    identification of known structures, a task we call cross-hitting, and tentative identification of potentially new bioactive compounds, a task we call new-hitting, in HPLC data from analysis of fungal extracts. Both tasks are illustrated using 18 important reference compounds and complex fungal extracts obtained......A major challenge in lead discovery is to detect well-known and trivial compounds rapidly, a process known as dereplication, so that isolation, structure elucidation, and pharmacological investigations can be focused on novel compounds. In this paper, we present a new algorithm, X-hitting, based...... on cross sample comparison of full UV spectra from HPLC analysis of highly complex natural product extracts/samples. X-Hitting allows automatic identification of known compounds but more important also allows finding of potentially new or similar compounds. We demonstrate this new algorithm by automatic...

  4. Successful management of acute thromboembolic disease complicated with heparin induced thrombocytopenia type II (HIT II: a case series

    Directory of Open Access Journals (Sweden)

    Trellopoulos George

    2008-07-01

    Full Text Available Abstract Heparin-induced thrombocytopenia type II (HIT II is a rare immune-mediated complication of heparin. The diagnosis of HIT is considered in patients exposed to heparin, presenting with thrombocytopenia and thrombosis. We present two cases with massive pulmonary embolism and HIT, successfully treated with the administration of fondaparinux, an alternative anticoagulant, combined with the insertion of an inferior vena cava filter for the prevention of new thromboembolic events. The two cases supplement the available data of the use of fondaparinux in patients with HIT and pulmonary embolism, before further large studies establish its efficacy and safety in this group of patients. Moreover, the management of these patients reveals the need for future evaluation of the combined therapy of alternative anticoagulant agents with the placement of vena cava filters.

  5. HIT, hallucination focused integrative treatment as early intervention in psychotic adolescents with auditory hallucinations : a pilot study

    NARCIS (Netherlands)

    Jenner, JA; van de Willige, G

    Objective: Early intervention in psychosis is considered important in relapse prevention. Limited results of monotherapies prompt to development of multimodular programmes. The present study tests feasibility and effectiveness of HIT, an integrative early intervention treatment for auditory

  6. Antimicrobial Peptides (AMPs

    Directory of Open Access Journals (Sweden)

    Mehrzad Sadredinamin

    2016-04-01

    Full Text Available Antimicrobial peptides (AMPs are extensive group of molecules that produced by variety tissues of invertebrate, plants, and animal species which play an important role in their immunity response. AMPs have different classifications such as; biosynthetic machines, biological sources, biological functions, molecular properties, covalent bonding patterns, three dimensional structures, and molecular targets.These molecules have multidimensional properties including antimicrobial activity, antiviral activity, antifungal activity, anti-parasite activity, biofilm control, antitumor activity, mitogens activity and linking innate to adaptive immunity that making them promising agents for therapeutic drugs. In spite of this advantage of AMPs, their clinical developments have some limitation for commercial development. But some of AMPs are under clinical trials for the therapeutic purpose such as diabetic foot ulcers, different bacterial infections and tissue damage. In this review, we emphasized on the source, structure, multidimensional properties, limitation and therapeutic applications of various antimicrobial peptides.

  7. Lessons learnt from the Wenchuan earthquake: performance evaluation of treatment of critical injuries in hardest-hit areas.

    Science.gov (United States)

    Jiang, Jie; Li, Youping; Huang, Xiaolin; Li, Bing; Su, Lin; Zhong, Dake; Shi, Chenghu; Li, Mingxu; Shan, Juan; Chen, Yin

    2012-08-01

    Critical injury treatment in the hardest-hit areas after a great earthquake was retrospectively analyzed to determine how best to reduce mortality and disability and increase the rehabilitation rate through postquake medical relief. Retrospective analysis, primary sources, and secondary sources were comprehensively retrieved and analyzed. According to incomplete data, 30,620 injured were rescued by themselves among the hardest-hit areas in the 72 hours immediately following the earthquake. Critically injured patients accounted for 22% of total inpatients. Mortality rates declined with greater distance from the epicenter: rates were 12.21% for municipal healthcare centers in the hardest-hit areas, 4.50% for municipal medical units in peripheral quake-hit areas, 2.50% for provincial medical units in peripheral quake-hit areas, and 2.17% for Ministry of Health-affiliated hospitals in peripheral quake-hit areas. The number of injured with fractures on body, limbs or unknown-parts, severe conditions as well as other kinds of non-traumatic diseases received in second-line hospitals was much more than those treated in first-line hospitals with more severe injuries. Among 10,373 injured in stable condition transferred to third-line hospitals, 99.07% were discharged from hospitals within four months, while the mortality rate was 0.017%. The medical relief model of "supervising body helping subordinate unit, severely stricken areas assisting hardest-hit areas, least-hit areas supporting both hardest-hit and severely stricken areas, and self help and mutual assistance applied between hardest-hit areas" was roughly established for injured from severely stricken areas after the Wenchuan Earthquake. The "four-centralization" treatment principle, which referred to concentrating patients, experts, resources and treatment for those injured in critical condition effectively reduced the mortality from 15.06% to 2.9%. Timely, scientific, and standard on-site triage and postmedical

  8. Are antimicrobial peptides an alternative for conventional antibiotics?

    International Nuclear Information System (INIS)

    Kamysz, W.

    2005-01-01

    Antimicrobial peptides are widespread in living organisms and constitute an important component of innate immunity to microbial infections. By the early 1980' s , more than 800 different antimicrobial peptides had been isolated from mammals, amphibians, fish, insects, plants and bacterial species. In humans, they are produced by granulocytes, macrophages and most epithelial and endothelial cells. Newly discovered antibiotics have antibacterial, antifungal, antiviral and even antiprotozoal activity. Occasionally, a single antibiotic may have a very wide spectrum of activity and may show activity towards various kinds of microorganisms. Although antimicrobial activity is the most typical function of peptides, they are also characterized by numerous other properties. They stimulate the immune system, have anti-neoplastic properties and participate in cell signalling and proliferation regulation. As antimicrobial peptides from higher eukaryotes differ structurally from conventional antibiotics produced by bacteria and fungi, they offer novel templates for pharmaceutical compounds, which could be used effectively against the increasing number of resistant microbes. (author)

  9. Best hits of 11110110111: model-free selection and parameter-free sensitivity calculation of spaced seeds.

    Science.gov (United States)

    Noé, Laurent

    2017-01-01

    Spaced seeds , also named gapped q-grams, gapped k-mers, spaced q-grams , have been proven to be more sensitive than contiguous seeds ( contiguous q-grams, contiguous k-mers ) in nucleic and amino-acid sequences analysis. Initially proposed to detect sequence similarities and to anchor sequence alignments, spaced seeds have more recently been applied in several alignment-free related methods. Unfortunately, spaced seeds need to be initially designed. This task is known to be time-consuming due to the number of spaced seed candidates. Moreover, it can be altered by a set of arbitrary chosen parameters from the probabilistic alignment models used. In this general context, Dominant seeds have been introduced by Mak and Benson (Bioinformatics 25:302-308, 2009) on the Bernoulli model, in order to reduce the number of spaced seed candidates that are further processed in a parameter-free calculation of the sensitivity. We expand the scope of work of Mak and Benson on single and multiple seeds by considering the Hit Integration model of Chung and Park (BMC Bioinform 11:31, 2010), demonstrate that the same dominance definition can be applied, and that a parameter-free study can be performed without any significant additional cost. We also consider two new discrete models, namely the Heaviside and the Dirac models, where lossless seeds can be integrated. From a theoretical standpoint, we establish a generic framework on all the proposed models, by applying a counting semi-ring to quickly compute large polynomial coefficients needed by the dominance filter. From a practical standpoint, we confirm that dominant seeds reduce the set of, either single seeds to thoroughly analyse, or multiple seeds to store. Moreover, in http://bioinfo.cristal.univ-lille.fr/yass/iedera_dominance, we provide a full list of spaced seeds computed on the four aforementioned models, with one (continuous) parameter left free for each model, and with several (discrete) alignment lengths.

  10. You Can’t Think and Hit at the Same Time: Neural Correlates of Baseball Pitch Classification

    Directory of Open Access Journals (Sweden)

    Jason eSherwin

    2012-12-01

    Full Text Available Hitting a baseball is often described as the most difficult thing to do in sports. A key aptitude of a good hitter is the ability to determine which pitch is coming. This rapid decision requires the batter to make a judgment in a fraction of a second based largely on the trajectory and spin of the ball. When does this decision occur relative to the ball’s trajectory and is it possible to identify neural correlates that represent how the decision evolves over a split second? Using single-trial analysis of electroencephalography (EEG we address this question within the context of subjects discriminating three types of pitches (fastball, curveball, slider based on pitch trajectories. We find clear neural signatures of pitch classification and, using signal detection theory, we identify the times of discrimination on a trial-to-trial basis. Based on these neural signatures we estimate neural discrimination distributions as a function of the distance the ball is from the plate. We find all three pitches yield unique distributions, namely the timing of the discriminating neural signatures relative to the position of the ball in its trajectory. For instance, fastballs are discriminated at the earliest points in their trajectory, relative to the two other pitches, which is consistent with the need for some constant time to generate and execute the motor plan for the swing (or inhibition of the swing. We also find incorrect discrimination of a pitch (errors yields neural sources in Brodmann Area 10 (BA 10, which has been implicated in prospective memory, recall and task difficulty. In summary, we show that single-trial analysis of EEG yields informative distributions of the relative point in a baseball’s trajectory when the batter makes a decision on which pitch is coming.

  11. Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit.

    Science.gov (United States)

    Kounde, Cyrille S; Yeo, Hui-Quan; Wang, Qing-Yin; Wan, Kah Fei; Dong, Hongping; Karuna, Ratna; Dix, Ina; Wagner, Trixie; Zou, Bin; Simon, Oliver; Bonamy, Ghislain M C; Yeung, Bryan K S; Yokokawa, Fumiaki

    2017-03-15

    A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC 50 morphing from the HTS hit 4. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. THEORY OF ACTIVE HITTINGS IS IN PROCESSES OF ELECTRO-COAGULATION THE ADMIXTURES IN WATER TECHNOLOGICAL ENVIRONMENT

    Directory of Open Access Journals (Sweden)

    В.В. Березуцький

    2012-10-01

    Full Text Available  In the article theoretical bases of electro-coagulation of admixtures are examined in a water technological environment with the use of theory of the active hittings, which are based on the results of the executed researches and analysis of scientific information. Application of theory of the active hittings is in coagulation, provides high efficiency of process of extraction of admixtures from water environments during minimization of energy consumption and expenses of materials.

  13. Peptides containing antigenic and cationic domains have enhanced, multivalent immunogenicity when bound to DNA vaccines.

    Science.gov (United States)

    Riedl, Petra; Reimann, Jörg; Schirmbeck, Reinhold

    2004-02-01

    We explored strategies to codeliver DNA- and peptide-based vaccines in a way that enhances the immunogenicity of both components of the combination vaccine for T cells. Specific CD8(+) T cell responses to an antigenic peptide are primed when the peptide is fused to a cationic peptide domain that is bound to plasmid DNA or oligonucleotides (ODN; with or without CpG motifs). Plasmid DNA mixed with antigenic/cationic peptides or histones forms large complexes with different biological properties depending on the molar ratios of peptide/protein and polynucleotide. Complexes containing high (but not low) molar ratios of cationic peptide to DNA facilitate transfection (DNA uptake and expression of the plasmid-encoded product) of cells. In contrast, complexes containing low (but not high) molar ratios of cationic peptide to DNA prime potent multispecific T cell responses after a single intramuscular injection of the complexes. The general validity of this observation was confirmed mixing different antigenic/cationic peptides with different DNA vaccines. In these vaccine formulations, multispecific CD8(+) T cell responses specific for epitopes of the peptide- as well as the DNA-based vaccine were efficiently coprimed, together with humoral antibody responses to conformational determinants of large viral antigens encoded by the DNA vaccine. The data indicate that mixtures of DNA vaccines with antigenic, cationic peptides are immunogenic vaccine formulations particularly suited for the induction of multispecific T cell responses.

  14. Radiolabelled peptides vs. nanoparticle-peptide complexes for medical applications

    International Nuclear Information System (INIS)

    Ferro F, G.

    2007-01-01

    Full text: The principle that peptide receptors can be used successfully for in vivo targeting of human cancers has been provided and the peptide-receptor radionuclide therapy for malignant tumors is a real treatment option. Targeted entry into cells is an increasingly important area of research. The diagnoses and treatment of disease by novel methods would be enhanced greatly by the efficient transport of materials to living cell nuclei. Membrane-trans locating peptides complexed to nanoparticles are small enough (30 nm) to cross the nuclear membrane and to enter the cell via receptor-mediated endocytosis, emerging as a new type of pharmaceuticals. Pharmacokinetic properties and molecular specificity of iron or gold nanoparticle-peptide complexes that do not induce biological toxicity is a topic of world interest in current and future medical investigations. Some perspectives and achievements on the preparation, pharmacokinetics and dosimetry of radiolabelled peptides versus nanoparticle-peptide complexes for medical applications are presented. (Author)

  15. Inhibition of dengue virus entry into target cells using synthetic antiviral peptides.

    Science.gov (United States)

    Alhoot, Mohammed Abdelfatah; Rathinam, Alwin Kumar; Wang, Seok Mui; Manikam, Rishya; Sekaran, Shamala Devi

    2013-01-01

    Despite the importance of DENV as a human pathogen, there is no specific treatment or protective vaccine. Successful entry into the host cells is necessary for establishing the infection. Recently, the virus entry step has become an attractive therapeutic strategy because it represents a barrier to suppress the onset of the infection. Four putative antiviral peptides were designed to target domain III of DENV-2 E protein using BioMoDroid algorithm. Two peptides showed significant inhibition of DENV when simultaneously incubated as shown by plaque formation assay, RT-qPCR, and Western blot analysis. Both DET4 and DET2 showed significant inhibition of virus entry (84.6% and 40.6% respectively) using micromolar concentrations. Furthermore, the TEM images showed that the inhibitory peptides caused structural abnormalities and alteration of the arrangement of the viral E protein, which interferes with virus binding and entry. Inhibition of DENV entry during the initial stages of infection can potentially reduce the viremia in infected humans resulting in prevention of the progression of dengue fever to the severe life-threatening infection, reduce the infected vector numbers, and thus break the transmission cycle. Moreover these peptides though designed against the conserved region in DENV-2 would have the potential to be active against all the serotypes of dengue and might be considered as Hits to begin designing and developing of more potent analogous peptides that could constitute as promising therapeutic agents for attenuating dengue infection.

  16. Contribution of Visual Information about Ball Trajectory to Baseball Hitting Accuracy.

    Directory of Open Access Journals (Sweden)

    Takatoshi Higuchi

    Full Text Available The contribution of visual information about a pitched ball to the accuracy of baseball-bat contact may vary depending on the part of trajectory seen. The purpose of the present study was to examine the relationship between hitting accuracy and the segment of the trajectory of the flying ball that can be seen by the batter. Ten college baseball field players participated in the study. The systematic error and standardized variability of ball-bat contact on the bat coordinate system and pitcher-to-catcher direction when hitting a ball launched from a pitching machine were measured with or without visual occlusion and analyzed using analysis of variance. The visual occlusion timing included occlusion from 150 milliseconds (ms after the ball release (R+150, occlusion from 150 ms before the expected arrival of the launched ball at the home plate (A-150, and a condition with no occlusion (NO. Twelve trials in each condition were performed using two ball speeds (31.9 m·s-1 and 40.3 m·s-1. Visual occlusion did not affect the mean location of ball-bat contact in the bat's long axis, short axis, and pitcher-to-catcher directions. Although the magnitude of standardized variability was significantly smaller in the bat's short axis direction than in the bat's long axis and pitcher-to-catcher directions (p < 0.001, additional visible time from the R+150 condition to the A-150 and NO conditions resulted in a further decrease in standardized variability only in the bat's short axis direction (p < 0.05. The results suggested that there is directional specificity in the magnitude of standardized variability with different visible time. The present study also confirmed the limitation to visual information is the later part of the ball trajectory for improving hitting accuracy, which is likely due to visuo-motor delay.

  17. Computational Breakthrough of Natural Lead Hits from the Genus ofArisaemaagainst Human Respiratory Syncytial Virus.

    Science.gov (United States)

    Kant, Kamal; Lal, Uma Ranjan; Ghosh, Manik

    2018-01-01

    To date, efforts for the prevention and treatment of human respiratory syncytial virus (RSV) infection have been still vain, and there is no safe and effective clinical accepted vaccine. Arisaema genus has claimed for various traditional bioactivities, but scientific assessments are quite limited. This encouraged us to carry out our present study on around 60 phytoconstituents of different Arisaema species as a natural inhibitor against the human RSV. Selected 60 phytochemical entities were evaluated on the docking behavior of human RSV receptor (PDB: 4UCC) using Maestro 9.3 (Schrödinger, LLC, Cambridge, USA). Furthermore, kinetic properties and toxicity nature of top graded ligands were analyzed through QikProp and ProTox tools. Notably, rutin (glide score: -8.49), schaftoside (glide score: -8.18) and apigenin-6,8-di-C-β-D-galactoside (glide score - 7.29) have resulted in hopeful natural lead hits with an ideal range of kinetic descriptors values. ProTox tool (oral rodent toxicity) has resulted in likely toxicity targets of apex-graded tested ligands. Finally, the whole efforts can be explored further as a model to confirm its anti-human RSV potential with wet laboratory experiments. Rutin, schaftoside, and apigenin-6,8-di-C-β-D-galactoside showed promising top hits docking profile against human respiratory syncytial virusMoreover, absorption, distribution, metabolism, excretion properties (QikProp) of top hits resulted within an ideal range of kinetic descriptorsProTox tool highlighted toxicity class ranges, LD 50 values, and possible toxicity targets of apex-graded tested ligands. Abbreviations used: RSV: Respiratory syncytial virus, PRRSV: Porcine respiratory and reproductive syndrome virus, ADME-T: Absorption, distribution, metabolism, excretion, and toxicity.

  18. Peptide-enhanced oral delivery of therapeutic peptides and proteins

    DEFF Research Database (Denmark)

    Kristensen, Mie; Foged, Camilla; Berthelsen, Jens

    2013-01-01

    Systemic therapy upon oral delivery of biologics, such as peptide and protein drugs is limited due to their large molecular size, their low enzymatic stability and their inability to cross the intestinal epithelium. Ways to overcome the epithelial barrier include the use of peptide-based excipients...... throughout the gastrointestinal (GI) tract, chemical stability is an inherent challenge when employing amino acid-based excipients for oral delivery, and multiple approaches have been investigated to improve this. The exact mechanisms of transepithelial translocation are discussed, and it is believed...... for oral delivery of peptide and protein drugs highlighting recent studies and the most promising compounds from these classes of peptide excipients....

  19. Hitting times of local and global optima in genetic algorithms with very high selection pressure

    Directory of Open Access Journals (Sweden)

    Eremeev Anton V.

    2017-01-01

    Full Text Available The paper is devoted to upper bounds on the expected first hitting times of the sets of local or global optima for non-elitist genetic algorithms with very high selection pressure. The results of this paper extend the range of situations where the upper bounds on the expected runtime are known for genetic algorithms and apply, in particular, to the Canonical Genetic Algorithm. The obtained bounds do not require the probability of fitness-decreasing mutation to be bounded by a constant which is less than one.

  20. The pulsation-rotation interaction: Greatest hits and the B-side

    Science.gov (United States)

    Townsend, Rich

    2014-02-01

    It has long been known that rotation can have an appreciable impact on stellar pulsation - by modifying the usual p and g modes found in the non-rotating case, and by introducing new classes of modes. However, it's only relatively recently that advances in numerical simulations and complementary theoretical treatments have enabled us to model these phenomena in any great detail. In this talk I'll review highlights in this area (the `Greatest Hits'), before considering the flip side (or the `B-side', for those of us old enough to remember vinyl records) of the pulsation-rotation interaction: how pulsation can itself influence internal rotation profiles.

  1. Fingerprinting of Peptides with a Large Channel of Bacteriophage Phi29 DNA Packaging Motor.

    Science.gov (United States)

    Ji, Zhouxiang; Wang, Shaoying; Zhao, Zhengyi; Zhou, Zhi; Haque, Farzin; Guo, Peixuan

    2016-09-01

    Nanopore technology has become a highly sensitive and powerful tool for single molecule sensing of chemicals and biopolymers. Protein pores have the advantages of size amenability, channel homogeneity, and fabrication reproducibility. But most well-studied protein pores for sensing are too small for passage of peptide analytes that are typically a few nanometers in dimension. The funnel-shaped channel of bacteriophage phi29 DNA packaging motor has previously been inserted into a lipid membrane to serve as a larger pore with a narrowest N-terminal constriction of 3.6 nm and a wider C-terminal end of 6 nm. Here, the utility of phi29 motor channel for fingerprinting of various peptides using single molecule electrophysiological assays is reported. The translocation of peptides is proved unequivocally by single molecule fluorescence imaging. Current blockage percentage and distinctive current signatures are used to distinguish peptides with high confidence. Each peptide generated one or two distinct current blockage peaks, serving as typical fingerprint for each peptide. The oligomeric states of peptides can also be studied in real time at single molecule level. The results demonstrate the potential for further development of phi29 motor channel for detection of disease-associated peptide biomarkers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Peptide Signals Encode Protein Localization▿

    OpenAIRE

    Russell, Jay H.; Keiler, Kenneth C.

    2007-01-01

    Many bacterial proteins are localized to precise intracellular locations, but in most cases the mechanism for encoding localization information is not known. Screening libraries of peptides fused to green fluorescent protein identified sequences that directed the protein to helical structures or to midcell. These peptides indicate that protein localization can be encoded in 20-amino-acid peptides instead of complex protein-protein interactions and raise the possibility that the location of a ...

  3. The Equine PeptideAtlas

    DEFF Research Database (Denmark)

    Bundgaard, Louise; Jacobsen, Stine; Sorensen, Mette A.

    2014-01-01

    Equine PeptideAtlas encompassing high-resolution tandem MS analyses of 51 samples representing a selection of equine tissues and body fluids from healthy and diseased animals. The raw data were processed through the Trans-Proteomic Pipeline to yield high quality identification of proteins and peptides...... analyses, and emphasizes the value of the Equine PeptideAtlas as a resource for the design of targeted quantitative proteomic studies....

  4. Structural Characterization of Peptide Antibodies

    DEFF Research Database (Denmark)

    Chailyan, Anna; Marcatili, Paolo

    2015-01-01

    The role of proteins as very effective immunogens for the generation of antibodies is indisputable. Nevertheless, cases in which protein usage for antibody production is not feasible or convenient compelled the creation of a powerful alternative consisting of synthetic peptides. Synthetic peptides...... can be modified to obtain desired properties or conformation, tagged for purification, isotopically labeled for protein quantitation or conjugated to immunogens for antibody production. The antibodies that bind to these peptides represent an invaluable tool for biological research and discovery...

  5. One Hundred Years of Peptide Chemistry

    Indian Academy of Sciences (India)

    thus a chiral center. Today, 20 amino acids are known as genetically encoded as building blocks of peptides and proteins. Almost all of them present in peptides have L-configura- tion. D-amino acids have been found only in small peptides of bacterial cell walls, peptide antibiotics and peptides in South American frog skin.

  6. Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes – a randomized, single-blinded, cross-over pilot study

    DEFF Research Database (Denmark)

    Faber, Rebekka; Zander, Mette; Pena, Adam

    2015-01-01

    with either the GLP-1 analogue liraglutide or received no treatment for 10 weeks, in a randomized, single-blinded, cross-over setup with a 2 weeks wash-out period. The effect of liraglutide on coronary microcirculation was evaluated using non-invasive trans-thoracic Doppler-flow echocardiography during...... dipyridamole induced stress. Peripheral microvascular endothelial function was assessed by Endo-PAT2000®. Interventions were compared by two-sample t-test after ensuring no carry over effect. RESULTS: A total of 24 patients were included. Twenty patients completed the study (15 male; mean age 57 ± 9; mean BMI...

  7. A framework of induced hyperspace dynamical systems equipped with the hit-or-miss topology

    International Nuclear Information System (INIS)

    Wang Yangeng; Wei Guo; Campbell, William H.; Bourquin, Steven

    2009-01-01

    For any dynamical system (E,d,f), where E is Hausdorff locally compact second countable (HLCSC), let F (resp., 2 E ) denote the space of all closed subsets (resp., non-empty closed subsets) of E equipped with the hit-or-miss topology τ f . Both F and 2 E are again HLCSC (F actually compact), thus metrizable. Let ρ be such a metric (three metrics available). The main purpose is to determine the conditions on f that ensure the continuity of the induced hyperspace maps 2 f :F→F and 2 f :2 E →2 E defined by 2 f (F)=f(F). With this setting, the induced hyperspace systems (F,ρ,2 f ) and (2 E ,ρ,2 f ) are compact and locally compact dynamical systems, respectively. Consequently, dynamical properties, particularly metric related dynamical properties, of the given system (E,d,f) can be explored through these hyperspace systems. In contrast, when the Vietoris topology τ v is equipped on 2 E , the space of the induced hyperspace topological dynamical system (2 E ,τ v ,2 f ) is not metrizable if E is not compact metrizable, e.g., E=R n , implying that metric related dynamical concepts cannot be defined for (2 E ,τ v ,2 f ). Moreover, two examples are provided to illustrate the advantages of the hit-or-miss topology as compared to the Vietoris topology.

  8. Hubs and authorities in the world trade network using a weighted HITS algorithm.

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Deguchi

    Full Text Available We investigate the economic hubs and authorities of the world trade network (WTN from 1992 to 2012, an era of rapid economic globalization. Using a well-defined weighted hyperlink-induced topic search (HITS algorithm, we can calculate the values of the weighted HITS hub and authority for each country in a conjugate way. In the context of the WTN, authority values are large for countries with significant imports from large hub countries, and hub values are large for countries with significant exports to high-authority countries. The United States was the largest economic authority in the WTN from 1992 to 2012. The authority value of the United States has declined since 2001, and China has now become the largest hub in the WTN. At the same time, China's authority value has grown as China is transforming itself from the "factory of the world" to the "market of the world." European countries show a tendency to trade mostly within the European Union, which has decreased Europe's hub and authority values. Japan's authority value has increased slowly, while its hub value has declined. These changes are consistent with Japan's transition from being an export-driven economy in its high economic growth era in the latter half of the twentieth century to being a more mature, economically balanced nation.

  9. Progress on the HIT--II Multi-Point Thomson Scattering Diagnostic

    Science.gov (United States)

    Hamp, W. T.; Jarboe, T. R.; Smith, R. J.; Nelson, B. A.; Rogers, J. A.; Leblanc, B. P.; Phillips, P. E.

    2002-11-01

    The Helicity Injected Torus (HIT--II) multi-point Thomson scattering diagnostic (MPTS) has been designed and built to determine electron temperature and density at 11 radial positions at one time during the plasma discharge. The system includes collection optics and a Littrow mount spectrometer on loan from Princeton, and a 1 GW laser and multi-anode microchannel plate detector (MCP) from the University of Texas. The MPTS is currently operational at 6 spatial positions, indicating electron temperatures greater than 100 eV in transformer driven plasmas. The remaining 5 spatial positions are overloaded by stray laser light. Light reemerging from the beam dump is the primary suspect for stray light. A new beam dump has been constructed in an effort to reduce the stray light and increase the number of operational channels. A new diffraction grating has been constructed to increase the dispersion of the spectrometer to counteract the excessively broad frequency response of the MCP. Plans for MPTS operation include the characterization of density and temperature evolution across reconnection events in CHI driven plasmas, as well as temperature and density characterizations of optimized CHI and transformer driven plasmas in the HIT--II device.

  10. Pelvic rotation torque during fast-pitch softball hitting under three ball height conditions.

    Science.gov (United States)

    Iino, Yoichi; Fukushima, Atsushi; Kojima, Takeji

    2014-08-01

    The purpose of this study was to investigate the relevance of hip joint angles to the production of the pelvic rotation torque in fast-pitch softball hitting and to examine the effect of ball height on this production. Thirteen advanced female softball players hit stationary balls at three different heights: high, middle, and low. The pelvic rotation torque, defined as the torque acting on the pelvis through the hip joints about the pelvic superior-inferior axis, was determined from the kinematic and force plate data using inverse dynamics. Irrespective of the ball heights, the rear hip extension, rear hip external rotation, front hip adduction, and front hip flexion torques contributed to the production of pelvic rotation torque. Although the contributions of the adduction and external rotation torques at each hip joint were significantly different among the ball heights, the contributions of the front and rear hip joint torques were similar among the three ball heights owing to cancelation of the two torque components. The timings of the peaks of the hip joint torque components were significantly different, suggesting that softball hitters may need to adjust the timings of the torque exertions fairly precisely to rotate the upper body effectively.

  11. Hitting a cricket ball: what components of the interceptive action are most linked to expertise?

    Science.gov (United States)

    Weissensteiner, Juanita R; Abernethy, Bruce; Farrow, Damian

    2011-11-01

    Differences in interceptive skill between highly skilled and lesser skilled cricket batsmen were examined using a batting task that required participants to strike front-foot drive strokes from a machine-projected ball to a specified target. Task difficulty was manipulated by varying the width of the bat (normal, half, and third width) and target accuracy, and quality of bat-ball contact was monitored along with temporal and sequential elements of the hitting action. Analyses revealed that the highly skilled batsmen were distinguishable from less skilled counterparts by their higher accuracy under the normal and half-width bat conditions, significantly earlier initiation and completion of the front-foot stride, greater synchronization of the completion of the front-foot stride with the commencement of the downswing of the bat, and consistent timing of downswing relative to ball bounce and impact. In keeping with studies of other hitting sports, temporal and spatial coupling of the downswing to ball bounce to help minimize temporo-spatial error at the point of interception appeared critical to skilled performance. Implications for the understanding of interception and for coaching practice are briefly discussed.

  12. Hubs and authorities in the world trade network using a weighted HITS algorithm.

    Science.gov (United States)

    Deguchi, Tsuyoshi; Takahashi, Katsuhide; Takayasu, Hideki; Takayasu, Misako

    2014-01-01

    We investigate the economic hubs and authorities of the world trade network (WTN) from 1992 to 2012, an era of rapid economic globalization. Using a well-defined weighted hyperlink-induced topic search (HITS) algorithm, we can calculate the values of the weighted HITS hub and authority for each country in a conjugate way. In the context of the WTN, authority values are large for countries with significant imports from large hub countries, and hub values are large for countries with significant exports to high-authority countries. The United States was the largest economic authority in the WTN from 1992 to 2012. The authority value of the United States has declined since 2001, and China has now become the largest hub in the WTN. At the same time, China's authority value has grown as China is transforming itself from the "factory of the world" to the "market of the world." European countries show a tendency to trade mostly within the European Union, which has decreased Europe's hub and authority values. Japan's authority value has increased slowly, while its hub value has declined. These changes are consistent with Japan's transition from being an export-driven economy in its high economic growth era in the latter half of the twentieth century to being a more mature, economically balanced nation.

  13. Being hit twice: The psychological consequences of the economic crisis and an earthquake.

    Science.gov (United States)

    Starace, Fabrizio; Mungai, Francesco; Sarti, Elena; Addabbo, Tindara

    2016-06-01

    The Great Recession has caused worldwide tangible costs in terms of cuts in employment and income, which have been widely recognised also as major social determinants of mental health. Italy has not been spared from the financial crisis with severe societal and mental health consequences. In addition, a strong earthquake hit the province of Modena, Italy, in 2012, that is, amid the crisis. In this study, we explored and investigated the possible additional impact of concurrent events such as economic crisis and a natural disaster. Our analysis elaborated data from two local surveys, ICESmo2 (2006) and ICESmo3 (2012), and a national survey carried out in 2013 by the Italian National Institute of Statistics (Istituto Nazionale di Statistica (ISTAT)). A regression model was adopted to distinguish the effect of the crisis and the earthquake. Our analysis confirmed the negative effect of the economic crisis on psychological wellbeing, but within the province of Modena such an effect resulted as even stronger compared with the rest of Italy, particularly within those areas struck by the earthquake. Being hit by a combination of two major negative events might have a significantly increased negative effect on psychological health. The higher repercussion observed is not only attributable to the occurrence of a natural disaster but can be reasonably related to the additional effect of unemployment on psychological dimensions. © The Author(s) 2016.

  14. Peptide Vaccines for Cancer

    Directory of Open Access Journals (Sweden)

    Kono K

    2013-10-01

    Full Text Available Background: In general, the preferable characteristic of the target molecules for development of cancer vaccines are high immunogenicity, very common expression in cancer cells, specific expression in cancer cells and essential molecules for cell survival (to avoid loss of expression. We previously reported that three novel HLA-A24-restricted immunodominant peptides, which were derived from three different oncoantigens, TTK, LY6K, and IMP-3,were promising targets for cancer vaccination for esophageal squamous cell carcinoma (ESCCpatients. Then, we had performed a phase I clinical trial using three HLA-A24-binding peptides and the results had been shown to be promising for ESCC. Therefore, we further performed a multicenter, non-randomized phase II clinical trial. Patients and Methods: Sixty ESCC patients were enrolled to evaluate OS, PFS, immunological response employing ELISPOT and pentamer assays. Each of the three peptides was administered with IFA weekly. All patients received the vaccination without knowing an HLA-A type, and the HLA types were key-opened at the analysis point. Hence, the endpoints were set to evaluate differences between HLA-A*2402-positive (24(+ and -negative (24(- groups. Results: The OS in the 24 (+ group (n=35 tended to be better than that in the 24(- group (n=25 (MST 4.6 vs. 2.6 month, respectively, p = 0.121, although the difference was not statistically significant. However, the PFS in the 24(+ group was significantly better than that in the 24(- group (p = 0.032. In the 24(+ group, ELISPOT assay indicated that the LY6K-, TTK-, and IMP3-specific CTL responses were observed after the vaccination in 63%, 45%, and 60% of the 24(+ group, respectively. The patients having LY6K-, TTK-, and IMP3-specific CTL responses revealed the better OS than those not having CTL induction, respectively. The patients showing the CTL induction for multiple peptides have better clinical responses. Conclusion: The immune response induced

  15. Single-instruction multiple-data execution

    CERN Document Server

    Hughes, Christopher J

    2015-01-01

    Having hit power limitations to even more aggressive out-of-order execution in processor cores, many architects in the past decade have turned to single-instruction-multiple-data (SIMD) execution to increase single-threaded performance. SIMD execution, or having a single instruction drive execution of an identical operation on multiple data items, was already well established as a technique to efficiently exploit data parallelism. Furthermore, support for it was already included in many commodity processors. However, in the past decade, SIMD execution has seen a dramatic increase in the set of

  16. Evaluation of sequence variability in HIV-1 gp41 C-peptide helix-grafted proteins.

    Science.gov (United States)

    Tennyson, Rachel L; Walker, Susanne N; Ikeda, Terumasa; Harris, Reuben S; McNaughton, Brian R

    2017-08-01

    Many therapeutically-relevant protein-protein interactions (PPIs) have been reported that feature a helix and helix-binding cleft at the interface. Given this, different approaches to disrupting such PPIs have been developed. While short peptides (<15 amino acids) typically do not fold into a stable helix, researchers have reported chemical approaches to constraining helix structure. However, these approaches rely on laborious, and often expensive, chemical synthesis and purification. Our premise is that protein-based solutions that stabilize a therapeutically-relevant helix offer a number of advantages. In contrast to chemically constrained helical peptides, or minimal/miniature proteins, which must be synthesized (at great expense and labor), a protein can be expressed in a cellular system (like all current protein therapeutics). If selected properly, the protein scaffold can stabilize the therapeutically-relevant helix. We recently reported a protein engineering strategy, which we call "helix-grafted display", and applied it to the challenge of suppressing HIV entry. We have reported helix-grafted display proteins that inhibit formation of an intramolecular PPI involving HIV gp41 C-peptide helix, and HIV gp41 N-peptide trimer, which contain C-peptide helix-binding clefts. Here, we used yeast display to screen a library of grafted C-peptide helices for N-peptide trimer recognition. Using 'hits' from yeast display library screening, we evaluated the effect helix mutations have on structure, expression, stability, function (target recognition), and suppression of HIV entry. Copyright © 2017. Published by Elsevier Ltd.

  17. Immunomodulatory effects of anti-microbial peptides.

    Science.gov (United States)

    Otvos, Laszlo

    2016-09-01

    Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro- and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

  18. Exquisite peptide specificity of oral tolerance in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Javed, N H; Gienapp, I E; Cox, K L; Whitacre, C C

    1995-08-01

    Experimental autoimmune encephalomyelitis (EAE), induced in Lewis rats by injection of myelin basic protein (MBP) and adjuvant, is a T cell-mediated autoimmune disease. Earlier studies from our laboratory have shown that oral administration of guinea pig MBP before encephalitogenic challenge induces T cell anergy and results in the suppression of clinical signs and CNS histopathologic changes of EAE. In contrast, oral administration of rat MBP did not confer a similar degree of protection. This study was undertaken to determine the tolerogenicity of the synthetic peptide 68-88 derived from guinea pig (GP) MBP and rat MBP. These peptides differ by a single amino acid at position 80. Lewis rats fed GP 68-88 were protected from EAE induced with GP 68-88 or rat 68-88. In contrast, feeding rats 68-88 did not protect the animals from challenge with either peptide. Measurement of the frequency of peptide-reactive Th1 cells showed results consistent with the clinical picture. The in vitro proliferative response was significantly suppressed following oral administration of either whole GP MBP, the GP peptide, or the rat peptide, irrespective of clinical status. These results extend our earlier observation at the whole molecule level that GP but not rat MBP confers oral tolerance. These findings suggest that small structural differences at the amino acid level can produce dramatic differences in clinical outcome, with important implications for the design of multiple sclerosis clinical trials.

  19. Cloning of precursors for two MIH/VIH-related peptides in the prawn, Macrobrachium rosenbergii.

    Science.gov (United States)

    Yang, W J; Rao, K R

    2001-11-30

    Two cDNA clones (634 and 1366 bp) encoding MIH/VIH (molt-inhibiting hormone/vitellogenesis-inhibiting hormone)-related peptides were isolated and sequenced from a Macrobrachium rosenbergii eyestalk ganglia cDNA library. The clones contain a 360 and 339 bp open-reading frame, and their conceptually translated peptides consist of a 41 and 34 amino acid signal peptide, respectively, and a 78 amino acid residue mature peptide hormone. The amino acid sequences of the peptides exhibit higher identities with other known MIHs and VIH (44-69%) than with CHHs (28-33%). This is the first report describing the cloning and sequencing of two MIH/VIH-related peptides in a single crustacean species. Transcription of these mRNAs was detected in the eyestalk ganglia, but not in the thoracic ganglia, hepatopancreas, gut, gill, heart, or muscle.

  20. Natriuretic peptides in cardiometabolic regulation and disease

    DEFF Research Database (Denmark)

    Zois, Nora E; Bartels, Emil D; Hunter, Ingrid

    2014-01-01

    these conditions can coexist and potentially lead to heart failure, a syndrome associated with a functional natriuretic peptide deficiency despite high circulating concentrations of immunoreactive peptides. Therefore, dysregulation of the natriuretic peptide system, a 'natriuretic handicap', might be an important...

  1. Radiolabeling of methionine containing proteins and peptides

    International Nuclear Information System (INIS)

    Garlick, R.K.; Jirousek, L.

    1986-01-01

    A process for radiolabeling methionine-containing peptides and proteins is disclosed. The process comprises the steps of oxidizing the protein or peptide, radiolabeling and reducing the radiolabeled protein or peptide. (author)

  2. Accurate MALDI-TOF/TOF sequencing of one-bead-one-compound peptide libraries with application to the identification of multiligand protein affinity agents using in situ click chemistry screening.

    Science.gov (United States)

    Lee, Su Seong; Lim, Jaehong; Tan, Sylvia; Cha, Junhoe; Yeo, Shi Yun; Agnew, Heather D; Heath, James R

    2010-01-15

    Combinatorial one-bead-one-compound (OBOC) peptide libraries are widely used for affinity screening, and the sequencing of peptides from hit beads is a key step in the process. For rapid sequencing, CNBr cleavage of the peptides from the beads, followed by de novo sequencing by MALDI-TOF/TOF, is explored. We report on a semiautomated sequencing algorithm and validate it through comparison against Edman degradation sequencing. The initial 44% sequencing success rate of the standard de novo sequencing software was improved to nearly 100%. The sequencing algorithm incorporates existing knowledge of amino acid chemistry and a new strategy for differentiating isobaric amino acids. We tested the algorithm by using MALDI-TOF/TOF to identify a peptide biligand affinity agent against the protein bovine carbonic anhydrase II, starting from comprehensive one-bead-one-compound peptide libraries comprised of non-natural and artificial amino acid components and using the strategy of in situ click/OBOC library screening.

  3. Compact Torus Injection Experiments on the H.I.T. teststand and the JFT-2M tokamak

    Science.gov (United States)

    Fukumoto, Naoyuki; Fujiwara, Makoto; Kuramoto, Keiji; Ageishi, Masaya; Nagata, Masayoshi; Uyama, Tadao; Ogawa, Hiroaki; Kasai, Satoshi; Hasegawa, Kouichi; Shibata, Takatoshi

    1997-11-01

    A spheromak-type compact torus (CT) acceleration and injection experiment has been carried out using the Himeji Institute of Technology Compact Torus Injector (HIT-CTI). We investigate the possibility of refueling, density control, current drive, and edge electric field control of tokamak plasmas by means of CT injection. The HIT-CTI produces a CT with a speed of 200 km/s and a density of 1× 10^21m-3. We have constructed new electrodes and power supplies, and will install the HIT-CTI on the JFT-2M tokamak at JAERI in Autumn 1997. The outer electrode serves as a common ground for both the formation bank (144μF, 20kV) and the acceleration bank (92.4μF, 40kV). If the external toroidal field of the tokamak is applied across the CT acceleration region, the CT kinetic energy might decrease during penetration into the field lines joining the inner and outer electrode. This could result in the CT not being able to reach the core of the tokamak plasma. Determining the optimum position of the inner electrode is one of the near term goals of this research. We will present magnetic probe, He-Ne interferometer and fast framing camera data from experiments at H.I.T., where a CT was accelerated into a transverse field. We will also present initial results from the operation of the HIT-CTI on the JFT-2M tokamak.

  4. An FPGA Implementation to Detect Selective Cationic Antibacterial Peptides

    Science.gov (United States)

    Polanco González, Carlos; Nuño Maganda, Marco Aurelio; Arias-Estrada, Miguel; del Rio, Gabriel

    2011-01-01

    Exhaustive prediction of physicochemical properties of peptide sequences is used in different areas of biological research. One example is the identification of selective cationic antibacterial peptides (SCAPs), which may be used in the treatment of different diseases. Due to the discrete nature of peptide sequences, the physicochemical properties calculation is considered a high-performance computing problem. A competitive solution for this class of problems is to embed algorithms into dedicated hardware. In the present work we present the adaptation, design and implementation of an algorithm for SCAPs prediction into a Field Programmable Gate Array (FPGA) platform. Four physicochemical properties codes useful in the identification of peptide sequences with potential selective antibacterial activity were implemented into an FPGA board. The speed-up gained in a single-copy implementation was up to 108 times compared with a single Intel processor cycle for cycle. The inherent scalability of our design allows for replication of this code into multiple FPGA cards and consequently improvements in speed are possible. Our results show the first embedded SCAPs prediction solution described and constitutes the grounds to efficiently perform the exhaustive analysis of the sequence-physicochemical properties relationship of peptides. PMID:21738652

  5. Peptide radiopharmaceuticals in nuclear medicine

    International Nuclear Information System (INIS)

    Blok, D.; Vermeij, P.; Feitsma, R.I.J.; Pauwels, E.J.K.

    1999-01-01

    This article reviews the labelling of peptides that are recognised to be of interest for nuclear medicine or are the subject of ongoing nuclear medicine research. Applications and approaches to the labelling of peptide radiopharmaceuticals are discussed, and drawbacks in their development considered. (orig.)

  6. Antimicrobial peptides in the airway.

    Science.gov (United States)

    Laube, D M; Yim, S; Ryan, L K; Kisich, K O; Diamond, G

    2006-01-01

    The airway provides numerous defense mechanisms to prevent microbial colonization by the large numbers of bacteria and viruses present in ambient air. An important component of this defense is the antimicrobial peptides and proteins present in the airway surface fluid (ASF), the mucin-rich fluid covering the respiratory epithelium. These include larger proteins such as lysozyme and lactoferrin, as well as the cationic defensin and cathelicidin peptides. While some of these peptides, such as human beta-defensin (hBD)-1, are present constitutively, others, including hBD2 and -3 are inducible in response to bacterial recognition by Toll-like receptor-mediated pathways. These peptides can act as microbicides in the ASF, but also exhibit other activities, including potent chemotactic activity for cells of the innate and adaptive immune systems, suggesting they play a complex role in the host defense of the airway. Inhibition of antimicrobial peptide activity or gene expression can result in increased susceptibility to infections. This has been observed with cystic fibrosis (CF), where the CF phenotype leads to reduced antimicrobial capacity of peptides in the airway. Pathogenic virulence factors can inhibit defensin gene expression, as can environmental factors such as air pollution. Such an interference can result in infections by airway-specific pathogens including Bordetella bronchiseptica, Mycobacterium tuberculosis, and influenza virus. Research into the modulation of peptide gene expression in animal models, as well as the optimization of peptide-based therapeutics shows promise for the treatment and prevention of airway infectious diseases.

  7. Chemical Synthesis of Antimicrobial Peptides.

    Science.gov (United States)

    Münzker, Lena; Oddo, Alberto; Hansen, Paul R

    2017-01-01

    Solid-phase peptide synthesis (SPPS) is the method of choice for chemical synthesis of peptides. In this nonspecialist review, we describe commonly used resins, linkers, protecting groups, and coupling reagents in 9-fluorenylmethyloxycarbonyl (Fmoc) SPPS. Finally, a detailed protocol for manual Fmoc SPPS is presented.

  8. Synthetic peptides for antibody production

    NARCIS (Netherlands)

    N.D. Zegers (Netty)

    1995-01-01

    textabstractSynthetic peptides are useful tools for the generation of antibodies. The use of antibodies as specific reagents in inununochemical assays is widely applied. In this chapter, the application of synthetic peptides for the generation of antibodies is described. The different steps

  9. Synthetic peptides for antibody production

    NARCIS (Netherlands)

    Zegers, N.D.

    1995-01-01

    Synthetic peptides are useful tools for the generation of antibodies. The use of antibodies as specific reagents in inununochemical assays is widely applied. In this chapter, the application of synthetic peptides for the generation of antibodies is described. The different steps that lead to the

  10. Urinary Peptides in Rett Syndrome.

    Science.gov (United States)

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  11. Solid-phase peptide synthesis

    DEFF Research Database (Denmark)

    Jensen, Knud Jørgen

    2013-01-01

    This chapter provides an introduction to and overview of peptide chemistry with a focus on solid-phase peptide synthesis. The background, the most common reagents, and some mechanisms are presented. This chapter also points to the different chapters and puts them into perspective....

  12. Peptide receptor radionuclide therapy with somatostatin analogues in neuroendocrine tumors.

    Science.gov (United States)

    Giovacchini, Giampiero; Nicolas, Guillaume; Forrer, Flavio

    2012-06-01

    Neuroendocrine tumors (NETs) are rare tumors with variable malignant behavior. The majority of NETs express increased levels of somatostatin (SST) receptors, particularly SST2 receptors. Radiolabeled peptides specific for the SST2 receptors may be used for diagnosis of NETs and for peptide receptor radionuclide therapy (PRRT). [(111)In-DTPA(0)]-octreotide has been the first peptide used for PRRT. This radiolabeled peptide, emitting Auger electrons, often induced symptomatic relief, but objective morphological responses were rarely documented. After the introduction of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) other peptides, primarily [DOTA(0),Tyr(3)]octreotate (DOTATATE) and [DOTA(0),Tyr(3)]octreotide (DOTATOC) were labeled with (90)Y or (177)Lu and used for therapy applications. The rate of objective response obtained with these radiolabeled peptides ranges between 6% and 46%, owing to differences in inclusion criteria adopted in different studies, length and type of therapy, and criteria of evaluation of the response. The present data in the literature do not allow defining the most suitable peptide and radionuclide for the treatment of NETs. Instead emerging evidence indicates that a combination of nuclides with different physical characteristics might be more effective than the use of a single nuclide. Kidney and bone marrow toxicity are the limiting factors for PRRT. Mild toxicity is often encountered while severe toxicity is rarer. Toxicity could be reduced and therapeutic efficacy enhanced by patient-specific dosimetry. Future directions include different issues of PRRT, such as defining the most suitable treatment scheme, evaluation of new peptides with different affinity profiles to other SST receptor subtypes, and reduction of toxicity.

  13. Synthetic Advances in Insulin-like Peptides Enable Novel Bioactivity.

    Science.gov (United States)

    Liu, Fa; Li, Pengyun; Gelfanov, Vasily; Mayer, John; DiMarchi, Richard

    2017-08-15

    exploratory in vivo studies requiring a large quantity of peptide. Tangentially, we demonstrate the use of these methods to study the relative importance of the IGF-1 connecting peptide to its biological activity. We report the translation of these finding in search of an insulin analog that might be comparably enhanced by a suitable connecting peptide for interaction with the insulin receptor, as occurs with IGF-1 and its receptor. The results identify a unique receptor site in the IGF-1 receptor from which this enhancement derives. The selective substitution of this specific IGF-1 receptor sequence into the homologous site in the insulin receptor generated a chimeric receptor that was equally capable of signaling with insulin or IGF-1. This novel receptor proved to enhance the potency of lower affinity insulin ligands when they were supplemented with the IGF-1 connecting peptide that similarly enhanced IGF-1 activity at its receptor. The chimeric insulin receptor demonstrated no further enhancement of potency for native insulin when it was similarly prepared as a single-chain analogue with a native IGF-1 connecting peptide. These results suggest a more highly evolved insulin receptor structure where the requirement for an additional structural element to achieve high potency interaction as demonstrated for IGF-1 is no longer required.

  14. Maize Bioactive Peptides against Cancer

    Science.gov (United States)

    Díaz-Gómez, Jorge L.; Castorena-Torres, Fabiola; Preciado-Ortiz, Ricardo E.; García-Lara, Silverio

    2017-06-01

    Cancer is one of the main chronic degenerative diseases worldwide. In recent years, consumption of whole-grain cereals and their derived food products has been associated with reduction risks of various types of cancer. Cereals main biomolecules includes proteins, peptides, and amino acids present in different quantities within the grain. The nutraceutical properties associated with peptides exerts biological functions that promote health and prevent this disease. In this review, we report the current status and advances on maize peptides regarding bioactive properties that have been reported such as antioxidant, antihypertensive, hepatoprotective, and anti-tumour activities. We also highlighted its biological potential through which maize bioactive peptides exert anti-cancer activity. Finally, we analyse and emphasize the possible areas of application for maize peptides.

  15. Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation

    Energy Technology Data Exchange (ETDEWEB)

    Acar, Handan [Institute; Department; Samaeekia, Ravand [Institute; Department; Schnorenberg, Mathew R. [Institute; Department; Medical; Sasmal, Dibyendu K. [Institute; Huang, Jun [Institute; Tirrell, Matthew V. [Institute; Institute; LaBelle, James L. [Department

    2017-08-24

    Peptides synthesized in the likeness of their native interaction domain(s) are natural choices to target protein protein interactions (PPIs) due to their fidelity of orthostatic contact points between binding partners. Despite therapeutic promise, intracellular delivery of biofunctional peptides at concentrations necessary for efficacy remains a formidable challenge. Peptide amphiphiles (PAs) provide a facile method of intracellular delivery and stabilization of bioactive peptides. PAs consisting of biofunctional peptide headgroups linked to hydrophobic alkyl lipid-like tails prevent peptide hydrolysis and proteolysis in circulation, and PA monomers are internalized via endocytosis. However, endocytotic sequestration and steric hindrance from the lipid tail are two major mechanisms that limit PA efficacy to target intracellular PPIs. To address these problems, we have constructed a PA platform consisting of cathepsin-B cleavable PAs in which a selective p53-based inhibitory peptide is cleaved from its lipid tail within endosomes, allowing for intracellular peptide accumulation and extracellular recycling of the lipid moiety. We monitor for cleavage and follow individual PA components in real time using a resonance energy transfer (FRET)-based tracking system. Using this platform, components in real time using a Forster we provide a better understanding and quantification of cellular internalization, trafficking, and endosomal cleavage of PAs and of the ultimate fates of each component.

  16. Purification and use of E. coli peptide deformylase for peptide deprotection in chemoenzymatic peptide synthesis

    NARCIS (Netherlands)

    Di Toma, Claudia; Sonke, Theo; Quaedflieg, Peter J.; Janssen, Dick B.

    Peptide deformylases (PDFs) catalyze the removal of the formyl group from the N-terminal methionine residue in nascent polypeptide chains in prokaryotes. Its deformylation activity makes PDF an attractive candidate for the biocatalytic deprotection of formylated peptides that are used in

  17. Medicinal and Biological Chemistry (MBC) Library: An Efficient Source of New Hits.

    Science.gov (United States)

    Sebastián-Pérez, Víctor; Roca, Carlos; Awale, Mahendra; Reymond, Jean-Louis; Martinez, Ana; Gil, Carmen; Campillo, Nuria E

    2017-09-25

    Identification of new hits is one of the biggest challenges in drug discovery. Creating a library of well-characterized drug-like compounds is a key step in this process. Our group has developed an in-house chemical library called the Medicinal and Biological Chemistry (MBC) library. This collection has been successfully used to start several medicinal chemistry programs and developed in an accumulation of more than 30 years of experience in drug design and discovery of new drugs for unmet diseases. It contains over 1000 compounds, mainly heterocyclic scaffolds. In this work, analysis of drug-like properties and comparative study with well-known libraries by using different computer software are presented here.

  18. Hit-Validation Methodologies for Ligands Isolated from DNA-Encoded Chemical Libraries.

    Science.gov (United States)

    Zimmermann, Gunther; Li, Yizhou; Rieder, Ulrike; Mattarella, Martin; Neri, Dario; Scheuermann, Jörg

    2017-05-04

    DNA-encoded chemical libraries (DECLs) are large collections of compounds linked to DNA fragments, serving as amplifiable barcodes, which can be screened on target proteins of interest. In typical DECL selections, preferential binders are identified by high-throughput DNA sequencing, by comparing their frequency before and after the affinity capture step. Hits identified in this procedure need to be confirmed, by resynthesis and by performing affinity measurements. In this article we present new methods based on hybridization of oligonucleotide conjugates with fluorescently labeled complementary oligonucleotides; these facilitate the determination of affinity constants and kinetic dissociation constants. The experimental procedures were demonstrated with acetazolamide, a binder to carbonic anhydrase IX with a dissociation constant in the nanomolar range. The detection of binding events was compatible not only with fluorescence polarization methodologies, but also with Alphascreen technology and with microscale thermophoresis. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. A double hit model for the distribution of time to AIDS onset

    Science.gov (United States)

    Chillale, Nagaraja Rao

    2013-09-01

    Incubation time is a key epidemiologic descriptor of an infectious disease. In the case of HIV infection this is a random variable and is probably the longest one. The probability distribution of incubation time is the major determinant of the relation between the incidences of HIV infection and its manifestation to Aids. This is also one of the key factors used for accurate estimation of AIDS incidence in a region. The present article i) briefly reviews the work done, points out uncertainties in estimation of AIDS onset time and stresses the need for its precise estimation, ii) highlights some of the modelling features of onset distribution including immune failure mechanism, and iii) proposes a 'Double Hit' model for the distribution of time to AIDS onset in the cases of (a) independent and (b) dependent time variables of the two markers and examined the applicability of a few standard probability models.

  20. Assessment of HIT Antibody Complex in Hip Fracture Patients Receiving Enoxaparin or Unfractionated Heparin

    DEFF Research Database (Denmark)

    Griffin, Justin W; Hopkinson, William J; Rud-Lassen, Michael

    2011-01-01

    Thromboembolic disease is a common complication of hip fracture in the elderly. Anticoagulants represent a standard of care in preventing postoperative thrombotic complications following surgical fixation. We asked whether levels of antibody to heparin-platelet factor 4 (PF4) complex were...... differentially present in unfractionated heparin (UFH) versus Enoxaparin, following hip fracture and whether one particular subtype of antibodies was more prevalent. Plasma samples from elderly patients sustaining a hip fracture treated with either enoxaparin or UFH were collected pre- and postoperatively...... of antiheparin-PF4 antibodies and a greater prevalence of immunoglobulin G (IgG) subtype. Heparin and enoxaparin are capable of generating heparin-induced thrombocytopenia (HIT) antibodies in elderly patients undergoing orthopedic surgery but perhaps not to the same extent. When comparing low...

  1. Hit, Robbed, and Put Down (but not Bullied): Underreporting of Bullying by Minority and Male Students.

    Science.gov (United States)

    Lai, Tianjian; Kao, Grace

    2018-03-01

    To tackle adolescent bullying and identify students most vulnerable to being bullied, it is essential to examine both occurrences of bullying behaviors and students' own likelihoods of reporting bullying. This study examines ethnic and gender differences in students' odds of reporting bullying using the Education Longitudinal Study of 2002, a nationally representative study of United States high school sophomores (N = 15,362; ages 15-19; 50.2% female). Compared to White and female students, minority (particularly Black and Hispanic) and male students report comparable or greater experiences of bullying behaviors (such as being threatened, hit, put down by peers, or having belongings forced from them, stolen or damaged), but are less likely to report that they have been "bullied." These findings point to racialized and gendered differences in reporting bullying experiences such that indicators of "weakness" in peer relations may carry a greater stigma for minority and male students.

  2. Peptide Phage Display as a Tool for Drug Discovery: Targeting Membrane Receptors

    Directory of Open Access Journals (Sweden)

    Tomaz Bratkovic

    2011-01-01

    Full Text Available Ligands selected from phage-displayed random peptide libraries tend to be directed to biologically relevant sites on the surface of the target protein. Consequently, peptides derived from library screenings often modulate the target protein’s activity in vitro and in vivo and can be used as lead compounds in drug design and as alternatives to antibodies for target validation in both genomics and drug discovery. This review discusses the use of phage display to identify membrane receptor modulators with agonistic or antagonistic activities. Because isolating or producing recombinant membrane proteins for use as target molecules in library screening is often impossible, innovative selection strategies such as panning against whole cells or tissues, recombinant receptor ectodomains, or neutralizing antibodies to endogenous binding partners were devised. Prominent examples from a two-decade history of peptide phage display will be presented, focusing on the design of affinity selection experiments, methods for improving the initial hits, and applications of the identified peptides.

  3. Near-optimal alternative generation using modified hit-and-run sampling for non-linear, non-convex problems

    Science.gov (United States)

    Rosenberg, D. E.; Alafifi, A.

    2016-12-01

    Water resources systems analysis often focuses on finding optimal solutions. Yet an optimal solution is optimal only for the modelled issues and managers often seek near-optimal alternatives that address un-modelled objectives, preferences, limits, uncertainties, and other issues. Early on, Modelling to Generate Alternatives (MGA) formalized near-optimal as the region comprising the original problem constraints plus a new constraint that allowed performance within a specified tolerance of the optimal objective function value. MGA identified a few maximally-different alternatives from the near-optimal region. Subsequent work applied Markov Chain Monte Carlo (MCMC) sampling to generate a larger number of alternatives that span the near-optimal region of linear problems or select portions for non-linear problems. We extend the MCMC Hit-And-Run method to generate alternatives that span the full extent of the near-optimal region for non-linear, non-convex problems. First, start at a feasible hit point within the near-optimal region, then run a random distance in a random direction to a new hit point. Next, repeat until generating the desired number of alternatives. The key step at each iterate is to run a random distance along the line in the specified direction to a new hit point. If linear equity constraints exist, we construct an orthogonal basis and use a null space transformation to confine hits and runs to a lower-dimensional space. Linear inequity constraints define the convex bounds on the line that runs through the current hit point in the specified direction. We then use slice sampling to identify a new hit point along the line within bounds defined by the non-linear inequity constraints. This technique is computationally efficient compared to prior near-optimal alternative generation techniques such MGA, MCMC Metropolis-Hastings, evolutionary, or firefly algorithms because search at each iteration is confined to the hit line, the algorithm can move in one

  4. Cell wall trapping of autocrine peptides for human G-protein-coupled receptors on the yeast cell surface.

    Directory of Open Access Journals (Sweden)

    Jun Ishii

    Full Text Available G-protein-coupled receptors (GPCRs regulate a wide variety of physiological processes and are important pharmaceutical targets for drug discovery. Here, we describe a unique concept based on yeast cell-surface display technology to selectively track eligible peptides with agonistic activity for human GPCRs (Cell Wall Trapping of Autocrine Peptides (CWTrAP strategy. In our strategy, individual recombinant yeast cells are able to report autocrine-positive activity for human GPCRs by expressing a candidate peptide fused to an anchoring motif. Following expression and activation, yeast cells trap autocrine peptides onto their cell walls. Because captured peptides are incapable of diffusion, they have no impact on surrounding yeast cells that express the target human GPCR and non-signaling peptides. Therefore, individual yeast cells can assemble the autonomous signaling complex and allow single-cell screening of a yeast population. Our strategy may be applied to identify eligible peptides with agonistic activity for target human GPCRs.

  5. FMRFamide-related peptides (FaRPs): A new family of peptides from amphibian defensive skin secretions

    DEFF Research Database (Denmark)

    Wang, Lei; Smyth, Anita; Johnsen, Anders

    2009-01-01

    amide (EF-10 amide), from the defensive skin secretions of two different species of African hyperoliid frogs, Kassina maculata and Phylictimantis verrucosus, respectively. These represent the first canonical FMRF amide-related peptides (FaRPs) from a vertebrate source. The cDNA encoding IF-8 amide...... was cloned from a skin secretion library and found to contain a single copy of the peptide located at the C-terminus of a 58 amino acid residue open-reading frame. These data extend the potential targets of the defensive arsenal of amphibian tegumental secretions to parasitic/predatory invertebrates...

  6. Delivery systems for antimicrobial peptides

    DEFF Research Database (Denmark)

    Nordström, Randi; Malmsten, Martin

    2017-01-01

    on the identification such peptides, as well as on their optimization to reach potent antimicrobial and anti-inflammatory effects at simultaneously low toxicity against human cells. In comparison, delivery systems for antimicrobial peptides have attracted considerably less interest. However, such delivery systems......, or through achieving co-localization with intracellular pathogens. Here, an overview is provided of the current understanding of delivery systems for antimicrobial peptides, with special focus on AMP-carrier interactions, as well as consequences of these interactions for antimicrobial and related biological...

  7. Novel peptides with tyrosinase inhibitory activity

    NARCIS (Netherlands)

    Schurink, M.; Berkel, van W.J.H.; Wichers, H.J.; Boeriu, C.G.

    2007-01-01

    Tyrosinase inhibition by peptides may find its application in food, cosmetics or medicine. In order to identify novel tyrosinase inhibitory peptides, protein-based peptide libraries made by SPOT synthesis were used to screen for peptides that show direct interaction with tyrosinase. One of the

  8. Characterization of Synthetic Peptides by Mass Spectrometry.

    Science.gov (United States)

    Prabhala, Bala K; Mirza, Osman; Højrup, Peter; Hansen, Paul R

    2015-01-01

    Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI-TOF-MS and LC-MS of synthetic peptides.

  9. Molecular evolution of a peptide GPCR ligand driven by artificial neural networks.

    Directory of Open Access Journals (Sweden)

    Sebastian Bandholtz

    Full Text Available Peptide ligands of G protein-coupled receptors constitute valuable natural lead structures for the development of highly selective drugs and high-affinity tools to probe ligand-receptor interaction. Currently, pharmacological and metabolic modification of natural peptides involves either an iterative trial-and-error process based on structure-activity relationships or screening of peptide libraries that contain many structural variants of the native molecule. Here, we present a novel neural network architecture for the improvement of metabolic stability without loss of bioactivity. In this approach the peptide sequence determines the topology of the neural network and each cell corresponds one-to-one to a single amino acid of the peptide chain. Using a training set, the learning algorithm calculated weights for each cell. The resulting network calculated the fitness function in a genetic algorithm to explore the virtual space of all possible peptides. The network training was based on gradient descent techniques which rely on the efficient calculation of the gradient by back-propagation. After three consecutive cycles of sequence design by the neural network, peptide synthesis and bioassay this new approach yielded a ligand with 70fold higher metabolic stability compared to the wild type peptide without loss of the subnanomolar activity in the biological assay. Combining specialized neural networks with an exploration of the combinatorial amino acid sequence space by genetic algorithms represents a novel rational strategy for peptide design and optimization.

  10. Computationally designed peptides for self-assembly of nanostructured lattices.

    Science.gov (United States)

    Zhang, Huixi Violet; Polzer, Frank; Haider, Michael J; Tian, Yu; Villegas, Jose A; Kiick, Kristi L; Pochan, Darrin J; Saven, Jeffery G

    2016-09-01

    Folded peptides present complex exterior surfaces specified by their amino acid sequences, and the control of these surfaces offers high-precision routes to self-assembling materials. The complexity of peptide structure and the subtlety of noncovalent interactions make the design of predetermined nanostructures difficult. Computational methods can facilitate this design and are used here to determine 29-residue peptides that form tetrahelical bundles that, in turn, serve as building blocks for lattice-forming materials. Four distinct assemblies were engineered. Peptide bundle exterior amino acids were designed in the context of three different interbundle lattices in addition to one design to produce bundles isolated in solution. Solution assembly produced three different types of lattice-forming materials that exhibited varying degrees of agreement with the chosen lattices used in the design of each sequence. Transmission electron microscopy revealed the nanostructure of the sheetlike nanomaterials. In contrast, the peptide sequence designed to form isolated, soluble, tetrameric bundles remained dispersed and did not form any higher-order assembled nanostructure. Small-angle neutron scattering confirmed the formation of soluble bundles with the designed size. In the lattice-forming nanostructures, the solution assembly process is robust with respect to variation of solution conditions (pH and temperature) and covalent modification of the computationally designed peptides. Solution conditions can be used to control micrometer-scale morphology of the assemblies. The findings illustrate that, with careful control of molecular structure and solution conditions, a single peptide motif can be versatile enough to yield a wide range of self-assembled lattice morphologies across many length scales (1 to 1000 nm).

  11. Neoglycolipidation for modulating peptide properties

    DEFF Research Database (Denmark)

    van Witteloostuijn, Søren Blok

    regulation of appetite, food intake, and glucose homeostasis, and many of these peptides display a signicant potential for treatment of obesity and/or type 2 diabetes. This Ph.D. thesis describes three novel approaches for utilizing gut peptides as the starting point for developing obesity and diabetes drugs....... Subsequent stereological analyses of the pancreata showed that chronic treatment with GUB06-046 led to increased cell mass in db/db mice. The results of projects I and II clearly illustrate how chemical modications can improve the pharmacological properties of native peptides. Collectively, the ndings...... of this thesis contribute to emphasize the tremendous therapeutic potential of gut peptides for treatment of obesity and diabetes....

  12. New vasoactive peptides in cirrhosis

    DEFF Research Database (Denmark)

    Kimer, Nina; Goetze, Jens Peter; Bendtsen, Flemming

    2014-01-01

    BACKGROUND: Patients with cirrhosis have substantial circulatory imbalance between vasoconstrictive and vasodilating forces. The study of circulatory vasoactive peptides may provide important pathophysiological information. This study aimed to assess concentrations, organ extraction and relations...

  13. Structure and orientation study of Ebola fusion peptide inserted in lipid membrane models.

    Science.gov (United States)

    Agopian, Audrey; Castano, Sabine

    2014-01-01

    The fusion peptide of Ebola virus comprises a highly hydrophobic sequence located downstream from the N-terminus of the glycoprotein GP2 responsible for virus-host membrane fusion. The internal fusion peptide of GP2 inserts into membranes of infected cell to mediate the viral and the host cell membrane fusion. Since the sequence length of Ebola fusion peptide is still not clear, we study in the present work the behavior of two fusion peptides of different lengths which were named EBO17 and EBO24 referring to their amino acid length. The secondary structure and orientation of both peptides in lipid model systems made of DMPC:DMPG:cholesterol:DMPE (6:2:5:3) were investigated using PMIRRAS and polarized ATR spectroscopy coupled with Brewster angle microscopy. The infrared results showed a structural flexibility of both fusion peptides which are able to transit reversibly from an α-helix to antiparallel β-sheets. Ellipsometry results corroborate together with isotherm measurements that EBO peptides interacting with lipid monolayer highly affected the lipid organization. When interacting with a single lipid bilayer, at low peptide content, EBO peptides insert as mostly α-helices mainly perpendicular into the lipid membrane thus tend to organize the lipid acyl chains. Inserted in multilamellar vesicles at higher peptide content, EBO peptides are mostly in β-sheet structures and induce a disorganization of the lipid chain order. In this paper, we show that the secondary structure of the Ebola fusion peptide is reversibly flexible between α-helical and β-sheet conformations, this feature being dependent on its concentration in lipids, eventually inducing membrane fusion. © 2013.

  14. Relationships between Parents' Use of Corporal Punishment and Their Children's Endorsement of Spanking and Hitting Other Children

    Science.gov (United States)

    Simons, Dominique A.; Wurtele, Sandy K.

    2010-01-01

    Objectives: To explore the intergenerational cycle of violence, the present study examined the relationship between parental approval and children's approval of corporal punishment (CP) and the subsequent relationship between children's CP experience and preference for hitting to resolve interpersonal conflict. Method: Participants consisted of…

  15. A Polynomial Time Construction of a Hitting Set for Read-Once Branching Programs of Width 3

    Czech Academy of Sciences Publication Activity Database

    Šíma, Jiří; Žák, Stanislav

    -, subm. 2015 (2018) ISSN 0022-0000 R&D Projects: GA ČR GBP202/12/G061; GA ČR GAP202/10/1333 Institutional support: RVO:67985807 Keywords : derandomization * Hitting Set * read-once branching programs * bounded width Subject RIV: IN - Informatics, Computer Science Impact factor: 1.678, year: 2016

  16. Comparing among the Experiences of Self-Cutting, Hitting, and Scratching in Chinese Adolescents Attending Secondary Schools: An Interview Study

    Science.gov (United States)

    You, Jianing; Ma, Congfen; Lin, Min-Pei; Leung, Freedom

    2015-01-01

    This study examined adolescents' experiences associated with nonsuicidal self-injury (NSSI) and compared among the experiences of self-cutting, hitting, and scratching. Participants included 42 Chinese adolescents attending secondary schools. They had at least three NSSI episodes in the preceding year. Information about their experiences of NSSI…

  17. Formation and sustainment of a very low aspect ratio tokamak using coaxial helicity injection (the Helicity Injected Torus [HIT] experiment)

    International Nuclear Information System (INIS)

    Jarboe, T.R.; Nelson, B.A.

    1992-01-01

    In the paper we will detail the progress of the HIT experiment construction, including the following components: preliminary data and interpretation; diagnostic systems; vacuum vessel and pumping system; helicity source and power supplies; toroidal field coil and power supply; data acquisition system; collaboration with general atomics, with a brief summary given on each

  18. Genomes to Hits In Silico - A Country Path Today, A Highway Tomorrow: A Case Study of Chikungunya

    Science.gov (United States)

    Soni, Anjali; Pandey, Khushhali M; Ray, Pratima; Jayaram, B

    2013-01-01

    These are exciting times for bioinformaticians, computational biologists and drug designers with the genome and proteome sequences and related structural databases growing at an accelerated pace. The post-genomic era has triggered high expectations for a rapid and successful treatment of diseases. However, in this biological information rich and functional knowledge poor scenario, the challenges are indeed grand, no less than the assembly of the genome of the whole organism. These include functional annotation of genes, identification of druggable targets, prediction of three-dimensional structures of protein targets from their amino acid sequences, arriving at lead compounds for these targets followed by a transition from bench to bedside. We propose here a “Genome to Hits In Silico“ strategy (called Dhanvantari) and illustrate it on Chikungunya virus (CHIKV). “Genome to hits” is a novel pathway incorporating a series of steps such as gene prediction, protein tertiary structure determination, active site identification, hit molecule generation, docking and scoring of hits to arrive at lead compounds. The current state of the art for each of the steps in the pathway is high-lighted and the feasibility of creating an automated genome to hits assembly line is discussed. PMID:23260020

  19. Directed Evolution of FLS2 towards Novel Flagellin Peptide Recognition.

    Directory of Open Access Journals (Sweden)

    Laura Helft

    Full Text Available Microbe-associated molecular patterns (MAMPs are molecules, or domains within molecules, that are conserved across microbial taxa and can be recognized by a plant or animal immune system. Although MAMP receptors have evolved to recognize conserved epitopes, the MAMPs in some microbial species or strains have diverged sufficiently to render them unrecognizable by some host immune systems. In this study, we carried out in vitro evolution of the Arabidopsis thaliana flagellin receptor FLAGELLIN-SENSING 2 (FLS2 to isolate derivatives that recognize one or more flagellin peptides from bacteria for which the wild-type Arabidopsis FLS2 confers little or no response. A targeted approach generated amino acid variation at FLS2 residues in a region previously implicated in flagellin recognition. The primary screen tested for elevated response to the canonical flagellin peptide from Pseudomonas aeruginosa, flg22. From this pool, we then identified five alleles of FLS2 that confer modest (quantitatively partial recognition of an Erwinia amylovora flagellin peptide. Use of this Erwinia-based flagellin peptide to stimulate Arabidopsis plants expressing the resulting FLS2 alleles did not lead to a detectable reduction of virulent P. syringae pv. tomato growth. However, combination of two identified mutations into a single allele further increased FLS2-mediated responses to the E. amylovora flagellin peptide. These studies demonstrate the potential to raise the sensitivity of MAMP receptors toward particular targets.

  20. Folding and insertion thermodynamics of the transmembrane WALP peptide.

    Science.gov (United States)

    Bereau, Tristan; Bennett, W F Drew; Pfaendtner, Jim; Deserno, Markus; Karttunen, Mikko

    2015-12-28

    The anchor of most integral membrane proteins consists of one or several helices spanning the lipid bilayer. The WALP peptide, GWW(LA)n (L)WWA, is a common model helix to study the fundamentals of protein insertion and folding, as well as helix-helix association in the membrane. Its structural properties have been illuminated in a large number of experimental and simulation studies. In this combined coarse-grained and atomistic simulation study, we probe the thermodynamics of a single WALP peptide, focusing on both the insertion across the water-membrane interface, as well as folding in both water and a membrane. The potential of mean force characterizing the peptide's insertion into the membrane shows qualitatively similar behavior across peptides and three force fields. However, the Martini force field exhibits a pronounced secondary minimum for an adsorbed interfacial state, which may even become the global minimum-in contrast to both atomistic simulations and the alternative PLUM force field. Even though the two coarse-grained models reproduce the free energy of insertion of individual amino acids side chains, they both underestimate its corresponding value for the full peptide (as compared with atomistic simulations), hinting at cooperative physics beyond the residue level. Folding of WALP in the two environments indicates the helix as the most stable structure, though with different relative stabilities and chain-length dependence.

  1. Matrix-assisted peptide synthesis on nanoparticles.

    Science.gov (United States)

    Khandadash, Raz; Machtey, Victoria; Weiss, Aryeh; Byk, Gerardo

    2014-09-01

    We report a new method for multistep peptide synthesis on polymeric nanoparticles of differing sizes. Polymeric nanoparticles were functionalized via their temporary embedment into a magnetic inorganic matrix that allows multistep peptide synthesis. The matrix is removed at the end of the process for obtaining nanoparticles functionalized with peptides. The matrix-assisted synthesis on nanoparticles was proved by generating various biologically relevant peptides. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

  2. Material Binding Peptides for Nanotechnology

    Directory of Open Access Journals (Sweden)

    Urartu Ozgur Safak Seker

    2011-02-01

    Full Text Available Remarkable progress has been made to date in the discovery of material binding peptides and their utilization in nanotechnology, which has brought new challenges and opportunities. Nowadays phage display is a versatile tool, important for the selection of ligands for proteins and peptides. This combinatorial approach has also been adapted over the past decade to select material-specific peptides. Screening and selection of such phage displayed material binding peptides has attracted great interest, in particular because of their use in nanotechnology. Phage display selected peptides are either synthesized independently or expressed on phage coat protein. Selected phage particles are subsequently utilized in the synthesis of nanoparticles, in the assembly of nanostructures on inorganic surfaces, and oriented protein immobilization as fusion partners of proteins. In this paper, we present an overview on the research conducted on this area. In this review we not only focus on the selection process, but also on molecular binding characterization and utilization of peptides as molecular linkers, molecular assemblers and material synthesizers.

  3. Peptide insertion, positioning, and stabilization in a membrane: insight from an all-atom molecular dynamics simulation.

    Science.gov (United States)

    Babakhani, Arneh; Gorfe, Alemayehu A; Gullingsrud, Justin; Kim, Judy E; Andrew McCammon, J

    Peptide insertion, positioning, and stabilization in a model membrane are probed via an all-atom molecular dynamics (MD) simulation. One peptide (WL5) is simulated in each leaflet of a solvated dimyristoylglycero-3-phosphate (DMPC) membrane. Within the first 5 ns, the peptides spontaneously insert into the membrane and then stabilize during the remaining 70 ns of simulation time. In both leaflets, the peptides localize to the membrane interface, and this localization is attributed to the formation of peptide-lipid hydrogen bonds. We show that the single tryptophan residue in each peptide contributes significantly to these hydrogen bonds; specifically, the nitrogen heteroatom of the indole ring plays a critical role. The tilt angles of the indole rings relative to the membrane normal in the upper and lower leaflets are approximately 26 degrees and 54 degrees , respectively. The tilt angles of the entire peptide chain are 62 degrees and 74 degrees . The membrane induces conformations of the peptide that are characteristic of beta-sheets, and the peptide enhances the lipid ordering in the membrane. Finally, the diffusion rate of the peptides in the membrane plane is calculated (based on experimental peptide concentrations) to be approximately 6 A(2)/ns, thus suggesting a 500 ns time scale for intermolecular interactions.

  4. The impact of α-hydrazino acids embedded in short fluorescent peptides on peptide interactions with DNA and RNA.

    Science.gov (United States)

    Suć, Josipa; Tumir, Lidija-Marija; Glavaš-Obrovac, Ljubica; Jukić, Marijana; Piantanida, Ivo; Jerić, Ivanka

    2016-06-07

    A series of novel hydrazino-based peptidomimetics and analogues comprising N-terminal lysine and C-terminal phenanthridinyl-l-alanine were prepared. The presented results demonstrate the up to now unknown possibility to finely modulate peptide interactions with DNA/RNA by α-hydrazino group insertion and how the different positioning of two α-hydrazino groups in peptides controls binding to various double stranded and single stranded DNA and RNA. All peptidomimetics bind with 1-10 micromolar affinity to ds-DNA/RNA, whereby the binding mode is a combination of electrostatic interactions and hydrophobic interactions within DNA/RNA grooves. Insertion of the α-hydrazino group into the peptide systematically decreased its fluorimetric response to DNA/RNA binding in the order: mono-hydrazino < alternating-hydrazino < sequential-hydrazino group. Binding studies of ss-polynucleotides suggest intercalation of phenanthridine between polynucleotide bases, whereby affinity and fluorimetric response decrease with the number of α-hydrazino groups in the peptide sequence. Particularly interesting was the interaction of two sequential α-hydrazino acids-peptidomimetic with poly rG, characterised by a specific strong increase of CD bands, while all other peptide/ssRNA combinations gave only a CD-band decrease. All mentioned interactions could also be reversibly controlled by adjusting the pH, due to the protonation of the fluorophore.

  5. A rapid and clean synthetic approach to cyclic peptides via micro-flow peptide chain elongation and photochemical cyclization: synthesis of a cyclic RGD peptide.

    Science.gov (United States)

    Mifune, Yuto; Nakamura, Hiroyuki; Fuse, Shinichiro

    2016-11-29

    A cyclic RGD peptide was efficiently synthesized based on micro-flow, triphosgene-mediated peptide chain elongation and micro-flow photochemical macrolactamization. Our approach enabled a rapid (amidation for peptide chain elongation peptide.

  6. Comparison of Video Head Impulse Test (vHIT) Gains Between Two Commercially Available Devices and by Different Gain Analytical Methods.

    Science.gov (United States)

    Lee, Sang Hun; Yoo, Myung Hoon; Park, Jun Woo; Kang, Byung Chul; Yang, Chan Joo; Kang, Woo Suk; Ahn, Joong Ho; Chung, Jong Woo; Park, Hong Ju

    2018-04-11

    To evaluate whether video head impulse test (vHIT) gains are dependent on the measuring device and method of analysis. Prospective study. vHIT was performed in 25 healthy subjects using two devices simultaneously. vHIT gains were compared between these instruments and using five different methods of comparing position and velocity gains during head movement intervals. The two devices produced different vHIT gain results with the same method of analysis. There were also significant differences in the vHIT gains measured using different analytical methods. The gain analytic method that compares the areas under the velocity curve (AUC) of the head and eye movements during head movements showed lower vHIT gains than a method that compared the peak velocities of the head and eye movements. The former method produced the vHIT gain with the smallest standard deviation among the five procedures tested in this study. vHIT gains differ in normal subjects depending on the device and method of analysis used, suggesting that it is advisable for each device to have its own normal values. Gain calculations that compare the AUC of the head and eye movements during the head movements show the smallest variance.

  7. An Open-Source Automated Peptide Synthesizer Based on Arduino and Python.

    Science.gov (United States)

    Gali, Hariprasad

    2017-10-01

    The development of the first open-source automated peptide synthesizer, PepSy, using Arduino UNO and readily available components is reported. PepSy was primarily designed to synthesize small peptides in a relatively small scale (<100 µmol). Scripts to operate PepSy in a fully automatic or manual mode were written in Python. Fully automatic script includes functions to carry out resin swelling, resin washing, single coupling, double coupling, Fmoc deprotection, ivDde deprotection, on-resin oxidation, end capping, and amino acid/reagent line cleaning. Several small peptides and peptide conjugates were successfully synthesized on PepSy with reasonably good yields and purity depending on the complexity of the peptide.

  8. Structural requirements for the interaction between class II MHC molecules and peptide antigens

    DEFF Research Database (Denmark)

    Sette, A; Buus, S; Appella, E

    1990-01-01

    IA(d) and IE(d) molecules and their peptide ligands, we found that some structural characteristics apply to both antigen-MHC interactions. In particular, we found: 1) each MHC molecule is capable of binding many unrelated peptides through the same peptide-binding site; 2) despite this permissiveness......Previous work from our and other laboratories indicates that T cells recognize a complex between the MHC restriction element and peptide antigen fragments. This paper reviews the structural characteristics of the formation of such a complex. By analyzing in detail the interactions between purified...... of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity (IA(d) or IE(d)); 3) IA(d) and IE(d) molecules recognize different and independent structures on the antigen molecule; 4) only about 10% of the single...

  9. Automated solid-phase peptide synthesis to obtain therapeutic peptides

    Directory of Open Access Journals (Sweden)

    Veronika Mäde

    2014-05-01

    Full Text Available The great versatility and the inherent high affinities of peptides for their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS offers a suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to essentially improved microwave-assisted instruments is discussed. In order to improve pharmacokinetic properties of peptides, lipidation and PEGylation are described as covalent conjugation methods, which can be applied by a combination of automated and manual synthesis approaches. The synthesis and application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies.

  10. Peptides and Food Intake

    Directory of Open Access Journals (Sweden)

    Carmen Sobrino Crespo

    2014-04-01

    Full Text Available Nutrients created by the digestion of food are proposed to active G protein coupled receptors on the luminal side of enteroendocrine cells e.g. the L-cell. This stimulates the release of gut hormones. Hormones released from the gut and adipose tissue play an important rol in the regulation of food intake and energy expenditure (1.Many circulating signals, including gut hormones, can influence the activity of the arcuate nucleus (ARC neurons directly, after passing across the median eminence. The ARC is adjacent to the median eminence, a circumventricular organ with fenestrated capillaries and hence an incomplete blood-brain barrier (2. The ARC of the hypothalamus is believed to play a crucial role in the regulation of food intake and energy homeostasis. The ARC contains two populations of neurons with opposing effect on food intake (3. Medially located orexigenic neurons (i.e those stimulating appetite express neuropeptide Y (NPY and agouti-related protein (AgRP (4-5. Anorexigenic neurons (i.e. those inhibiting appetite in the lateral ARC express alpha-melanocyte stimulating hormone (α-MSH derived from pro-opiomelanocortin (POMC and cocaine and amphetamine-regulated transcript (CART (6. The balance between activities of these neuronal circuits is critical to body weight regulation.In contrast, other peripheral signals influence the hypothalamus indirectly via afferent neuronal pathway and brainstem circuits. In this context gastrointestinal’s vagal afferents are activated by mechanoreceptors and chemoreceptors, and converge in the nucleus of the tractus solitaries (NTS of the brainstem. Neuronal projections from the NTS, in turn, carry signals to the hypotalamus (1, 7. Gut hormones also alter the activity of the ascending vagal pathway from the gut to the brainstem. In the cases of ghrelin and Peptide tyrosine tyrosine (PYY, there are evidences for both to have a direct action on the arcuate nucleus and an action via the vagus nerve a

  11. Does the Strategy of Risk Group Testing for Hepatitis C Hit the Target?

    Directory of Open Access Journals (Sweden)

    Mirjana R. Jovanovic

    2017-06-01

    Full Text Available In the European Union, it is estimated that there are 5.5 million individuals with chronic infection of hepatitis C. Intravenous drug abuse is undoubtedly the key source of the hepatitis C epidemic in Europe and the most efficient mode of transmission of HCV infections (primarily due to short incubation time, but also because the virus is introduced directly into the blood stream with the infected needle. Potentially high-risk and vulnerable populations in Europe (and the world include immigrants, prisoners, sex workers, men having sex with men, individuals infected with HIV, psychoactive substance users etc. Since there is a lack of direct evidence of clinical benefits of HCV testing, decisions related to testing are made based on indirect evidence. Clinical practice has shown that HCV antibody tests are mostly adequate for identification of HCV infection, but the problem is that this testing strategy does not hit the target. As a result of this health care system strategy, a large number of infected patients remain undetected or they are diagnosed late. There is only a vague link between screening and treatment outcomes since there is a lack of evidence on transmission risks, multiple causes, risk behavior, ways of reaching screening decisions, treatment efficiency, etc. According to results of limited number of studies it can be concluded that there is a need to develop targeted programmes for detection of HCV and other infections, but there also a need to decrease potential harms.

  12. Designing small universal k-mer hitting sets for improved analysis of high-throughput sequencing.

    Directory of Open Access Journals (Sweden)

    Yaron Orenstein

    2017-10-01

    Full Text Available With the rapidly increasing volume of deep sequencing data, more efficient algorithms and data structures are needed. Minimizers are a central recent paradigm that has improved various sequence analysis tasks, including hashing for faster read overlap detection, sparse suffix arrays for creating smaller indexes, and Bloom filters for speeding up sequence search. Here, we propose an alternative paradigm that can lead to substantial further improvement in these and other tasks. For integers k and L > k, we say that a set of k-mers is a universal hitting set (UHS if every possible L-long sequence must contain a k-mer from the set. We develop a heuristic called DOCKS to find a compact UHS, which works in two phases: The first phase is solved optimally, and for the second we propose several efficient heuristics, trading set size for speed and memory. The use of heuristics is motivated by showing the NP-hardness of a closely related problem. We show that DOCKS works well in practice and produces UHSs that are very close to a theoretical lower bound. We present results for various values of k and L and by applying them to real genomes show that UHSs indeed improve over minimizers. In particular, DOCKS uses less than 30% of the 10-mers needed to span the human genome compared to minimizers. The software and computed UHSs are freely available at github.com/Shamir-Lab/DOCKS/ and acgt.cs.tau.ac.il/docks/, respectively.

  13. Development of the PRE-HIT instrument: patient readiness to engage in health information technology.

    Science.gov (United States)

    Koopman, Richelle J; Petroski, Gregory F; Canfield, Shannon M; Stuppy, Julie A; Mehr, David R

    2014-01-28

    Technology-based aids for lifestyle change are becoming more prevalent for chronic conditions. Important "digital divides" remain, as well as concerns about privacy, data security, and lack of motivation. Researchers need a way to characterize participants' readiness to use health technologies. To address this need, we created an instrument to measure patient readiness to engage with health technologies among adult patients with chronic conditions. Initial focus groups to determine domains, followed by item development and refinement, and exploratory factor analysis to determine final items and factor structure. The development sample included 200 patients with chronic conditions from 6 family medicine clinics. From 98 potential items, 53 best candidate items were examined using exploratory factor analysis. Pearson's Correlation for Test/Retest reliability at 3 months. The final instrument had 28 items that sorted into 8 factors with associated Cronbach's alpha: 1) Health Information Need (0.84), 2) Computer/Internet Experience (0.87), 3) Computer Anxiety (0.82), 4) Preferred Mode of Interaction (0.73), 5) Relationship with Doctor (0.65), 6) Cell Phone Expertise (0.75), 7) Internet Privacy (0.71), and 8) No News is Good News (0.57). Test-retest reliability for the 8 subscales ranged from (0.60 to 0.85). The Patient Readiness to Engage in Health Internet Technology (PRE-HIT) instrument has good psychometric properties and will be an aid to researchers investigating technology-based health interventions. Future work will examine predictive validity.

  14. Fixed target combined with spectral mapping: approaching 100% hit rates for serial crystallography.

    Science.gov (United States)

    Oghbaey, Saeed; Sarracini, Antoine; Ginn, Helen M; Pare-Labrosse, Olivier; Kuo, Anling; Marx, Alexander; Epp, Sascha W; Sherrell, Darren A; Eger, Bryan T; Zhong, Yinpeng; Loch, Rolf; Mariani, Valerio; Alonso-Mori, Roberto; Nelson, Silke; Lemke, Henrik T; Owen, Robin L; Pearson, Arwen R; Stuart, David I; Ernst, Oliver P; Mueller-Werkmeister, Henrike M; Miller, R J Dwayne

    2016-08-01

    The advent of ultrafast highly brilliant coherent X-ray free-electron laser sources has driven the development of novel structure-determination approaches for proteins, and promises visualization of protein dynamics on sub-picosecond timescales with full atomic resolution. Significant efforts are being applied to the development of sample-delivery systems that allow these unique sources to be most efficiently exploited for high-throughput serial femtosecond crystallography. Here, the next iteration of a fixed-target crystallography chip designed for rapid and reliable delivery of up to 11 259 protein crystals with high spatial precision is presented. An experimental scheme for predetermining the positions of crystals in the chip by means of in situ spectroscopy using a fiducial system for rapid, precise alignment and registration of the crystal positions is presented. This delivers unprecedented performance in serial crystallography experiments at room temperature under atmospheric pressure, giving a raw hit rate approaching 100% with an effective indexing rate of approximately 50%, increasing the efficiency of beam usage and allowing the method to be applied to systems where the number of crystals is limited.

  15. Ice Hockey Summit II: zero tolerance for head hits and fighting.

    Science.gov (United States)

    Smith, Aynsley M; Stuart, Michael J; Dodick, David W; Roberts, William O; Alford, Patrick W; Ashare, Alan B; Aubrey, Mark; Benson, Brian W; Burke, Chip J; Dick, Randall; Eickhoff, Chad; Emery, Carolyn A; Flashman, Laura A; Gaz, Daniel V; Giza, Chris C; Greenwald, Richard M; Herring, Stanley A; Hoshizaki, T Blaine; Hudziak, James J; Huston, John; Krause, David; LaVoi, Nicole; Leaf, Matt; Leddy, John J; MacPherson, Alison; McKee, Ann C; Mihalik, Jason P; Moessner, Anne M; Montelpare, William J; Putukian, Margot; Schneider, Kathryn J; Szalkowski, Ron; Tabrum, Mark; Whitehead, James R; Wiese-Bjornstal, Diane M

    2015-01-01

    This study aimed to present currently known basic science and on-ice influences of sport-related concussion (SRC) in hockey, building upon the Ice Hockey Summit I action plan (2011) to reduce SRC. The prior summit proceedings included an action plan intended to reduce SRC. As such, the proceedings from Summit I served as a point of departure for the science and discussion held during Summit II (Mayo Clinic, Rochester, MN, October 2013). Summit II focused on (1) Basic Science of Concussions in Ice Hockey: Taking Science Forward, (2) Acute and Chronic Concussion Care: Making a Difference, (3) Preventing Concussions via Behavior, Rules, Education, and Measuring Effectiveness, (4) Updates in Equipment: Their Relationship to Industry Standards, and (5) Policies and Plans at State, National, and Federal Levels To Reduce SRC. Action strategies derived from the presentations and discussion described in these sectors were voted on subsequently for purposes of prioritization. The following proceedings include the knowledge and research shared by invited faculty, many of whom are health care providers and clinical investigators. The Summit II evidence-based action plan emphasizes the rapidly evolving scientific content of hockey SRC. It includes the most highly prioritized strategies voted on for implementation to decrease concussion. The highest-priority action items identified from the Summit include the following: (1) eliminate head hits from all levels of ice hockey, (2) change body checking policies, and (3) eliminate fighting in all amateur and professional hockey.

  16. Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens.

    Science.gov (United States)

    Rice, Christopher A; Colon, Beatrice L; Alp, Mehmet; Göker, Hakan; Boykin, David W; Kyle, Dennis E

    2015-04-01

    Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of 500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  17. Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits.

    Science.gov (United States)

    B-Rao, Chandrika; Kulkarni-Almeida, Asha; Katkar, Kamlesh V; Khanna, Smriti; Ghosh, Usha; Keche, Ashish; Shah, Pranay; Srivastava, Ankita; Korde, Vaidehi; Nemmani, Kumar V S; Deshmukh, Nitin J; Dixit, Amol; Brahma, Manoja K; Bahirat, Umakant; Doshi, Lalit; Sharma, Rajiv; Sivaramakrishnan, H

    2012-05-01

    In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Evidence for Ancestral Programming of Resilience in a Two-Hit Stress Model

    Directory of Open Access Journals (Sweden)

    Jamshid Faraji

    2017-05-01

    Full Text Available In a continuously stressful environment, the effects of recurrent prenatal stress (PS may accumulate across generations and alter stress vulnerability and resilience. Here, we report in female rats that a family history of recurrent ancestral PS facilitates certain aspects of movement performance, and that these benefits are abolished by the experience of a second hit, induced by a silent ischemia during adulthood. Female F4-generation rats with and without a family history of cumulative multigenerational PS (MPS were tested for skilled motor function before and after the induction of a minor ischemic insult by endothelin-1 infusion into the primary motor cortex. MPS resulted in improved skilled motor abilities and blunted hypothalamic-pituitary-adrenal (HPA axis function compared to non-stressed rats. Deep sequencing revealed downregulation of miR-708 in MPS rats along with upregulation of its predicted target genes Mapk10 and Rasd2. Through miR-708 stress may regulate mitogen-activated protein kinase (MAPK pathway activity. Hair trace elemental analysis revealed an increased Na/K ratio, which suggests a chronic shift in adrenal gland function. The ischemic lesion activated the HPA axis in MPS rats only; the lesion, however, abolished the advantage of MPS in skilled reaching. The findings indicate that MPS generates adaptive flexibility in movement, which is challenged by a second stressor, such as a neuropathological condition. Thus, a second “hit” by a stressor may limit behavioral flexibility and neural plasticity associated with ancestral stress.

  19. Technologies for the Synthesis of mRNA-Encoding Libraries and Discovery of Bioactive Natural Product-Inspired Non-Traditional Macrocyclic Peptides

    Directory of Open Access Journals (Sweden)

    Hiroaki Suga

    2013-03-01

    Full Text Available In this review, we discuss emerging technologies for drug discovery, which yields novel molecular scaffolds based on natural product-inspired non-traditional peptides expressed using the translation machinery. Unlike natural products, these technologies allow for constructing mRNA-encoding libraries of macrocyclic peptides containing non-canonical sidechains and N-methyl-modified backbones. The complexity of sequence space in such libraries reaches as high as a trillion (>1012, affording initial hits of high affinity ligands against protein targets. Although this article comprehensively covers several related technologies, we discuss in greater detail the technical development and advantages of the Random non-standard Peptide Integration Discovery (RaPID system, including the recent identification of inhibitors against various therapeutic targets.

  20. Multiple hit infection and autoimmunity: the dysbiotic microbiota-ACPA connection in rheumatoid arthritis.

    Science.gov (United States)

    Sakkas, Lazaros I; Bogdanos, Dimitrios P

    2018-03-13

    This review highlights the most recent data obtained in this field and provides clues toward the better understanding of the close interplay between microbiota and host, leading to autoimmune diseases. A well-described model of microbiota/host interaction of relevance to autoimmunity is that linking anti-citrullinated peptide antibody positive rheumatoid arthritis and alterations of microbiota largely concentrating on Porphyromonas gingivalis and more recently of Aggregatibacter actinomycetemcomitans and Prevotella copri. The perception of the classical link between microbial infection and development of autoimmune disease has evolved to the more recent concept of the connection between the microbiome/dysbiosis and breaking of immunological tolerance.

  1. Exploration of the Medicinal Peptide Space.

    Science.gov (United States)

    Gevaert, Bert; Stalmans, Sofie; Wynendaele, Evelien; Taevernier, Lien; Bracke, Nathalie; D'Hondt, Matthias; De Spiegeleer, Bart

    2016-01-01

    The chemical properties of peptide medicines, known as the 'medicinal peptide space' is considered a multi-dimensional subset of the global peptide space, where each dimension represents a chemical descriptor. These descriptors can be linked to biofunctional, medicinal properties to varying degrees. Knowledge of this space can increase the efficiency of the peptide-drug discovery and development process, as well as advance our understanding and classification of peptide medicines. For 245 peptide drugs, already available on the market or in clinical development, multivariate dataexploration was performed using peptide relevant physicochemical descriptors, their specific peptidedrug target and their clinical use. Our retrospective analysis indicates that clusters in the medicinal peptide space are located in a relatively narrow range of the physicochemical space: dense and empty regions were found, which can be explored for the discovery of novel peptide drugs.

  2. Cyclic peptide therapeutics: past, present and future.

    Science.gov (United States)

    Zorzi, Alessandro; Deyle, Kaycie; Heinis, Christian

    2017-06-01

    Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that make them an attractive modality for the development of therapeutics. Over 40 cyclic peptide drugs are currently in clinical use and around one new cyclic peptide drug enters the market every year on average. The vast majority of clinically approved cyclic peptides are derived from natural products, such as antimicrobials or human peptide hormones. New powerful techniques based on rational design and in vitro evolution have enabled the de novo development of cyclic peptide ligands to targets for which nature does not offer solutions. A look at the cyclic peptides currently under clinical evaluation shows that several have been developed using such techniques. This new source for cyclic peptide ligands introduces a freshness to the field, and it is likely that de novo developed cyclic peptides will be in clinical use in the near future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Perspectives and Peptides of the Next Generation

    Science.gov (United States)

    Brogden, Kim A.

    Shortly after their discovery, antimicrobial peptides from prokaryotes and eukaryotes were recognized as the next potential generation of pharmaceuticals to treat antibiotic-resistant bacterial infections and septic shock, to preserve food, or to sanitize surfaces. Initial research focused on identifying the spectrum of antimicrobial agents, determining the range of antimicrobial activities against bacterial, fungal, and viral pathogens, and assessing the antimicrobial activity of synthetic peptides versus their natural counterparts. Subsequent research then focused on the mechanisms of antimicrobial peptide activity in model membrane systems not only to identify the mechanisms of antimicrobial peptide activity in microorganisms but also to discern differences in cytotoxicity for prokaryotic and eukaryotic cells. Recent, contemporary work now focuses on current and future efforts to construct hybrid peptides, peptide congeners, stabilized peptides, peptide conjugates, and immobilized peptides for unique and specific applications to control the growth of microorganisms in vitro and in vivo.

  4. Probing the interaction mechanisms between transmembrane peptides and the chaperonin GroEL with fluorescence anisotropy

    Science.gov (United States)

    Wang, Xiaoqiang; Chen, Han; Lu, Xinwei; Chi, Haixia; Li, Shixin; Huang, Fang

    2018-04-01

    Proper translocation, membrane insertion and folding are crucial biophysical steps in the biogenesis of functional transmembrane peptides/proteins (TMPs). ATP-dependent chaperonins are able to regulate each of these processes, but the underlying mechanisms remain unclear. In this work, interaction between the bacterial chaperonin GroEL and a synthetic fluorescent transmembrane peptide was investigated by fluorescence anisotropy. Binding of the peptide with GroEL resulted in increased fluorescence anisotropy and intensity. The dissociation constant and binding stoichiometry, as assessed by titration of the peptide with GroEL, were estimated to be 0.6 ± 0.2 μM and 2.96 ± 0.35, respectively. Complementary study with the single-ring version of GroEL confirmed the high-affinity peptide binding, and indicates that the two GroEL rings may function alternatively in binding the peptides. The co-chaperonin GroES was found to be effective at releasing the peptides initially bound to GroEL with the help of ATP. Moreover, our observation with the single-ring GroEL mutant demonstrated that during the encapsulation of GroEL by GroES, the bound peptides may either be confined in the cage thus formed, or escape outside. Competitive binding experiments indicated that the peptides studied interact with GroEL through the paired helices H and I on its apical domain. Our spectroscopic studies revealed some basic mechanisms of interaction between transmembrane peptides and GroEL, which would be instrumental for deciphering the chaperonin-mediated TMP biogenesis.

  5. Enhancing Vaccine Efficacy by Engineering a Complex Synthetic Peptide To Become a Super Immunogen.

    Science.gov (United States)

    Nordström, Therése; Pandey, Manisha; Calcutt, Ainslie; Powell, Jessica; Phillips, Zachary N; Yeung, Grace; Giddam, Ashwini K; Shi, Yun; Haselhorst, Thomas; von Itzstein, Mark; Batzloff, Michael R; Good, Michael F

    2017-10-15

    Peptides offer enormous promise as vaccines to prevent and protect against many infectious and noninfectious diseases. However, to date, limited vaccine efficacy has been reported and none have been licensed for human use. Innovative ways to enhance their immunogenicity are being tested, but rational sequence modification as a means to improve immune responsiveness has been neglected. Our objective was to establish a two-step generic protocol to modify defined amino acids of a helical peptide epitope to create a superior immunogen. Peptide variants of p145, a conserved helical peptide epitope from the M protein of Streptococcus pyogenes , were designed by exchanging one amino acid at a time, without altering their α-helical structure, which is required for correct antigenicity. The immunogenicities of new peptides were assessed in outbred mice. Vaccine efficacy was assessed in a skin challenge and invasive disease model. Out of 86 variants of p145, seven amino acid substitutions were selected and made the basis of the design for 18 new peptides. Of these, 13 were more immunogenic than p145; 7 induced Abs with significantly higher affinity for p145 than Abs induced by p145 itself; and 1 peptide induced more than 10,000-fold greater protection following challenge than the parent peptide. This peptide also only required a single immunization (compared with three immunizations with the parent peptide) to induce complete protection against invasive streptococcal disease. This study defines a strategy to rationally improve the immunogenicity of peptides and will have broad applicability to the development of vaccines for infectious and noninfectious diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

  6. Characterization of Synthetic Peptides by Mass Spectrometry

    DEFF Research Database (Denmark)

    Prabhala, Bala K; Mirza, Osman; Højrup, Peter

    2015-01-01

    Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI-TOF-MS an......Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI...

  7. Biased selection of propagation-related TUPs from phage display peptide libraries.

    Science.gov (United States)

    Zade, Hesam Motaleb; Keshavarz, Reihaneh; Shekarabi, Hosna Sadat Zahed; Bakhshinejad, Babak

    2017-08-01

    Phage display is rapidly advancing as a screening strategy in drug discovery and drug delivery. Phage-encoded combinatorial peptide libraries can be screened through the affinity selection procedure of biopanning to find pharmaceutically relevant cell-specific ligands. However, the unwanted enrichment of target-unrelated peptides (TUPs) with no true affinity for the target presents an important barrier to the successful screening of phage display libraries. Propagation-related TUPs (Pr-TUPs) are an emerging but less-studied category of phage display-derived false-positive hits that are displayed on the surface of clones with faster propagation rates. Despite long regarded as an unbiased selection system, accumulating evidence suggests that biopanning may create biological bias toward selection of phage clones with certain displayed peptides. This bias can be dependent on or independent of the displayed sequence and may act as a major driving force for the isolation of fast-growing clones. Sequence-dependent bias is reflected by censorship or over-representation of some amino acids in the displayed peptide and sequence-independent bias is derived from either point mutations or rare recombination events occurring in the phage genome. It is of utmost interest to clean biopanning data by identifying and removing Pr-TUPs. Experimental and bioinformatic approaches can be exploited for Pr-TUP discovery. With no doubt, obtaining deeper insight into how Pr-TUPs emerge during biopanning and how they could be detected provides a basis for using cell-targeting peptides isolated from phage display screening in the development of disease-specific diagnostic and therapeutic platforms.

  8. Quantification of dabsylated di- and tri-peptides in fermented milk.

    Science.gov (United States)

    Eisele, T; Stressler, T; Kranz, B; Fischer, L

    2012-12-15

    An improved HPLC method using pre-column dabsyl chloride derivatisation for the separation and quantification of antihypertensive di- and tri-peptides in fermented milk products was established. The dabsylated peptides Val-Pro-Pro (VPP), Ile-Pro-Pro (IPP), Leu-Pro-Pro (LPP) and Phe-Pro (FP) were separated on a C18-column coupled to UV/VIS and mass spectrometric detector, respectively. Due to the derivatisation of the peptides, an HPLC base line separation was achieved and the peak width was improved. The VIS-spectrometry did not allow a good quantification of these peptides since more than one peptide co-eluted under one single peak. In contrast applying LC-ESI-MS with a single quadrupole much better quantification of the dabsylated peptides was done. In Evolus® (Valio Ltd., Finland), a fermented milk drink, 6.9 mg L(-1) for VPP, 6.1 mg L(-1) for IPP, 0.8 mg L(-1) for LPP and 3.2 mg L(-1) for FP were determined. In fermented reconstituted milk (Lactobacillus helveticus, 37°C, 48 h) lower concentrations of these peptides were determined (0.7, 0.6, 0.0 and 2.2 mg L(-1), respectively). Copyright © 2012. Published by Elsevier Ltd.

  9. Improving the representation of peptide-like inhibitor and antibiotic molecules in the Protein Data Bank.

    Science.gov (United States)

    Dutta, Shuchismita; Dimitropoulos, Dimitris; Feng, Zukang; Persikova, Irina; Sen, Sanchayita; Shao, Chenghua; Westbrook, John; Young, Jasmine; Zhuravleva, Marina A; Kleywegt, Gerard J; Berman, Helen M

    2014-06-01

    With the accumulation of a large number and variety of molecules in the Protein Data Bank (PDB) comes the need on occasion to review and improve their representation. The Worldwide PDB (wwPDB) partners have periodically updated various aspects of structural data representation to improve the integrity and consistency of the archive. The remediation effort described here was focused on improving the representation of peptide-like inhibitor and antibiotic molecules so that they can be easily identified and analyzed. Peptide-like inhibitors or antibiotics were identified in over 1000 PDB entries, systematically reviewed and represented either as peptides with polymer sequence or as single components. For the majority of the single-component molecules, their peptide-like composition was captured in a new representation, called the subcomponent sequence. A novel concept called "group" was developed for representing complex peptide-like antibiotics and inhibitors that are composed of multiple polymer and nonpolymer components. In addition, a reference dictionary was developed with detailed information about these peptide-like molecules to aid in their annotation, identification and analysis. Based on the experience gained in this remediation, guidelines, procedures, and tools were developed to annotate new depositions containing peptide-like inhibitors and antibiotics accurately and consistently. © 2013 The Authors Biopolymers Published by Wiley Periodicals, Inc.

  10. Characterization of unique amphipathic antimicrobial peptides from venom of the scorpion Pandinus imperator.

    Science.gov (United States)

    Corzo, G; Escoubas, P; Villegas, E; Barnham, K J; He, W; Norton, R S; Nakajima, T

    2001-10-01

    Two novel antimicrobial peptides have been identified and characterized from venom of the African scorpion Pandinus imperator. The peptides, designated pandinin 1 and 2, are alpha-helical polycationic peptides, with pandinin 1 belonging to the group of antibacterial peptides previously described from scorpions, frogs and insects, and pandinin 2 to the group of short magainin-type helical peptides from frogs. Both peptides demonstrated high antimicrobial activity against a range of Gram-positive bacteria (2.4-5.2 microM), but were less active against Gram-negative bacteria (2.4-38.2 microM), and only pandinin 2 affected the yeast Candida albicans. Pandinin 2 also demonstrated strong haemolytic activity (11.1-44.5 microM) against sheep erythrocytes, in contrast with pandinin 1, which was not haemolytic. CD studies and a high-resolution structure of pandinin 2 determined by NMR, showed that the two peptides are both essentially helical, but differ in their overall structure. Pandinin 2 is composed of a single alpha-helix with a predominantly hydrophobic N-terminal sequence, whereas pandinin 1 consists of two distinct alpha-helices separated by a coil region of higher flexibility. This is the first report of magainin-type polycationic antimicrobial peptides in scorpion venom. Their presence brings new insights into the mode of action of scorpion venom and also opens new avenues for the discovery of novel antibiotic molecules from arthropod venoms.

  11. Coassembly of Peptides Derived from β-Sheet Regions of β-Amyloid.

    Science.gov (United States)

    Truex, Nicholas L; Nowick, James S

    2016-10-26

    In this paper, we investigate the coassembly of peptides derived from the central and C-terminal regions of the β-amyloid peptide (Aβ). In the preceding paper, J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b06000 , we established that peptides containing residues 17-23 (LVFFAED) from the central region of Aβ and residues 30-36 (AIIGLMV) from the C-terminal region of Aβ assemble to form homotetramers consisting of two hydrogen-bonded dimers. Here, we mix these tetramer-forming peptides and determine how they coassemble. Incorporation of a single 15 N isotopic label into each peptide provides a spectroscopic probe with which to elucidate the coassembly of the peptides by 1 H, 15 N HSQC. Job's method of continuous variation and nonlinear least-squares fitting reveal that the peptides form a mixture of heterotetramers in 3:1, 2:2, and 1:3 stoichiometries, in addition to the homotetramers. These studies also establish the relative stability of each tetramer and show that the 2:2 heterotetramer predominates. 15 N-Edited NOESY shows the 2:2 heterotetramer comprises two different homodimers, rather than two heterodimers. The peptides within the heterotetramer segregate in forming the homodimer subunits, but the two homodimers coassemble in forming the heterotetramer. These studies show that the central and C-terminal regions of Aβ can preferentially segregate within β-sheets and that the resulting segregated β-sheets can further coassemble.

  12. Single-Molecule Spectroscopic Investigations of Amphipathic Helix Formation

    Science.gov (United States)

    Cunningham, Joy Ann; Okamoto, Kenji; English, Douglas

    2004-03-01

    We are using single molecule spectroscopy to examine surface-induced conformational states occurring through interaction of a polypeptide with an interface. Specifically, we investigate the folding of amphipathic helices by using single-molecule fluorescence resonance energy transfer to construct peptide conformational distributions in solution and at interfaces. Analysis of the conformational distributions and kinetics of peptides in different environments reveals properties of the free energy surface for helix formation at an interface relative to formation in solution.

  13. Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1.

    Directory of Open Access Journals (Sweden)

    Adeline Gasser

    Full Text Available Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

  14. Protection of Cattle against Foot-and-Mouth Disease by a Synthetic Peptide

    Science.gov (United States)

    Dimarchi, Richard; Brooke, Gerald; Gale, Charles; Cracknell, Victor; Doel, Timothy; Mowat, Noel

    1986-05-01

    A chemically synthesized peptide consisting essentially of two separate regions (residues 141 to 158 and 200 to 213) of a virus coat protein (VP1) from the 01 Kaufbeuren strain of foot-and-mouth disease virus was prepared free of any carrier protein. It elicited high levels of neutralizing antibody and protected cattle against intradermolingual challenge by inoculation with infectious virus. Comparative evaluation of this peptide with a single-site peptide (residues 141 to 158) in guinea pigs suggests the importance of the VP1 carboxyl terminal residues in enhancing the protective response.

  15. Antiviral active peptide from oyster

    Science.gov (United States)

    Zeng, Mingyong; Cui, Wenxuan; Zhao, Yuanhui; Liu, Zunying; Dong, Shiyuan; Guo, Yao

    2008-08-01

    An active peptide against herpes virus was isolated from the enzymic hydrolysate of oyster ( Crassostrea gigas) and purified with the definite direction hydrolysis technique in the order of alcalase and bromelin. The hydrolysate was fractioned into four ranges of molecular weight (>10 kDa, 10 5 kDa, 5 1 kDa and <1 kDa) using ultrafiltration membranes and dialysis. The fraction of 10 5 kDa was purified using consecutive chromatographic methods including DEAE Sephadex A-25 column, Sephadex G-25 column, and high performance liquid chromatogram (HPLC) by activity-guided isolation. The antiviral effect of the obtained peptide on herpetic virus was investigated in Vero cells by observing cytopathic effect (CPE). The result shows that the peptide has high inhibitory activity on herpetic virus.

  16. Dietary bioactive peptides: Human studies.

    Science.gov (United States)

    Bouglé, Dominique; Bouhallab, Saïd

    2017-01-22

    Current opinion strongly links nutrition and health. Among nutrients, proteins, and peptides which are encrypted in their sequences and released during digestion could play a key role in improving health. These peptides have been claimed to be active on a wide spectrum of biological functions or diseases, including blood pressure and metabolic risk factors (coagulation, obesity, lipoprotein metabolism, and peroxidation), gut and neurological functions, immunity, cancer, dental health, and mineral metabolism. A majority of studies involved dairy peptides, but the properties of vegetal, animal, and sea products were also assessed. However, these allegations are mainly based on in vitro and experimental studies which are seldom confirmed in humans. This review focused on molecules which were tested in humans, and on the mechanisms explaining discrepancies between experimental and human studies.

  17. Shared fine specificity between T-cell receptors and an antibody recognizing a peptide/major histocompatibility class I complex

    DEFF Research Database (Denmark)

    Stryhn, A; Andersen, P S; Pedersen, L O

    1996-01-01

    Cytotoxic T cells recognize mosaic structures consisting of target peptides embedded within self-major histocompatibility complex (MHC) class I molecules. This structure has been described in great detail for several peptide-MHC complexes. In contrast, how T-cell receptors recognize peptide-MHC...... complexes have been less well characterized. We have used a complete set of singly substituted analogs of a mouse MHC class I, Kk-restricted peptide, influenza hemagglutinin (Ha)255-262, to address the binding specificity of this MHC molecule. Using the same peptide-MHC complexes we determined the fine...... each other showing that peptide residues 1, 3, 4, 6, and 7 were exposed on the MHC surface and recognized by the T cells. Thus, the majority, and perhaps all, of the side chains of the non-primary anchor residues may be available for T-cell recognition, and contribute to the stringent specificity of T...

  18. Collisional activation by MALDI tandem time-of-flight mass spectrometry induces intramolecular migration of amide hydrogens in protonated peptides

    DEFF Research Database (Denmark)

    Jørgensen, Thomas J D; Bache, Nicolai; Roepstorff, Peter

    2005-01-01

    -specific information about the incorporation of deuterium into peptides and proteins in solution. Using a unique set of peptides with their carboxyl-terminal half labeled with deuterium we have shown unambiguously that hydrogen (1H/2H) scrambling is such a dominating factor during low energy collisional activation...... of doubly protonated peptides that the original regioselective deuterium pattern of these peptides is completely erased (Jørgensen, T. J. D., Gårdsvoll, H., Ploug, M., and Roepstorff, P. (2005) Intramolecular migration of amide hydrogens in protonated peptides upon collisional activation. J. Am. Chem. Soc...... randomization among all exchangeable sites (i.e. all N- and O-linked hydrogens) also occurs upon high energy collisional activation of singly protonated peptides. This intense proton/deuteron traffic precludes the use of MALDI tandem time-of-flight mass spectrometry to obtain reliable information...

  19. Histone peptide AKRHRK enhances H2O2-induced DNA damage and alters its site specificity

    International Nuclear Information System (INIS)

    Midorikawa, Kaoru; Murata, Mariko; Kawanishi, Shosuke

    2005-01-01

    Histone proteins are involved in compaction of DNA and the protection of cells from oxygen toxicity. However, several studies have demonstrated that the metal-binding histone reacts with H 2 O 2 , leading to oxidative damage to a nucleobase. We investigated whether histone can accelerate oxidative DNA damage, using a minimal model for the N-terminal tail of histone H4, CH 3 CO-AKRHRK-CONH 2 , which has a metal-binding site. This histone peptide enhanced DNA damage induced by H 2 O 2 and Cu(II), especially at cytosine residues, and induced additional DNA cleavage at the 5'-guanine of GGG sequences. The peptide also enhanced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine and ESR spin-trapping signal from H 2 O 2 and Cu(II). Cyclic redox reactions involving histone-bound Cu(II) and H 2 O 2 , may give rise to multiple production of radicals leading to multiple hits in DNA. It is noteworthy that the histone H4 peptide with specific sequence AKRHRK can cause DNA damage rather than protection under metal-overloaded condition

  20. A Hurricane Hits Home: An Interactive Science Museum Exhibit on Ocean Mapping and Marine Debris

    Science.gov (United States)

    Butkiewicz, T.; Vasta, D. J.; Gager, N. C.; Fruth, B. W.; LeClair, J.

    2016-12-01

    As part of the outreach component for a project involving the detection and analysis of marine debris generated by Super Storm Sandy, The Center for Coastal and Ocean Mapping / Joint Hydrographic Center partnered with The Seacoast Science Center to develop an interactive museum exhibit that engages the public with a touchscreen based game revolving around the detection and identification of marine debris. "A Hurricane Hits Home" is a multi-station touchscreen exhibit geared towards children, and integrates a portion of a historical wooden shipwreck into its physical design. The game invites museum guests to examine a number of coastal regions and harbors in Sandy affected areas. It teaches visitors about modern mapping technology by having them control boats with multibeam sonars and airplanes with lidar sensors. They drag these vehicles around maps to reveal the underlying bathymetry below the satellite photos. They learn the applications and limitations of sonar and lidar by where the vehicles can and cannot collect survey data (e.g. lidar doesn't work in deep water, and the boat can't go in shallow areas). As users collect bathymetry data, they occasionally reveal marine debris objects on the seafloor. Once all the debris objects in a level have been located, the game challenges them to identify them based on their appearance in the bathymetry data. They must compare the simulated bathymetry images of the debris targets to photos of possible objects, and choose the correct matches to achieve a high score. The exhibit opened January 2016 at the Seacoast Science Center in Rye, NH.

  1. Hypertrophic Cardiomyopathy: A Vicious Cycle Triggered by Sarcomere Mutations and Secondary Disease Hits.

    Science.gov (United States)

    Wijnker, Paul J M; Sequeira, Vasco; Kuster, Diederik W D; Velden, Jolanda van der

    2018-04-11

    Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease onset occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. HCM is caused by mutations in sarcomere proteins, the contractile building blocks of the heart. Despite increased knowledge of causal mutations, the exact path from genetic defect leading to cardiomyopathy is complex and involves additional disease hits. Recent Advances: Laboratory-based studies indicate that HCM development not only depends on the primary sarcomere impairment caused by the mutation but also on secondary disease-related alterations in the heart. Here we propose a vicious mutation-induced disease cycle, in which a mutation-induced energy depletion alters cellular metabolism with increased mitochondrial work, which triggers secondary disease modifiers that will worsen disease and ultimately lead to end-stage HCM. Evidence shows excessive cellular reactive oxygen species (ROS) in HCM patients and HCM animal models. Oxidative stress markers are increased in the heart (oxidized proteins, DNA, and lipids) and serum of HCM patients. In addition, increased mitochondrial ROS production and changes in endogenous antioxidants are reported in HCM. Mutant sarcomeric protein may drive excessive levels of cardiac ROS via changes in cardiac efficiency and metabolism, mitochondrial activation and/or dysfunction, impaired protein quality control, and microvascular dysfunction. Interventions restoring metabolism, mitochondrial function, and improved ROS balance may be promising therapeutic approaches. We discuss the effects of current HCM pharmacological therapies and potential future therapies to prevent and reverse HCM. Antioxid. Redox Signal. 00, 000-000.

  2. Mental health problems among the survivors in the hard-hit areas of the Yushu earthquake.

    Directory of Open Access Journals (Sweden)

    Zhen Zhang

    Full Text Available BACKGROUND: On April 14, 2010, an earthquake registering 7.1 on the Richter scale shook Qinghai Province in southwest China. The earthquake caused numerous casualties and much damage. The epicenter, Yushu County, suffered the most severe damage. As a part of the psychological relief work, the present study evaluated the mental health statuses of the people affected and identified the mental disorder risk factors related to earthquakes. METHODS: Five hundred and five earthquake survivors living in Yushu County were investigated 3-4 months after the earthquake. Participant demographic data including gender, age, marital status, ethnicity, educational level, and religious beliefs were collected. The Earthquake-Specific Trauma Exposure Indicators assessed the intensity of exposure to trauma during the earthquake. The PTSD Checklist-Civilian version (PCL-C and the Hopkins Symptoms Checklist-25 (HSCL-25 assessed the symptoms and prevalence rates of probable Posttraumatic Stress Disorder (PTSD as well as anxiety and depression, respectively. The Perceived Social Support Scale (PSSS evaluated subjective social support. RESULTS: The prevalence rates of probable PTSD, anxiety, and depression were 33.7%, 43.8% and 38.6%, respectively. Approximately one fifth of participants suffered from all three conditions. Individuals who were female, felt initial fear during the earthquake, and had less social support were the most likely to have poor mental health. CONCLUSIONS: The present study revealed that there are serious mental problems among the hard-hit survivors of the Yushu earthquake. Survivors at high risk for mental disorders should be specifically considered. The present study provides useful information for rebuilding and relief work.

  3. Mental health problems among the survivors in the hard-hit areas of the Yushu earthquake.

    Science.gov (United States)

    Zhang, Zhen; Wang, Wenzhong; Shi, Zhanbiao; Wang, Li; Zhang, Jianxin

    2012-01-01

    On April 14, 2010, an earthquake registering 7.1 on the Richter scale shook Qinghai Province in southwest China. The earthquake caused numerous casualties and much damage. The epicenter, Yushu County, suffered the most severe damage. As a part of the psychological relief work, the present study evaluated the mental health statuses of the people affected and identified the mental disorder risk factors related to earthquakes. Five hundred and five earthquake survivors living in Yushu County were investigated 3-4 months after the earthquake. Participant demographic data including gender, age, marital status, ethnicity, educational level, and religious beliefs were collected. The Earthquake-Specific Trauma Exposure Indicators assessed the intensity of exposure to trauma during the earthquake. The PTSD Checklist-Civilian version (PCL-C) and the Hopkins Symptoms Checklist-25 (HSCL-25) assessed the symptoms and prevalence rates of probable Posttraumatic Stress Disorder (PTSD) as well as anxiety and depression, respectively. The Perceived Social Support Scale (PSSS) evaluated subjective social support. The prevalence rates of probable PTSD, anxiety, and depression were 33.7%, 43.8% and 38.6%, respectively. Approximately one fifth of participants suffered from all three conditions. Individuals who were female, felt initial fear during the earthquake, and had less social support were the most likely to have poor mental health. The present study revealed that there are serious mental problems among the hard-hit survivors of the Yushu earthquake. Survivors at high risk for mental disorders should be specifically considered. The present study provides useful information for rebuilding and relief work.

  4. Natriuretic peptides and cerebral hemodynamics

    DEFF Research Database (Denmark)

    Guo, Song; Barringer, Filippa; Zois, Nora Elisabeth

    2014-01-01

    in decompensated disease. In contrast, their biological effects on the cerebral hemodynamics are poorly understood. In this mini-review, we summarize the hemodynamic effects of the natriuretic peptides with a focus on the cerebral hemodynamics. In addition, we will discuss its potential implications in diseases...... where alteration of the cerebral hemodynamics plays a role such as migraine and acute brain injury including stroke. We conclude that a possible role of the peptides is feasible as evaluated from animal and in vitro studies, but more research is needed in humans to determine the precise response...

  5. Novel Formulations for Antimicrobial Peptides

    Directory of Open Access Journals (Sweden)

    Ana Maria Carmona-Ribeiro

    2014-10-01

    Full Text Available Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy.

  6. Biodegradable Peptide-Silica Nanodonuts.

    Science.gov (United States)

    Maggini, Laura; Travaglini, Leana; Cabrera, Ingrid; Castro-Hartmann, Pablo; De Cola, Luisa

    2016-03-07

    We report hybrid organosilica toroidal particles containing a short peptide sequence as the organic component of the hybrid systems. Once internalised in cancer cells, the presence of the peptide allows for interaction with peptidase enzymes, which attack the nanocarrier effectively triggering its structural breakdown. Moreover, these biodegradable nanovectors are characterised by high cellular uptake and exocytosis, showing great potential as biodegradable drug carriers. To demonstrate this feature, doxorubicin was employed and its delivery in HeLa cells investigated. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

    Science.gov (United States)

    Jin, Liang; Wu, Xuri; Xue, Yanjiu; Jin, Yue; Wang, Shuzhen

    2016-01-01

    ABSTRACT Nosiheptide, a typical member of the ribosomally synthesized and posttranslationally modified peptides (RiPPs), exhibits potent activity against multidrug-resistant Gram-positive bacterial pathogens. The precursor peptide of nosiheptide (NosM) is comprised of a leader peptide with 37 amino acids and a core peptide containing 13 amino acids. To pinpoint elements in the leader peptide that are essential for nosiheptide biosynthesis, a collection of mutants with unique sequence features, including N- and C-terminal motifs, peptide length, and specific sites in the leader peptide, was generated by mutagenesis in vivo. The effects of various mutants on nosiheptide biosynthesis were evaluated. In addition to the necessity of a conserved motif LEIS box, native length and the N-terminal 12 amino acid residues were indispensable, and single-site substitutions of these 12 amino acid residues resulted in changes ranging from a greater-than-5-fold decrease to a 2-fold increase of nosiheptide production, depending on the sites and substituted residues. Moreover, although the C-terminal motif is not conservative, significant effects of this portion on nosiheptide production were also evident. Taken together, the present results further highlight the importance of the leader peptide in nosiheptide biosynthesis, and provide new insights into the diversity and specificity of leader peptides in the biosynthesis of various RiPPs. IMPORTANCE As a representative thiopeptide, nosiheptide exhibits excellent antibacterial activity. Although the biosynthetic gene cluster and several modification steps have been revealed, the presence and roles of the leader peptide within the precursor peptide of the nosiheptide gene cluster remain elusive. Thus, identification of specific elements in the leader peptide can significantly facilitate the genetic manipulation of the gene cluster for increasing nosiheptide production or generating diverse analogues. Given the complexity of the

  8. Peptide Level Turnover Measurements Enable the Study of Proteoform Dynamics.

    Science.gov (United States)

    Zecha, Jana; Meng, Chen; Zolg, Daniel Paul; Samaras, Patroklos; Wilhelm, Mathias; Kuster, Bernhard

    2018-05-01

    The coordination of protein synthesis and degradation regulating protein abundance is a fundamental process in cellular homeostasis. Today, mass spectrometry-based technologies allow determination of endogenous protein turnover on a proteome-wide scale. However, standard dynamic SILAC (Stable Isotope Labeling in Cell Culture) approaches can suffer from missing data across pulse time-points limiting the accuracy of such analysis. This issue is of particular relevance when studying protein stability at the level of proteoforms because often only single peptides distinguish between different protein products of the same gene. To address this shortcoming, we evaluated the merits of combining dynamic SILAC and tandem mass tag (TMT)-labeling of ten pulse time-points in a single experiment. Although the comparison to the standard dynamic SILAC method showed a high concordance of protein turnover rates, the pulsed SILAC-TMT approach yielded more comprehensive data (6000 proteins on average) without missing values. Replicate analysis further established that the same reproducibility of turnover rate determination can be obtained for peptides and proteins facilitating proteoform resolved investigation of protein stability. We provide several examples of differentially turned over splice variants and show that post-translational modifications can affect cellular protein half-lives. For example, N-terminally processed peptides exhibited both faster and slower turnover behavior compared with other peptides of the same protein. In addition, the suspected proteolytic processing of the fusion protein FAU was substantiated by measuring vastly different stabilities of the cleavage products. Furthermore, differential peptide turnover suggested a previously unknown mechanism of activity regulation by post-translational destabilization of cathepsin D as well as the DNA helicase BLM. Finally, our comprehensive data set facilitated a detailed evaluation of the impact of protein

  9. Characterisation and evaluation of antiviral recombinant peptides based on the heptad repeat regions of NDV and IBV fusion glycoproteins

    International Nuclear Information System (INIS)

    Wang Xiaojia; Li Chuangen; Chi Xiaojing; Wang Ming

    2011-01-01

    Mixed virus infections can cause livestock losses that are more devastating than those caused by single virus infections. Newcastle disease virus (NDV) and infectious bronchitis virus (IBV), serious threats to the poultry industry, can give rise to complex mixed infections that hinder diagnosis and prevention. In this study, we show that newly designed peptides, which are based on the heptad repeat (HR) region of the fusion glycoproteins from NDV and IBV, have more potent antiviral activity than the mother HR peptides. Plaque formation and chicken embryo infectivity assays confirmed these results. The novel peptides completely inhibited single virus infections and mixed infections caused by NDV and IBV. Furthermore, we assessed cell toxicity and possible targets for the peptides, thereby strengthening the notion that HR2 is an attractive site for therapeutic intervention. These results suggest the possibility of designing a relatively broad-spectrum class of antiviral peptides that can reduce the effects of mixed-infections.

  10. Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert(®) HIT) for the diagnosis of heparin-induced thrombocytopenia.

    Science.gov (United States)

    Leroux, Dorothée; Hezard, Nathalie; Lebreton, Aurélien; Bauters, Anne; Suchon, Pierre; de Maistre, Emmanuel; Biron, Christine; Huisse, Marie-Genevieve; Ternisien, Catherine; Voisin, Sophie; Gruel, Yves; Pouplard, Claire

    2014-09-01

    A rapid lateral flow immunoassay (LFIA) (STic Expert(®) HIT), recently developed for the diagnosis of heparin-induced thrombocytopenia (HIT), was evaluated in a prospective multicentre cohort of 334 consecutive patients. The risk of HIT was estimated by the 4Ts score as low, intermediate and high in 28·7%, 61·7% and 9·6% of patients, respectively. Definite HIT was diagnosed in 40 patients (12·0%) with positive results on both enzyme-linked immunosorbent assay (Asserachrom(®) HPIA IgG) and serotonin release assay. The inter-reader reproducibility of results obtained was excellent (kappa ratio > 0·9). The negative predictive value of LFIA with plasma samples was 99·6% with a negative likelihood ratio (LR) of 0·03, and was comparable to those of the particle gel immunoassay (H/PF4-PaGIA(®) ) performed in 124 cases. Positive predictive value and positive LR were 44·4% and 5·87, respectively, and the results were similar for serum samples. The probability of HIT in intermediate risk patients decreased from 11·2% to 0·4% when the LFIA result was negative and increased to 42·5% when it was positive. In conclusion, the STic Expert(®) HIT combined with the 4Ts score is a reliable tool to rule out the diagnosis of HIT. © 2014 John Wiley & Sons Ltd.

  11. Production and characterization of peptide antibodies

    DEFF Research Database (Denmark)

    Trier, Nicole Hartwig; Hansen, Paul Robert; Houen, Gunnar

    2012-01-01

    Proteins are effective immunogens for generation of antibodies. However, occasionally the native protein is known but not available for antibody production. In such cases synthetic peptides derived from the native protein are good alternatives for antibody production. These peptide antibodies...... are powerful tools in experimental biology and are easily produced to any peptide of choice. A widely used approach for production of peptide antibodies is to immunize animals with a synthetic peptide coupled to a carrier protein. Very important is the selection of the synthetic peptide, where factors...... such as structure, accessibility and amino acid composition are crucial. Since small peptides tend not to be immunogenic, it may be necessary to conjugate them to carrier proteins in order to enhance immune presentation. Several strategies for conjugation of peptide-carriers applied for immunization exist...

  12. The intracellular pharmacokinetics of terminally capped peptides.

    NARCIS (Netherlands)

    Ruttekolk, I.R.R.; Witsenburg, J.J.; Glauner, H.B.; Bovee-Geurts, P.H.M.; Ferro, E.S.; Verdurmen, W.P.R.; Brock, R.E.

    2012-01-01

    With significant progress in delivery technologies, peptides and peptidomimetics are receiving increasing attention as potential therapeutics also for intracellular applications. However, analyses of the intracellular behavior of peptides are a challenge; therefore, knowledge on the intracellular

  13. Strategic approaches to optimizing peptide ADME properties.

    Science.gov (United States)

    Di, Li

    2015-01-01

    Development of peptide drugs is challenging but also quite rewarding. Five blockbuster peptide drugs are currently on the market, and six new peptides received first marketing approval as new molecular entities in 2012. Although peptides only represent 2% of the drug market, the market is growing twice as quickly and might soon occupy a larger niche. Natural peptides typically have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Strategies have been developed to improve peptide drugability through enhancing permeability, reducing proteolysis and renal clearance, and prolonging half-life. In vivo, in vitro, and in silico tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability.

  14. Histidine-Containing Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2000-01-01

    Peptide nucleic acids containing histidine moieties are provided. These compounds have applications including diagnostics, research and potential therapeutics.......Peptide nucleic acids containing histidine moieties are provided. These compounds have applications including diagnostics, research and potential therapeutics....

  15. Tumor Associated Antigenic Peptides in Prostate Cancer

    National Research Council Canada - National Science Library

    Tiwari, Raj

    2001-01-01

    .... Since this tumor rejection property was specifically mediated by tumor denved and not non-tumor derived gp96-peptide complexes, and that gp96 preparations stripped of its peptides are non-immunogenic...

  16. Peptides: Production, bioactivity, functionality, and applications

    DEFF Research Database (Denmark)

    Hajfathalian, Mona; Ghelichi, Sakhi; García Moreno, Pedro Jesús

    2017-01-01

    Production of peptides with various effects from proteins of different sources continues to receive academic attention. Researchers of different disciplines are putting increasing efforts to produce bioactive and functional peptides from different sources such as plants, animals, and food industry...

  17. The two-hit hypothesis for neuroinflammation: role of exogenous ATP in modulating inflammation in the brain

    Directory of Open Access Journals (Sweden)

    Bernd L. Fiebich

    2014-09-01

    Full Text Available Brain inflammation is a common occurrence following responses to varied insults such as bacterial infections, stroke, traumatic brain injury and neurodegenerative disorders. A common mediator for these varied inflammatory responses is prostaglandin E2 (PGE2, produced by the enzymatic activity of cyclooxygenases (COX 1 and 2. Previous attempts to reduce neuronal inflammation through COX inhibition, by use of nonsteroidal anti-inflammatory drugs (NSAIDs, have met with limited success. We are proposing the two-hit model for neuronal injury – an initial localized inflammation mediated by PGE2 (first hit and the simultaneous release of adenosine triphosphate (ATP by injured cells (second hit, which significantly enhances the inflammatory response through increased synthesis of PGE2. Several evidences on the role of exogenous ATP in inflammation have been reported, including contrary instances where extracellular ATP reduces inflammatory events. In this review, we will examine the current literature on the role of P2 receptors, to which ATP binds, in modulating inflammatory reactions during neurodegeneration. Targeting the P2 receptors, therefore, provides a therapeutic alternative to reduce inflammation in the brain. P2 receptor-based anti-inflammatory drugs (PBAIDs will retain the activities of essential COX enzymes, yet will significantly reduce neuroinflammation by decreasing the enhanced production of PGE2 by extracellular ATP.

  18. A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex.

    Science.gov (United States)

    Tyburczy, Magdalena E; Jozwiak, Sergiusz; Malinowska, Izabela A; Chekaluk, Yvonne; Pugh, Trevor J; Wu, Chin-Lee; Nussbaum, Robert L; Seepo, Sara; Dzik, Tomasz; Kotulska, Katarzyna; Kwiatkowski, David J

    2015-04-01

    Tuberous sclerosis complex (TSC) is a genetic disorder characterized by seizures and tumor formation in multiple organs, mainly in the brain, skin, kidney, lung and heart. Renal cell carcinoma (RCC) occurs in ∼3% of TSC patients, and typically develops at age 1 tumor. The second (male) TSC patient had bilateral partial nephrectomies (both at age 36), with similar findings of multifocal PRCC. NGS analysis of TSC2 in two of these tumors identified a second hit mutation c.2355+1G>T in one sample that was not seen in other tumors. In conclusion, we report the first detailed genetic analysis of RCCs in TSC patients. Molecular studies indicate that tumors developed independently due to various second hit events, suggesting that these patients experienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe phenotype. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Frequency of brain cell hits by high-LET particles in a low-earth-orbit space mission

    International Nuclear Information System (INIS)

    Yasuda, Hiroshi; Fujitaka, Kazunobu; Komiyama, Tatsuto

    2000-01-01

    The fluence of high-LET particles in space radiation was measured with plastic nuclear track detectors (PNTDs) in the brain of a life-size human phantom in the 9th Shuttle-Mir Mission (STS-91). The relationship between PNTD track-formation sensitivity (S) and LET ∞ ·H 2 O was examined using heavy-ion beams at the NIRS-HIMAC and the incident-angle dependence of S was corrected using an empirical function. The particle fluence of space radiation with LET ∞ ·H 2 O greater than 10 keV μm -1 in the brain was evaluated as 1.3 x 10 4 n cm -2 in a 9.8-day low-Earth-orbit mission at 400 km x 51.6 deg. Based on these data, the ratio (the number) of hits to hippocampus cells and cell-nuclei were calculated for long missions. As a result, it was estimated that 45% (2.2 x 10 7 ) cells and 7.0% (3.4 x 10 6 ) cell-nuclei will be hit by high-LET particles (LET ∞ ·H 2 O> 10 keV μm -1 ) in a 90-day mission, and 91% (4.4 x 10 7 ) and 25% (1.2 x 10 7 ) of cell-nuclei will be hit in a 1-year mission. (author)

  20. Development and use of engineered peptide deformylase in chemoenzymatic peptide synthesis

    NARCIS (Netherlands)

    Di Toma, Claudia

    2012-01-01

    Deze thesis beschrijft het onderzoek naar potentieel van het gebruik van het peptide deformylase (PDF) in chemo enzymatische peptide synthese. PDF is geschikt voor selective N terminale deformylatie van bepaalde N-formyl-peptides zonder gelijktijdige hydrolyse van de peptide binding. Door de

  1. STM studies of synthetic peptide monolayers

    Science.gov (United States)

    Bergeron, David J.; Clauss, Wilfried; Pilloud, Denis L.; Leslie Dutton, P.; Johnson, Alan T.

    1998-08-01

    We have used scanning probe microscopy to investigate self-assembled monolayers of chemically synthesized peptides. We find that the peptides form a dense uniform monolayer, above which is found a sparse additional layer. Using scanning tunneling microscopy, submolecular resolution can be obtained, revealing the alpha helices which constitute the peptide. The nature of the images is not significantly affected by the incorporation of redox cofactors (hemes) in the peptides.

  2. Antimicrobial activities of heparin-binding peptides.

    OpenAIRE

    Andersson, Emma; Rydengård, Victoria; Sonesson, Andreas; Mörgelin, Matthias; Björck, Lars; Schmidtchen, Artur

    2004-01-01

    Antimicrobial peptides are effector molecules of the innate immune system. We recently showed that the human antimicrobial peptides alpha-defensin and LL-37 bind to glycosaminoglycans (heparin and dermatan sulphate). Here we demonstrate the obverse, i.e. structural motifs associated with heparin affinity (cationicity, amphipaticity, and consensus regions) may confer antimicrobial properties to a given peptide. Thus, heparin-binding peptides derived from laminin isoforms, von Willebrand factor...

  3. C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles

    DEFF Research Database (Denmark)

    Hansen, Jonas; Diness, Frederik; Meldal, Morten Peter

    2016-01-01

    A large variety of C-terminally modified peptides was obtained by nucleophilic cleavage of the ester bond in solid phase linked peptide esters of 4-hydroxymethyl benzamide (HMBA). The developed methods provided peptides, C-terminally functionalized as esters, amides and thioesters, with high purity...... directly from the resin in a single reaction step. A comprehensive screening of the reaction conditions and scope for nucleophilic cleavage of peptides from the HMBA linker was performed....

  4. TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants.

    Science.gov (United States)

    Hartmann, Erik K; Thomas, Rainer; Liu, Tanghua; Stefaniak, Joanna; Ziebart, Alexander; Duenges, Bastian; Eckle, Daniel; Markstaller, Klaus; David, Matthias

    2014-01-01

    Inhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B). Following animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring. The repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring. In comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics.

  5. One Hundred Years of Peptide Chemistry

    Indian Academy of Sciences (India)

    ber of residues are often denoted as peptides. The chemical synthesis of peptides, as envisaged by Fischer, involves ... known as genetically encoded as building blocks of peptides and proteins. Almost all of .... inhibit final stages of the enzymatic construction of the bacterial peptidoglycan cell wall component, a network of.

  6. Toxins and antimicrobial peptides: interactions with membranes

    Science.gov (United States)

    Schlamadinger, Diana E.; Gable, Jonathan E.; Kim, Judy E.

    2009-08-01

    The innate immunity to pathogenic invasion of organisms in the plant and animal kingdoms relies upon cationic antimicrobial peptides (AMPs) as the first line of defense. In addition to these natural peptide antibiotics, similar cationic peptides, such as the bee venom toxin melittin, act as nonspecific toxins. Molecular details of AMP and peptide toxin action are not known, but the universal function of these peptides to disrupt cell membranes of pathogenic bacteria (AMPs) or a diverse set of eukaryotes and prokaryotes (melittin) is widely accepted. Here, we have utilized spectroscopic techniques to elucidate peptide-membrane interactions of alpha-helical human and mouse AMPs of the cathelicidin family as well as the peptide toxin melittin. The activity of these natural peptides and their engineered analogs was studied on eukaryotic and prokaryotic membrane mimics consisting of <200-nm bilayer vesicles composed of anionic and neutral lipids as well as cholesterol. Vesicle disruption, or peptide potency, was monitored with a sensitive fluorescence leakage assay. Detailed molecular information on peptidemembrane interactions and peptide structure was further gained through vibrational spectroscopy combined with circular dichroism. Finally, steady-state fluorescence experiments yielded insight into the local environment of native or engineered tryptophan residues in melittin and human cathelicidin embedded in bilayer vesicles. Collectively, our results provide clues to the functional structures of the engineered and toxic peptides and may impact the design of synthetic antibiotic peptides that can be used against the growing number of antibiotic-resistant pathogens.

  7. Ribosome evolution: Emergence of peptide synthesis machinery

    Indian Academy of Sciences (India)

    allows the histidine to position close to the PTC during the reaction, it may contribute to improving peptide bond formation. Thus, it is important to analyse biomolecular interactions in terms of the dynamic nature of the structure. 3. Origin of peptide bond formation and the RNA world. Minihelix-based peptide bond formation ...

  8. Double-Stranded Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2001-01-01

    A novel class of compounds, known as peptide nucleic acids, form double-stranded structures with one another and with ssDNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  9. Synthetic Procedures for Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  10. Glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Deacon, C F; Holst, Jens Juul; Carr, R D

    1999-01-01

    Type 2 diabetes mellitus is a metabolic disease resulting in raised blood sugar which, if not satisfactorily controlled, can cause severe and often debilitating complications. Unfortunately, for many patients, the existing therapies do not give adequate control. Glucagon-like peptide-1 (GLP-1...

  11. Peptide Receptor Radionuclide Therapy & Oncology

    NARCIS (Netherlands)

    H. Bergsma (Hendrik)

    2017-01-01

    markdownabstractNeuroendocrine tumors (NETs) are rare neoplasms with differences in clinical presentation, course and prognosis. Most of the NETs express the somatostatine receptor, which can be utilized for imaging and therapy. Radiolabeled somatostatin analogs can be used for peptide receptor

  12. Glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Deacon, C F; Holst, Jens Juul; Carr, R D

    1999-01-01

    Type 2 diabetes mellitus is a metabolic disease resulting in raised blood sugar which, if not satisfactorily controlled, can cause severe and often debilitating complications. Unfortunately, for many patients, the existing therapies do not give adequate control. Glucagon-like peptide-1 (GLP-1...... advantages offered by GLP-1 and give the hope of providing effective glycemic control without the risk of overt hypoglycemia....

  13. Synthetic peptides for diagnostic use

    NARCIS (Netherlands)

    Meloen, R.H.; Langedijk, J.P.M.; Langeveld, J.P.M.

    1997-01-01

    Synthetic peptides representing relevant B-cell epitopes are, potentially, ideal antigens to be used in diagnostic assays because of their superior properties with respect to quality control as compared to those of biologically derived molecules and the much higher specificity that sometimes can be

  14. Next generation natriuretic peptide measurement

    DEFF Research Database (Denmark)

    Hunter, Ingrid; Goetze, Jens P

    2012-01-01

    in the molecular heterogeneity could in itself contain valuable information of clinical status, and the time seems right for industry and dedicated researchers in the field to get together and discuss the next generation natriuretic peptide measurement. In such an environment, new strategies can be developed...

  15. Atrial natriuretic peptides in plasma

    DEFF Research Database (Denmark)

    Goetze, Jens P; Holst Hansen, Lasse; Terzic, Dijana

    2015-01-01

    derivatizations. In this mini-review, we summarize measurement of the principal cardiac hormone, e.g. atrial natriuretic peptide (ANP) and its precursor fragments. We also highlight some of the analytical pitfalls and problems and the concurrent clinical "proof of concept". We conclude that biochemical research...

  16. More than 1,001 problems with protein domain databases: transmembrane regions, signal peptides and the issue of sequence homology.

    Directory of Open Access Journals (Sweden)

    Wing-Cheong Wong

    Full Text Available Large-scale genome sequencing gained general importance for life science because functional annotation of otherwise experimentally uncharacterized sequences is made possible by the theory of biomolecular sequence homology. Historically, the paradigm of similarity of protein sequences implying common structure, function and ancestry was generalized based on studies of globular domains. Having the same fold imposes strict conditions over the packing in the hydrophobic core requiring similarity of hydrophobic patterns. The implications of sequence similarity among non-globular protein segments have not been studied to the same extent; nevertheless, homology considerations are silently extended for them. This appears especially detrimental in the case of transmembrane helices (TMs and signal peptides (SPs where sequence similarity is necessarily a consequence of physical requirements rather than common ancestry. Thus, matching of SPs/TMs creates the illusion of matching hydrophobic cores. Therefore, inclusion of SPs/TMs into domain models can give rise to wrong annotations. More than 1001 domains among the 10,340 models of Pfam release 23 and 18 domains of SMART version 6 (out of 809 contain SP/TM regions. As expected, fragment-mode HMM searches generate promiscuous hits limited to solely the SP/TM part among clearly unrelated proteins. More worryingly, we show explicit examples that the scores of clearly false-positive hits, even in global-mode searches, can be elevated into the significance range just by matching the hydrophobic runs. In the PIR iProClass database v3.74 using conservative criteria, we find that at least between 2.1% and 13.6% of its annotated Pfam hits appear unjustified for a set of validated domain models. Thus, false-positive domain hits enforced by SP/TM regions can lead to dramatic annotation errors where the hit has nothing in common with the problematic domain model except the SP/TM region itself. We suggest a workflow of

  17. Creation of lipid partitions by deposition of amphipathic viral peptides.

    Science.gov (United States)

    Cho, Nam-Joon; Cho, Sang-Joon; Hardesty, Jasper O; Glenn, Jeffrey S; Frank, Curtis W

    2007-10-09

    Phospholipid vesicles exhibit a natural characteristic to fuse and reform into a continuous single bilayer membrane on hydrophilic solid substrates such as glass, mica, and silica. The resulting solid-supported bilayer mimics physiological tendencies such as lipid flip-flop and lateral mobility. The lateral mobility of fluorescently labeled lipids fused into solid-supported bilayers is found to change upon deposition on the membrane surface of an amphipathic alpha-helical peptide (AH) derived from the hepatitis C virus (HCV) NS5A protein. The binding of the AH peptide to a phospholipid bilayer, with the helical axis parallel to the bilayer, leads to immobilization of the bilayer. We used AFM to better understand the mechanistic details of this specific interaction, and determined that the diminished fluidity of the bilayer is due to membrane thinning. Utilizing this specific interaction between AH peptides and lipid molecules, we demonstrate a novel process for the creation of lipid partition by employing AH peptides as agents to immobilize lipid molecules, thus creating a patterned solid support with partition-defined areas of freely mobile lipid bilayers. This architecture could have a wide range of applications in novel sensing, biotechnology, high-throughput screening, and biomimetic strategies.

  18. The distribution of alpha hits per target cell: a parameter to improve risk assessment after inhalation exposure to actinide oxides

    International Nuclear Information System (INIS)

    Fritsch, P.

    2006-01-01

    After inhalation exposure to radionuclides, according to ICRP recommendations, the equivalent dose delivered to the different target regions of the respiratory tract corresponds to a mean value. Some actinide oxides have a very high specific activity, so that, the Annual Limit of Intake (A.L.I.) can be reached when only a few particles have been deposited. In this case, because of the short range of α radiation, only a small fraction of the tissues is irradiated, due to the presence of hot spots. Recently, animal studies have shown that, in the rat, for the same a dose delivered to the lungs, the risk for lung tumour induction varies over more than 1 order of magnitude, depending on the number of deposited particles. The aim of this work is to identify a parameter which could take into account heterogeneity of dose distribution for a realistic risk assessment from the result of a standard dose calculation. In vitro experiments have shown that, the risk for pre-neoplastic transformation per unit of dose gradually decreases when more than 1 α hit is received per target cell. This could be explained by a gradual increase of the ratio of cell death versus cell transformation. Thus, the distribution of the number of α hits per cell could be a useful parameter to improve dose calculation for a risk assessment purpose. The α hit distribution has been characterized in basal cells of the extra thoracic and bronchial epithelia irradiated from the sequestered regions (E.T. seq and B.B. seq ) after exposure inhalation to 1 A.L.I. of 238 U or 238-239 Pu oxide aerosols. Default parameters were used for calculation (aerosol size 5 μm, type S compounds, standard workers). In a first step, the number of particles deposited in the source regions and their activity was obtained after simulations which corresponded to a stochastic application of the ICRP 66 deposition model (the behaviour of each particle was taken into account, and for each particle size, the fraction deposited

  19. Post-discharge heart failure monitoring program in Turkey: Hit-PoinT

    Science.gov (United States)

    Çavuşoğlu, Yüksel; Zoghi, Mehdi; Eren, Mehmet; Bozçalı, Evin; Kozdağ, Güliz; Şentürk, Tunay; Alicik, Güray; Soylu, Korhan; Sarı, İbrahim; Berilgen, Rida; Temizhan, Ahmet; Gencer, Erkan; Orhan, Ahmet Lütfü; Polat, Veli; Kaderli, Aysel Aydın; Aktoz, Meryem; Zengin, Halit; Aksoy, Mehmet; Selçuk, Mehmet Timur; Ergene, Oktay; Soran, Özlem

    2017-01-01

    Objective: The aim of this study was to assess the efficacy and feasibility of an enhanced heart failure (HF) education with a 6-month telephone follow- up program in post-discharge ambulatory HF patients. Methods: The Hit-Point trial was a multicenter, randomized, controlled trial of enhanced HF education with a 6-month telephone follow-up program (EHFP) vs routine care (RC) in patients with HF and reduced ejection fraction. A total of 248 patients from 10 centers in various geographical areas were randomized: 125 to EHFP and 123 to RC. Education included information on adherence to treatment, symptom recognition, diet and fluid intake, weight monitoring, activity and exercise training. Patients were contacted by telephone after 1, 3, and 6 months. The primary study endpoint was cardiovascular death. Results: Although all-cause mortality didn’t differ between the EHFP and RC groups (p=NS), the percentage of cardiovascular deaths in the EHFP group was significantly lower than in the RC group at the 6-month follow up (5.6% vs. 8.9%, p=0.04). The median number of emergency room visits was one and the median number of all cause hospitalizations and heart failure hospitalizations were zero. Twenty-tree percent of the EHFP group and 35% of the RC group had more than a median number of emergency room visits (p=0.05). There was no significant difference regarding the median number of all–cause or heart failure hospitalizations. At baseline, 60% of patients in EHFP and 61% in RC were in NYHA Class III or IV, while at the 6-month follow up only 12% in EHFP and 32% in RC were in NYHA Class III or IV (p=0.001). Conclusion: These results demonstrate the potential clinical benefits of an enhanced HF education and follow up program led by a cardiologist in reducing cardiovascular deaths and number of emergency room visits with an improvement in functional capacity at 6 months in post-discharge ambulatory HF patients. PMID:27488754

  20. Insect Peptides - Perspectives in Human Diseases Treatment.

    Science.gov (United States)

    Chowanski, Szymon; Adamski, Zbigniew; Lubawy, Jan; Marciniak, Pawel; Pacholska-Bogalska, Joanna; Slocinska, Malgorzata; Spochacz, Marta; Szymczak, Monika; Urbanski, Arkadiusz; Walkowiak-Nowicka, Karolina; Rosinski, Grzegorz

    2017-01-01

    Insects are the largest and the most widely distributed group of animals in the world. Their diversity is a source of incredible variety of different mechanisms of life processes regulation. There are many agents that regulate immunology, reproduction, growth and development or metabolism. Hence, it seems that insects may be a source of numerous substances useful in human diseases treatment. Especially important in the regulation of insect physiology are peptides, like neuropeptides, peptide hormones or antimicrobial peptides. There are two main aspects where they can be helpful, 1) Peptides isolated from insects may become potential drugs in therapy of different diseases, 2) A lot of insect peptide hormones show structural or functional homology to mammalian peptide hormones and the comparative studies may give a new look on human disorders. In our review we focused on three group of insect derived peptides: 1) immune-active peptides, 2) peptide hormones and 3) peptides present in venoms. In our review we try to show the considerable potential of insect peptides in searching for new solutions for mammalian diseases treatment. We summarise the knowledge about properties of insect peptides against different virulent agents, anti-inflammatory or anti-nociceptive properties as well as compare insect and mammalian/vertebrate peptide endocrine system to indicate usefulness of knowledge about insect peptide hormones in drug design. The field of possible using of insect delivered peptide to therapy of various human diseases is still not sufficiently explored. Undoubtedly, more attention should be paid to insects due to searching new drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Preparation of polypeptides comprising multiple TAA peptides.

    Science.gov (United States)

    Ni, Bing; Jia, Zhengcai; Wu, Yuzhang

    2014-01-01

    Polypeptides consisting of multiple tumor-associated antigen epitopes (multiepitope peptides) are commonly used as therapeutic peptide cancer vaccines in experimental studies and clinical trials. These methods include polypeptides composed of multiple major histocompatibility complex (MHC) class I-restricted cytotoxic T cell (CTL) epitopes and those containing multiple CTL epitopes and one T helper (Th) epitope. This chapter describes a complete set of methods for preparing multiepitope peptides and branched multiple antigen peptides (MAPs), including sequence design, peptide synthesis, purification, preservation, and the preparation of polypeptide solutions.

  2. Computer-Aided Design of Antimicrobial Peptides

    DEFF Research Database (Denmark)

    Fjell, Christopher D.; Hancock, Robert E.W.; Jenssen, Håvard

    2010-01-01

    An increasing number of reported cases of drug resistant Staphylococcus aureus and Pseudomonas aeruginosa, demonstrate the urgent need for new therapeutics that are effective against such and other multi-drug resistant bacteria. Antimicrobial peptides have for two decades now been looked upon...... as interesting leads for development of new therapeutics combating these drug resistant microbes. High-throughput screening of peptide libraries have generated large amounts of information on peptide activities. However, scientists still struggle with explaining the specific peptide motifs resulting...... in antimicrobial activity. Consequently, the majority of peptides put into clinical trials have failed at some point, underlining the importance of a thorough peptide optimization. An important tool in peptide design and optimization is quantitative structure-activity relationship (QSAR) analysis, correlating...

  3. Natural and synthetic peptides with antifungal activity.

    Science.gov (United States)

    Ciociola, Tecla; Giovati, Laura; Conti, Stefania; Magliani, Walter; Santinoli, Claudia; Polonelli, Luciano

    2016-08-01

    In recent years, the increase of invasive fungal infections and the emergence of antifungal resistance stressed the need for new antifungal drugs. Peptides have shown to be good candidates for the development of alternative antimicrobial agents through high-throughput screening, and subsequent optimization according to a rational approach. This review presents a brief overview on antifungal natural peptides of different sources (animals, plants, micro-organisms), peptide fragments derived by proteolytic cleavage of precursor physiological proteins (cryptides), synthetic unnatural peptides and peptide derivatives. Antifungal peptides are schematically reported based on their structure, antifungal spectrum and reported effects. Natural or synthetic peptides and their modified derivatives may represent the basis for new compounds active against fungal infections.

  4. The Pseudo signal peptide of the corticotropin-releasing factor receptor type 2A prevents receptor oligomerization.

    Science.gov (United States)

    Teichmann, Anke; Rutz, Claudia; Kreuchwig, Annika; Krause, Gerd; Wiesner, Burkhard; Schülein, Ralf

    2012-08-03

    N-terminal signal peptides mediate the interaction of native proteins with the translocon complex of the endoplasmic reticulum membrane and are cleaved off during early protein biogenesis. The corticotropin-releasing factor receptor type 2a (CRF(2(a))R) possesses an N-terminal pseudo signal peptide, which represents a so far unique domain within the large protein family of G protein-coupled receptors (GPCRs). In contrast to a conventional signal peptide, the pseudo signal peptide remains uncleaved and consequently forms a hydrophobic extension at the N terminus of the receptor. The functional consequence of the presence of the pseudo signal peptide is not understood. Here, we have analyzed the significance of this domain for receptor dimerization/oligomerization in detail. To this end, we took the CRF(2(a))R and the homologous corticotropin-releasing factor receptor type 1 (CRF(1)R) possessing a conventional cleaved signal peptide and conducted signal peptide exchange experiments. Using single cell and single molecule imaging methods (fluorescence resonance energy transfer and fluorescence cross-correlation spectroscopy, respectively) as well as biochemical experiments, we obtained two novel findings; we could show that (i) the CRF(2(a))R is expressed exclusively as a monomer, and (ii) the presence of the pseudo signal peptide prevents its oligomerization. Thus, we have identified a novel functional domain within the GPCR protein family, which plays a role in receptor oligomerization and which may be useful to study the functional significance of this process in general.

  5. Composition and method for self-assembly and mineralization of peptide amphiphiles

    Science.gov (United States)

    Stupp, Samuel I [Chicago, IL; Beniash, Elia [Newton, MA; Hartgerink, Jeffrey D [Houston, TX

    2009-06-30

    The present invention is directed to a composition useful for making homogeneously mineralized self assembled peptide-amphiphile nanofibers and nanofiber gels. The composition is generally a solution comprised of a positively or negatively charged peptide-amphiphile and a like signed ion from the mineral. Mixing this solution with a second solution containing a dissolved counter-ion of the mineral and/or a second oppositely charged peptide amphiphile, results in the rapid self assembly of the peptide-amphiphiles into a nanofiber gel and templated mineralization of the ions. Templated mineralization of the initially dissolved mineral cations and anions in the mixture occurs with preferential orientation of the mineral crystals along the fiber surfaces within the nanofiber gel. One advantage of the present invention is that it results in homogenous growth of the mineral throughout the nanofiber gel. Another advantage of the present invention is that the nanofiber gel formation and mineralization reactions occur in a single mixing step and under substantially neutral or physiological pH conditions. These homogeneous nanostructured composite materials are useful for medical applications especially the regeneration of damaged bone in mammals. This invention is directed to the synthesis of peptide-amphiphiles with more than one amphiphilic moment and to supramolecular compositions comprised of such multi-dimensional peptide-amphiphiles. Supramolecular compositions can be formed by self assembly of multi-dimensional peptide-amphiphiles by mixing them with a solution comprising a monovalent cation.

  6. Composition and method for self-assembly and mineralization of peptide-amphiphiles

    Science.gov (United States)

    Stupp, Samuel I [Chicago, IL; Beniash, Elia [Newton, MA; Hartgerink, Jeffrey D [Pearland, TX

    2012-02-28

    The present invention is directed to a composition useful for making homogeneously mineralized self assembled peptide-amphiphile nanofibers and nanofiber gels. The composition is generally a solution comprised of a positively or negatively charged peptide-amphiphile and a like signed ion from the mineral. Mixing this solution with a second solution containing a dissolved counter-ion of the mineral and/or a second oppositely charged peptide amphiphile, results in the rapid self assembly of the peptide-amphiphiles into a nanofiber gel and templated mineralization of the ions. Templated mineralization of the initially dissolved mineral cations and anions in the mixture occurs with preferential orientation of the mineral crystals along the fiber surfaces within the nanofiber gel. One advantage of the present invention is that it results in homogenous growth of the mineral throughout the nanofiber gel. Another advantage of the present invention is that the nanofiber gel formation and mineralization reactions occur in a single mixing step and under substantially neutral or physiological pH conditions. These homogeneous nanostructured composite materials are useful for medical applications especially the regeneration of damaged bone in mammals. This invention is directed to the synthesis of peptide-amphiphiles with more than one amphiphilic moment and to supramolecular compositions comprised of such multi-dimensional peptide-amphiphiles. Supramolecular compositions can be formed by self assembly of multi-dimensional peptide-amphiphiles by mixing them with a solution comprising a monovalent cation.

  7. Message in a bottle: small signalling peptide outputs during growth and development.

    Science.gov (United States)

    Czyzewicz, Nathan; Yue, Kun; Beeckman, Tom; De Smet, Ive

    2013-12-01

    Classical and recently found phytohormones play an important role in plant growth and development, but plants additionally control these processes through small signalling peptides. Over 1000 potential small signalling peptide sequences are present in the Arabidopsis genome. However, to date, a mere handful of small signalling peptides have been functionally characterized and few have been linked to a receptor. Here, we assess the potential small signalling peptide outputs, namely the molecular, biochemical, and morphological changes they trigger in Arabidopsis. However, we also include some notable studies in other plant species, in order to illustrate the varied effects that can be induced by small signalling peptides. In addition, we touch on some evolutionary aspects of small signalling peptides, as studying their signalling outputs in single-cell green algae and early land plants will assist in our understanding of more complex land plants. Our overview illustrates the growing interest in the small signalling peptide research area and its importance in deepening our understanding of plant growth and development.

  8. Measurement of beta-amyloid peptides in specific cells using a photo thin-film transistor

    Science.gov (United States)

    Kim, Chang-Beom; Chae, Cheol-Joo; Shin, Hye-Rim; Song, Ki-Bong

    2012-01-01

    The existence of beta-amyloid [Aβ] peptides in the brain has been regarded as the most archetypal biomarker of Alzheimer's disease [AD]. Recently, an early clinical diagnosis has been considered a great importance in identifying people who are at high risk of AD. However, no microscale electronic sensing devices for the detection of Aβ peptides have been developed yet. In this study, we propose an effective method to evaluate a small quantity of Aβ peptides labeled with fluorescein isothiocyanate [FITC] using a photosensitive field-effect transistor [p-FET] with an on-chip single-layer optical filter. To accurately evaluate the quantity of Aβ peptides within the cells cultured on the p-FET device, we measured the photocurrents which resulted from the FITC-conjugated Aβ peptides expressed from the cells and measured the number of photons of the fluorochrome in the cells using a photomultiplier tube. Thus, we evaluated the correlation between the generated photocurrents and the number of emitted photons. We also evaluated the correlation between the number of emitted photons and the amount of FITC by measuring the FITC volume using AFM. Finally, we estimated the quantity of Aβ peptides of the cells placed on the p-FET sensing area on the basis of the binding ratio between FITC molecules and Aβ peptides.

  9. Prospects in the use of aptamers for characterizing the structure and stability of bioactive proteins and peptides in food.

    Science.gov (United States)

    Agyei, Dominic; Acquah, Caleb; Tan, Kei Xian; Hii, Hieng Kok; Rajendran, Subin R C K; Udenigwe, Chibuike C; Danquah, Michael K

    2018-01-01

    Food-derived bioactive proteins and peptides have gained acceptance among researchers, food manufacturers and consumers as health-enhancing functional food components that also serve as natural alternatives for disease prevention and/or management. Bioactivity in food proteins and peptides is determined by their conformations and binding characteristics, which in turn depend on their primary and secondary structures. To maintain their bioactivities, the molecular integrity of bioactive peptides must remain intact, and this warrants the study of peptide form and structure, ideally with robust, highly specific and sensitive techniques. Short single-stranded nucleic acids (i.e. aptamers) are known to have high affinity for cognate targets such as proteins and peptides. Aptamers can be produced cost-effectively and chemically derivatized to increase their stability and shelf life. Their improved binding characteristics and minimal modification of the target molecular signature suggests their suitability for real-time detection of conformational changes in both proteins and peptides. This review discusses the developmental progress of systematic evolution of ligands by exponential enrichment (SELEX), an iterative technology for generating cost-effective aptamers with low dissociation constants (K d ) for monitoring the form and structure of bioactive proteins and peptides. The review also presents case studies of this technique in monitoring the structural stability of bioactive peptide formulations to encourage applications in functional foods. The challenges and potential of aptamers in this research field are also discussed. Graphical abstract Advancing bioactive proteins and peptide functionality via aptameric ligands.

  10. Isolation and characterization of the human parathyroid hormone-like peptide gene

    International Nuclear Information System (INIS)

    Mangin, M.; Ikeda, K.; Dreyer, B.E.; Broadus, A.E.

    1989-01-01

    A parathyroid hormone-like peptide (PTH-LP) has recently been identified in human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The peptide appears to be encoded by a single-copy gene that gives rise to multiple mRNAs that are heterogeneous at both their 5' and their 3' ends. Alternative RNA splicing is responsible for the 3' heterogeneity and results in mRNAs encoding three different peptides, each with a unique C terminus. The authors have isolated and characterized the human PTHLP gene. The gene is a complex transcriptional unit spanning more than 12 kilobases of DNA and containing six exons. Two 5' exons encode distinct 5' untranslated regions and are separated by a putative promoter element, indicating that the gene either has two promoters or is alternatively spliced from a single promoter upstream of the first exon. The middle portion of the PTHLP gene, comprising exons 2-4, has an organizational pattern of introns and exons identical to that of the parathyroid hormone gene, consistent with a common ancestral origin of these two genes. Exon 4 of the PTHLP gene encodes the region common to all three peptides and the C terminus of the shortest peptide, and exons 5 and 6 encode the unique C termini of the other two peptides. Northern analysis of mRNAs from four human tumors of different histological types reveals the preferential use of 3' splicing patterns of individual tumors

  11. Are Two Better Than One? A New Approach for Multidentate Grafting of Peptides to a Gold Substrate

    Science.gov (United States)

    Caruso, Mario; Gatto, Emanuela; Palleschi, Antonio; Scarselli, Manuela; De Crescenzi, Maurizio; Formaggio, Fernando; Longo, Edoardo; Toniolo, Claudio; Wright, Karen; Venanzi, Mariano

    2016-09-01

    Multidentate binding of two helical hexapeptides to a gold surface was obtained by introducing in the peptide chain a non ribosomial amino acid, i.e. the 4-amino-1,2-dithiolane-4-carboxylic acid (Adt) residue, a Cα-tetrasubstituted α-amino acid bearing a heterocyclic side chain characterized by a disulfide group. The two peptides, mainly formed by strongly helicogenic Cα-tetrasubstituted α-amino acids, were both functionalized at the N-terminus by a ferrocenoyl (Fc) group, but differ in the number of Adt residues included in the peptide chain: the former (Fc6Adt2) contains two Adt residues at positions 1 and 4, while its analog (Fc6Adt1) contains a single Adt at position 4, since the Adt at position 1 is substituted by an α-amino isobutyric acid (Aib) residue. This peptide design allowed us to explore the different electrochemical properties and morphologies shown by the two peptide layers immobilized on a gold surface by two (Fc6Adt2) or a single (Fc6Adt1) bidentate linker, respectively. The electrochemical activity of the ferrocenoyl probe embedded in the peptide film was characterized by cyclic voltammetry, chronoamperometry and square wave voltammetry, while the binding and the morphology of the peptide layers were studied by X-ray photoelectron spectroscopy (XPS) and ultra high vacuum scanning tunneling microscopy (UHV-STM), respectively. Significant differences were observed in the electron transfer (ET) properties of the two peptides investigated, which emerge from the diverging morphology achieved by the peptide layers on the gold surface. It was found that while a standing-up configuration of the peptide layer, realized by a single bidentate linkage, maximizes the ET efficiency, a lying down configuration (two Adt linkages) allows for precise positioning of Fc in the proximity of a gold surface.

  12. Degradation and antioxidant activities of peptides and zinc-peptide complexes during in vitro gastrointestinal digestion.

    Science.gov (United States)

    Wang, Chan; Li, Bo; Wang, Bo; Xie, Ningning

    2015-04-15

    The degradation characteristics of three peptides (Ser-Met, Asn-Cys-Ser, and glutathione) and their zinc-peptide complexes were studied using a two-stage in vitro digestion model. Enzyme-resistant peptides and zinc-peptide complexes, antioxidant activities, and free amino acids released by digestive enzymes, were measured in this study. The results revealed that the three peptides and their zinc-peptide complexes were resistant to pepsin but not to pancreatin. Pancreatin can partly hydrolyse both peptides and zinc-peptide complexes, but more than half of them remaining in their original form after gastrointestinal digestion. The coordination of zinc improved the enzymatic resistance of the peptide due to lower solubility of complexes and affected the hydrolytic site of pepsin and pancreatin. Zinc-Asn-Cys-Ser, which is highly resistant to enzymatic hydrolysis and maintains Zn in a soluble form, may have potential to improve Zn bioavailability. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Analysis of peptide uptake and location of root hair-promoting peptide accumulation in plant roots.

    Science.gov (United States)

    Matsumiya, Yoshiki; Taniguchi, Rikiya; Kubo, Motoki

    2012-03-01

    Peptide uptake by plant roots from degraded soybean-meal products was analyzed in Brassica rapa and Solanum lycopersicum. B. rapa absorbed about 40% of the initial water volume, whereas peptide concentration was decreased by 75% after 24 h. Analysis by reversed-phase HPLC showed that number of peptides was absorbed by the roots during soaking in degraded soybean-meal products for 24 h. Carboxyfluorescein-labeled root hair-promoting peptide was synthesized, and its localization, movement, and accumulation in roots were investigated. The peptide appeared to be absorbed by root hairs and then moved to trichoblasts. Furthermore, the peptide was moved from trichoblasts to atrichoblasts after 24 h. The peptide was accumulated in epidermal cells, suggesting that the peptide may have a function in both trichoblasts and atrichoblasts. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

  14. Gene transfer strategies for improving radiolabeled peptide imaging and therapy

    International Nuclear Information System (INIS)

    Rogers, B.E.; Buchsbaum, D.J.; Zinn, K.R.

    2000-01-01

    Utilization of molecular biology techniques offers attractive options in nuclear medicine for improving cancer imaging and therapy with radiolabeled peptides. Two of these options include utilization of phage-panning to identify novel tumor specific peptides or single chain antibodies and gene transfer techniques to increase the antibodies and gene transfer techniques to increase the number of antigen/receptor sites expressed on malignant cells. The group has focused on the latter approach for improving radiolabeled peptide imaging and therapy. The most widely used gene transfer vectors in clinical gene therapy trials include retrovirus, cationic lipids and adenovirus. It has been utilized adenovirus vectors for gene transfer because of their ability to accomplish efficient in vivo gene transfer. Adenovirus vectors encoding the genes for a variety of antigens/receptors (carcinoembryonic antigen, gastrin-releasing peptide receptor, somatostatin receptor subtype 2 (SSTr2) have all shown that their expression is increased on cancer cells both in vitro and in vivo following adenovirus infection. Of particular interest has been the adenovirus encoding for SSTr2 (AdCMVSSTr2). Various radioisotopes have been attached to somatostatin analogues for imaging and therapy of SSTr2-positive tumors both clinically and in animal models. The use of these analogues in combination with AdCMVSSTr2 is a promising approach for improving the detection sensitivity and therapeutic efficacy of these radiolabeled peptides against solid tumors. In addition, it has been proposed the use of SSTr2 as a marker for imaging the expression of another cancer therapeutic transgene (e.g. cytosine deaminase, thymidine kinase) encoded within the same vector. This would allow for non-invasive monitoring of gene delivery to tumor sites

  15. Peptide Antibiotics for ESKAPE Pathogens

    DEFF Research Database (Denmark)

    Thomsen, Thomas Thyge

    Multi-drug resistance to antibiotics represents a global health challenge that results in increased morbidity and mortality rates. The annual death-toll is >700.000 people world-wide, rising to ~10 million by 2050. New antibiotics are lacking, and few are under development as return on investment...... is considered poor compared to medicines for lifestyle diseases. According to the WHO we could be moving towards a post-antibiotic era in which previously treatable infections become fatal. Of special importance are multidrug resistant bacteria from the ESKAPE group (Enterococcus faecium, Staphylococcus aureus...... and toxicity by utilizing of the fruit fly Drosophila melanogaster as a whole animal model. This was carried out by testing of antimicrobial peptides targeting Gram-positive bacteria exemplified by the important human pathogen methicillin resistant S. aureus (MRSA). The peptide BP214 was developed from...

  16. The neXtProt peptide uniqueness checker: a tool for the proteomics community.

    Science.gov (United States)

    Schaeffer, Mathieu; Gateau, Alain; Teixeira, Daniel; Michel, Pierre-André; Zahn-Zabal, Monique; Lane, Lydie

    2017-11-01

    The neXtProt peptide uniqueness checker allows scientists to define which peptides can be used to validate the existence of human proteins, i.e. map uniquely versus multiply to human protein sequences taking into account isobaric substitutions, alternative splicing and single amino acid variants. The pepx program is available at https://github.com/calipho-sib/pepx and can be launched from the command line or through a cgi web interface. Indexing requires a sequence file in FASTA format. The peptide uniqueness checker tool is freely available on the web at https://www.nextprot.org/tools/peptide-uniqueness-checker and from the neXtProt API at https://api.nextprot.org/. lydie.lane@sib.swiss. © The Author(s) 2017. Published by Oxford University Press.

  17. Determination of Disulfide Bond Connectivity of Cysteine-rich Peptide IpTx{sub a}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Chul Won; Kim, Jim Il [Chonnam National Univ., Gwangju (Korea, Republic of); Sato, Kazuki [Fukuoka Women' s Univ., Fukuoka (Japan)

    2013-06-15

    Cysteine-rich peptides stabilized by intramolecular disulfide bonds have often been isolated from venoms of microbes, animals and plants. These peptides typically have much higher stability and improved biopharmaceutical properties compared to their linear counterparts. Therefore the correct disulfide bond formation of small proteins and peptides has been extensively studied for a better understanding of their folding mechanism and achieving efficient generation of the naturally occurring biologically active product. Imperatoxin A (IpTx{sub a}), a peptide toxin containing 6 cysteine residues, was isolated from the venom of scorpion Pandinus imperator, selectively binds the ryanodine receptors and activates Ca{sup 2+} release from sarcoplasmic reticulum (SR). IpTx{sub a} increases the binding of ryanodine to ryanodine receptors (RyRs) and encourages reconstituted single channel to induce subconductance states.

  18. High-resolution mapping of linear antibody epitopes using ultrahigh-density peptide microarrays

    DEFF Research Database (Denmark)

    Buus, Søren; Rockberg, Johan; Forsström, Björn

    2012-01-01

    against unwanted (e.g. autoimmune) reactivities. Antibodies target proteins as either conformational or linear epitopes. The latter are typically probed with peptides, but the cost of peptide screening programs tends to prohibit comprehensive specificity analysis. To perform high-throughput, high......-resolution mapping of linear antibody epitopes, we have used ultrahigh-density peptide microarrays generating several hundred thousand different peptides per array. Using exhaustive length and substitution analysis, we have successfully examined the specificity of a panel of polyclonal antibodies raised against...... linear epitopes of the human proteome and obtained very detailed descriptions of the involved specificities. The epitopes identified ranged from 4 to 12 amino acids in size. In general, the antibodies were of exquisite specificity, frequently disallowing even single conservative substitutions. In several...

  19. Gliadin peptides induce tissue transglutaminase activation and ER-stress through Ca2+ mobilization in Caco-2 cells.

    Directory of Open Access Journals (Sweden)

    Ivana Caputo

    Full Text Available BACKGROUND: Celiac disease (CD is an intestinal inflammatory condition that develops in genetically susceptible individuals after exposure to dietary wheat gliadin. The role of post-translational modifications of gliadin catalyzed by tissue transglutaminase (tTG seems to play a crucial role in CD. However, it remains to be established how and where tTG is activated in vivo. We have investigated whether gliadin peptides modulate intracellular Ca(2+ homeostasis and tTG activity. METHODS/PRINCIPAL FINDINGS: We studied Ca(2+ homeostasis in Caco-2 cells by single cell microfluorimetry. Under our conditions, A-gliadin peptides 31-43 and 57-68 rapidly mobilized Ca(2+ from intracellular stores. Specifically, peptide 31-43 mobilized Ca(2+ from the endoplasmic reticulum (ER and mitochondria, whereas peptide 57-68 mobilized Ca(2+ only from mitochondria. We also found that gliadin peptide-induced Ca(2+ mobilization activates the enzymatic function of intracellular tTG as revealed by in situ tTG activity using the tTG substrate pentylamine-biotin. Moreover, we demonstrate that peptide 31-43, but not peptide 57-68, induces an increase of tTG expression. Finally, we monitored the expression of glucose-regulated protein-78 and of CCAAT/enhancer binding protein-homologous protein, which are two biochemical markers of ER-stress, by real-time RT-PCR and western blot. We found that chronic administration of peptide 31-43, but not of peptide 57-68, induces the expression of both genes. CONCLUSIONS: By inducing Ca(2+ mobilization from the ER, peptide 31-43 could promote an ER-stress pathway that may be relevant in CD pathogenesis. Furthermore, peptides 31-43 and 57-68, by activating intracellular tTG, could alter inflammatory key regulators, and induce deamidation of immunogenic peptides and gliadin-tTG crosslinking in enterocytes and specialized antigen-presenting cells.

  20. Peptide-targeted polymer cancerostatics

    Czech Academy of Sciences Publication Activity Database

    Böhmová, Eliška; Pola, Robert

    2016-01-01

    Roč. 65, Suppl. 2 (2016), S153-S164 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : HPMA copolymers * tumor targeting * peptides Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.461, year: 2016 http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S153.pdf