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Sample records for 111in-labeled cyclic peptide

  1. Nephrotoxicity in mice after repeated imaging using 111In-labeled peptides.

    NARCIS (Netherlands)

    Melis, M.; Vegt, E.; Konijnenberg, M.W.; Visser, M. de; Bijster, M.; Vermeij, M.; Krenning, E.P.; Boerman, O.C.; Jong, M. de

    2010-01-01

    We determined the renal radiation dose of a series of (111)In-labeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. METHODS: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention after inj

  2. Nephrotoxicity in mice after repeated imaging using 111In- labeled peptides

    NARCIS (Netherlands)

    M.L. Melis (Marleen); E. Vegt (Erik); M.W. Konijnenberg (Mark); M. de Visser (Monique); M. Bijster (Magda); M. Vermeij (Marcel); E.P. Krenning (Eric); O.C. Boerman (Otto); M. de Jong (Marion)

    2010-01-01

    textabstractWe determined the renal radiation dose of a series of111Inlabeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. Methods: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention a

  3. Effects of linker variation on the in vitro and in vivo characteristics of an {sup 111}In-labeled RGD peptide

    Energy Technology Data Exchange (ETDEWEB)

    Dijkgraaf, Ingrid [Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, HB Nijmegen 6500 (Netherlands) and Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht (Netherlands)]. E-mail: i.dijkgraaf@nucmed.umcn.nl; Liu, Shuang [School of Health Sciences, Purdue University, West Lafayette, Indiana (United States); Kruijtzer, John A.W. [Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht (Netherlands); Soede, Annemieke C. [Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, HB Nijmegen 6500 (Netherlands); Oyen, Wim J.G. [Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, HB Nijmegen 6500 (Netherlands); Liskamp, Rob M.J. [Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht (Netherlands); Corstens, Frans H.M. [Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, HB Nijmegen 6500 (Netherlands); Boerman, Otto C. [Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, HB Nijmegen 6500 (Netherlands)

    2007-01-15

    Introduction: Due to the selective expression of the {alpha}{sub v}{beta}{sub 3} integrin in tumors, radiolabeled arginine-glycine-aspartic acid (RGD) peptides are attractive candidates for tumor targeting. Minor modifications of these peptides could have a major impact on in vivo characteristics. In this study, we systematically investigated the effects of linker modification between two cyclic RGD sequences and DOTA (1,4,7,10-tetraazadodecane-N,N',N{sub '},N'''-tetraacetic acid) on the in vitro and in vivo characteristics of the tracer. Methods: A dimeric RGD peptide was synthesized and conjugated either directly with DOTA or via different linkers: PEG{sub 4} (polyethylene glycol), glutamic acid or lysine. The RGD peptides were radiolabeled with {sup 111}In, and their in vitro and in vivo {alpha}{sub v}{beta}{sub 3}-binding characteristics were determined. Results: LogP values varied between -2.82{+-}0.06 and -3.95{+-}0.33. The IC{sub 50} values for DOTA-E-[c(RGDfK)]{sub 2}, DOTA-PEG{sub 4}-E-[c(RGDfK)]{sub 2}, DOTA-E-E-[c(RGDfK)]{sub 2} and DOTA-K-E-[c(RGDfK)]{sub 2} were comparable. Two hours after injection, the tumor uptakes of the {sup 111}In-labeled compounds were not significantly different. The kidney accumulation of [{sup 111}In]-DOTA-K-E-[c(RGDfK)]{sub 2} [4.05{+-}0.20% of the injected dose per gram (ID/g)] was significantly higher as compared with that of [{sup 111}In]-DOTA-E-[c(RGDfK)]{sub 2} (2.63{+-}0.19% ID/g; P<.05) as well as that of [{sup 111}In]-DOTA-E-E-[c(RGDfK)]{sub 2} (2.16{+-}0.21% ID/g; P<.01). The liver uptake of [{sup 111}In]-DOTA-E-E-[c(RGDfK)]{sub 2} (2.12{+-}0.09% ID/g) was significantly higher as compared with that of [{sup 111}In]-DOTA-E-[c(RGDfK)]{sub 2} (1.64{+-}0.1% ID/g; P<.05) as well as that of [{sup 111}In]-DOTA-K-E-[c(RGDfK)]{sub 2} (1.52{+-}0.04% ID/g; P<.01). Conclusions: Linker variation did not affect affinity for {alpha}{sub v}{beta}{sub 3} and tumor uptake. Insertion of lysine caused enhanced

  4. Novel targeted nuclear imaging agent for gastric cancer diagnosis: glucose-regulated protein 78 binding peptide-guided 111In-labeled polymeric micelles

    Directory of Open Access Journals (Sweden)

    Cheng CC

    2013-04-01

    radioisotope indium-111 (111In was measured and analyzed by instant thin layer chromatography. The coupling efficiency of DTPA-conjugated micelles and DTPA/GRP78BP-conjugated micelles with 111In was 85% and 93%, respectively. For characterization and trace imaging, the radioisotope 111In-targeting tumors were detected and imaged in a xenograft murine model using nano single photon emission computed tomography/computed tomography. The results revealed that the radioactive intensity measured in the animals administered with GRP78BP-guided 111In-labeled micelles was statistically higher than that in animals administered with 111In-labeled micelles, demonstrating that GRP78BP more than doubled the accumulation of micelles to the tumor tissue (P < 0.05. The results indicate that the gastric cancer biomarker GRP78 is a probing target in the application of nuclear imaging for tumor diagnosis. This novel GRP78BP-guided micelle agent may be applied in clinical practice to complement the histological diagnosis.Keywords: biomarker, glucose-regulated protein 78, nuclear imaging, gastric cancer, micelles

  5. Cellular penetration and nuclear importation properties of {sup 111}In-labeled and {sup 123}I-labeled HIV-1 tat peptide immunoconjugates in BT-474 human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cornelissen, Bart [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3M2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Hu, Meiduo [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3M2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); McLarty, Kristin [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3M2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Costantini, Dan [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3M2 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Reilly, Raymond M. [Division of Nuclear Medicine, University Health Network, Toronto, ON, M5S 3M2 (Canada) and Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3M2 (Canada) and Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada) and Toronto General Research Institute, University Health Network, Toronto, ON, M5S 3M2 (Canada)]. E-mail: raymond.reilly@utoronto.ca

    2007-01-15

    Introduction: Our objective was to compare the cell penetration and nuclear importation properties of {sup 111}In-labeled and {sup 123}I-labeled immunoconjugates (ICs) composed of 16-mer peptides (GRKKRRQRRRPPQGYG) derived from HIV-1 transactivator of transcription (tat) protein and anti-mouse IgG (mIgG) in BT-474 breast cancer (BC) cells. Methods: [{sup 111}In]tat ICs were constructed by site-specific conjugation of tat peptides to NaIO{sub 4} {sup -}-oxidized carbohydrates in the Fc domain of diethylenetriaminepentaacetic-acid-modified anti-mIgG antibodies. Immunoreactivity against mIgG was assessed in a competition assay. The kinetics of the accumulation of [{sup 111}In]anti-mIgG-tat IC and [{sup 123}I]anti-mIgG-tat ICs in BT-474 cells and the elimination of radioactivity from cells, cytoplasm or nuclei were determined. The effects of excess tat peptides or NH{sub 4}Cl (an inhibitor of endosomal acidification) on cellular uptake and nuclear importation of [{sup 111}In]anti-mIgG-tat were measured. Results: [{sup 111}In]anti-mIgG-tat was >97% radiochemically pure and exhibited preserved immunoreactivity with mIgG epitopes. [{sup 123}I]Anti-mIgG-tat penetrated BT-474 cells more rapidly than [{sup 111}In]anti-mIgG-tat ICs and achieved a 1.5-fold to a 2-fold higher uptake in cells and nuclei. Cell penetration and nuclear uptake of [{sup 111}In]anti-mIgG-tat were inhibited by excess tat peptides and NH{sub 4}Cl. Elimination of radioactivity from BT-474 cells and nuclei was more rapid and complete for {sup 123}I-labeled than for {sup 111}In-labeled anti-mIgG-tat ICs. Conclusion: Tat peptides derived from HIV-1 tat protein promoted the penetration and nuclear uptake of radioactivity following the incubation of {sup 111}In-labeled and {sup 123}I-labeled anti-mIgG antibodies with BT-474 human BC cells. {sup 111}In-labeled tat ICs are feasible for inserting radionuclides into cancer cells with potential for targeting intracellular and, particularly, nuclear epitopes for

  6. Antimicrobial cyclic peptides for plant disease control.

    Science.gov (United States)

    Lee, Dong Wan; Kim, Beom Seok

    2015-03-01

    Antimicrobial cyclic peptides derived from microbes bind stably with target sites, have a tolerance to hydrolysis by proteases, and a favorable degradability under field conditions, which make them an attractive proposition for use as agricultural fungicides. Antimicrobial cyclic peptides are classified according to the types of bonds within the ring structure; homodetic, heterodetic, and complex cyclic peptides, which in turn reflect diverse physicochemical features. Most antimicrobial cyclic peptides affect the integrity of the cell envelope. This is achieved through direct interaction with the cell membrane or disturbance of the cell wall and membrane component biosynthesis such as chitin, glucan, and sphingolipid. These are specific and selective targets providing reliable activity and safety for non-target organisms. Synthetic cyclic peptides produced through combinatorial chemistry offer an alternative approach to develop antimicrobials for agricultural uses. Those synthesized so far have been studied for antibacterial activity, however, the recent advancements in powerful technologies now promise to provide novel antimicrobial cyclic peptides that are yet to be discovered from natural resources.

  7. Antimicrobial Cyclic Peptides for Plant Disease Control

    Directory of Open Access Journals (Sweden)

    Dong Wan Lee

    2015-03-01

    Full Text Available Antimicrobial cyclic peptides derived from microbes bind stably with target sites, have a tolerance to hydrolysis by proteases, and a favorable degradability under field conditions, which make them an attractive proposition for use as agricultural fungicides. Antimicrobial cyclic peptides are classified according to the types of bonds within the ring structure; homodetic, heterodetic, and complex cyclic peptides, which in turn reflect diverse physicochemical features. Most antimicrobial cyclic peptides affect the integrity of the cell envelope. This is achieved through direct interaction with the cell membrane or disturbance of the cell wall and membrane component biosynthesis such as chitin, glucan, and sphingolipid. These are specific and selective targets providing reliable activity and safety for non-target organisms. Synthetic cyclic peptides produced through combinatorial chemistry offer an alternative approach to develop antimicrobials for agricultural uses. Those synthesized so far have been studied for antibacterial activity, however, the recent advancements in powerful technologies now promise to provide novel antimicrobial cyclic peptides that are yet to be discovered from natural resources.

  8. Targeting of a CCK{sub 2} receptor splice variant with {sup 111}In-labelled cholecystokinin-8 (CCK8) and {sup 111}In-labelled minigastrin

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    Laverman, Peter; Gotthardt, Martin; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, PO Box 9101, HB Nijmegen (Netherlands); Roosenburg, Susan [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, PO Box 9101, HB Nijmegen (Netherlands); Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen (Netherlands); Park, Jeseong; Hellmich, Mark R. [University of Texas Medical Branch, Department of Surgery and the Sealy Center for Cancer Cell Biology, Galveston, TX (United States); Jong, Marion de [Erasmus Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Rutjes, Floris P.J.T.; Delft, Floris L. van [Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen (Netherlands)

    2008-02-15

    Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated {sup 111}In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [{sup 111}In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. The receptor binding affinity of [{sup 111}In]DOTA-sCCK8 and [{sup 111}In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. [{sup 111}In]DOTA-sCCK8 as well as [{sup 111}In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21 {+-} 0.77 and 3.01 {+-} 0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [{sup 111}In]DOTA-MG0 (32.4 {+-} 7.5%ID/g, 24 h p.i.) was markedly higher than that of [{sup 111}In]DOTA-sCCK8 (2.75 {+-} 0.31%ID/g, 24 h p.i.). We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs. (orig.)

  9. Evolution of cyclic peptide protease inhibitors.

    Science.gov (United States)

    Young, Travis S; Young, Douglas D; Ahmad, Insha; Louis, John M; Benkovic, Stephen J; Schultz, Peter G

    2011-07-05

    We report a bacterial system for the evolution of cyclic peptides that makes use of an expanded set of amino acid building blocks. Orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pairs, together with a split intein system were used to biosynthesize a library of ribosomal peptides containing amino acids with unique structures and reactivities. This peptide library was subsequently used to evolve an inhibitor of HIV protease using a selection based on cellular viability. Two of three cyclic peptides isolated after two rounds of selection contained the keto amino acid p-benzoylphenylalanine (pBzF). The most potent peptide (G12: GIXVSL; X=pBzF) inhibited HIV protease through the formation of a covalent Schiff base adduct of the pBzF residue with the ε-amino group of Lys 14 on the protease. This result suggests that an expanded genetic code can confer an evolutionary advantage in response to selective pressure. Moreover, the combination of natural evolutionary processes with chemically biased building blocks provides another strategy for the generation of biologically active peptides using microbial systems.

  10. TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides.

    Science.gov (United States)

    Lu, Xiaomeng; Brickson, Claire R; Murphy, Regina M

    2016-09-21

    β-Amyloid peptide (Aβ) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer's disease. Compounds that bind to Aβ, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein-protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aβ. We have taken a different approach, by designing Aβ-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known Aβ-binding site on TTR, suppressed Aβ aggregation into fibrils and protected neurons against Aβ toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to Aβ, redirects Aβ toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.

  11. Intracellular Production of Cyclic Peptide Libraries with SICLOPPS.

    Science.gov (United States)

    Osher, Eliot L; Tavassoli, Ali

    2017-01-01

    Cyclic peptides are an important class of molecules that are increasingly viewed as an ideal scaffold for inhibition of protein-protein interactions (PPI). Here we detail an approach that enables the intracellular synthesis of cyclic peptide libraries of around 10(8) members. The method utilizes split intein mediated circular ligation of peptides and proteins (SICLOPPS), taking advantage of split intein splicing to cyclize a library of peptide sequences. SICLOPPS allows the ring size, set residues and number of random residues within a library to be predetermined by the user. SICLOPPS libraries have been combined with a variety of cell-based screens to identify cyclic peptide inhibitors of a variety of enzymes and protein-protein interactions.

  12. Constraining cyclic peptides to mimic protein structure motifs

    DEFF Research Database (Denmark)

    Hill, Timothy A.; Shepherd, Nicholas E.; Diness, Frederik;

    2014-01-01

    Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three-dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable...... protein-like structures in water. However, short peptides can be induced to fold into protein-like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic...... peptides can have protein-like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides...

  13. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang;

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending...... of this peptidic inhibitor, a concept different from conventional attempts at improving inhibitor affinity by reducing the entropic burden....

  14. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang;

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...

  15. Differential self-assembly behaviors of cyclic and linear peptides.

    Science.gov (United States)

    Choi, Sung-ju; Jeong, Woo-jin; Kang, Seong-Kyun; Lee, Myongsoo; Kim, Eunhye; Ryu, Du Yeol; Lim, Yong-beom

    2012-07-01

    Here we ask the fundamental questions about the effect of peptide topology on self-assembly. The study revealed that the self-assembling behaviors of cyclic and linear peptides are significantly different in several respects, in addition to sharing several similarities. Their clear differences included the morphological dissimilarities of the self-assembled nanostructures and their thermal stability. The similarities include their analogous critical aggregation concentration values and cytotoxicity profiles, which are in fact closely related. We believe that understanding topology-dependent self-assembly behavior of peptides is important for developing tailor-made self-assembled peptide nanostructures.

  16. Membrane-targeted self-assembling cyclic peptide nanotubes.

    Science.gov (United States)

    Rodríguez-Vázquez, Nuria; Ozores, H Lionel; Guerra, Arcadio; González-Freire, Eva; Fuertes, Alberto; Panciera, Michele; Priegue, Juan M; Outeiral, Juan; Montenegro, Javier; Garcia-Fandino, Rebeca; Amorin, Manuel; Granja, Juan R

    2014-01-01

    Peptide nanotubes are novel supramolecular nanobiomaterials that have a tubular structure. The stacking of cyclic components is one of the most promising strategies amongst the methods described in recent years for the preparation of nanotubes. This strategy allows precise control of the nanotube surface properties and the dimensions of the tube diameter. In addition, the incorporation of 3- aminocycloalkanecarboxylic acid residues in the nanotube-forming peptides allows control of the internal properties of the supramolecular tube. The research aimed at the application of membrane-interacting self-assembled cyclic peptide nanotubes (SCPNs) is summarized in this review. The cyclic peptides are designed to interact with phospholipid bilayers to induce nanotube formation. The properties and orientation of the nanotube can be tuned by tailoring the peptide sequence. Hydrophobic peptides form transmembrane pores with a hydrophilic orifice, the nature of which has been exploited to transport ions and small molecules efficiently. These synthetic ion channels are selective for alkali metal ions (Na(+), K(+) or Cs(+)) over divalent cations (Ca(2+)) or anions (Cl(-)). Unfortunately, selectivity was not achieved within the series of alkali metal ions, for which ion transport rates followed the diffusion rates in water. Amphipathic peptides form nanotubes that lie parallel to the membrane. Interestingly, nanotube formation takes place preferentially on the surface of bacterial membranes, thus making these materials suitable for the development of new antimicrobial agents.

  17. New cyclic peptides with osteoblastic proliferative activity from Dianthus superbus.

    Science.gov (United States)

    Tong, Yun; Luo, Jian-Guang; Wang, Rui; Wang, Xiao-Bing; Kong, Ling-Yi

    2012-03-01

    Two new cyclic peptides, dianthins G-H (1 and 2), together with the known dianthin E (3), were isolated from the traditional Chinese medicinal plant Dianthus superbus. The sequences of cyclic peptides 1 and 2 were elucidated as cyclo (-Gly(1)-Pro(2)-Leu(3)-Thr(4)-Leu(5)-Phe(6)-) and cyclo (-Gly(1)-Pro(2)-Val(3)-Thr(4)-Ile(5)-Phe(6)-), on the basis of ESI tandem mass fragmentation analysis, extensive 2D NMR methods and X-ray diffraction. The isolated three compounds all increase proliferation of MC3T3-E1 cells in vitro using MTT method.

  18. A New Cyclic Peptide from Schnabelia tetradonta

    Institute of Scientific and Technical Information of China (English)

    Hui DOU; Yan ZHOU; Shu lin PENG; Li Sheng DING

    2003-01-01

    A new cyclic octapeptide (schnabepeptide B) was isolated from the aerial part ofSchnabelia tetradonta (Sun) C. Y. Wu et C. Chen (Lamiaceae). Its structure was elucidated ascyclo-(NH-Trp-Gly1-Leu1-Gly2-Pro1-Pro2-Leu2-Pro3-CO) on the basis of extensive 2D NMR andMS spectra.

  19. Development of novel cyclic peptides as pro-apoptotic agents.

    Science.gov (United States)

    Brindisi, Margherita; Maramai, Samuele; Brogi, Simone; Fanigliulo, Emanuela; Butini, Stefania; Guarino, Egeria; Casagni, Alice; Lamponi, Stefania; Bonechi, Claudia; Nathwani, Seema M; Finetti, Federica; Ragonese, Francesco; Arcidiacono, Paola; Campiglia, Pietro; Valenti, Salvatore; Novellino, Ettore; Spaccapelo, Roberta; Morbidelli, Lucia; Zisterer, Daniela M; Williams, Clive D; Donati, Alessandro; Baldari, Cosima; Campiani, Giuseppe; Ulivieri, Cristina; Gemma, Sandra

    2016-07-19

    Our recent finding that paclitaxel behaves as a peptidomimetic of the endogenous protein Nur77 inspired the design of two peptides (PEP1 and PEP2) reproducing the effects of paclitaxel on Bcl-2 and tubulin, proving the peptidomimetic nature of paclitaxel. Starting from these peptide-hits, we herein describe the synthesis and the biological investigation of linear and cyclic peptides structurally related to PEP2. While linear peptides (2a,b, 3a,b, 4, 6a-f) were found inactive in cell-based assays, biological analysis revealed a pro-apoptotic effect for most of the cyclic peptides (5a-g). Cellular permeability of 5a (and also of 2a,b) on HL60 cells was assessed through confocal microscopy analysis. Further cellular studies on a panel of leukemic cell lines (HL60, Jurkat, MEC, EBVB) and solid tumor cell lines (breast cancer MCF-7 cells, human melanoma A375 and 501Mel cells, and murine melanoma B16F1 cells) confirmed the pro-apoptotic effect of the cyclic peptides. Cell cycle analysis revealed that treatment with 5a, 5c, 5d or 5f resulted in an increase in the number of cells in the sub-G0/G1 peak. Direct interaction with tubulin (turbidimetric assay) and with microtubules (immunostaining experiments) was assessed in vitro for the most promising compounds.

  20. /sup 111/In-labeled eosinophils: localization of inflammatory lesions and parasitic infections in mice

    Energy Technology Data Exchange (ETDEWEB)

    Runge, V.M.; Rand, T.H.; Clanton, J.A.; Jones, J.P.; Colley, D.G.; Partain, C.L.; James, A.E. Jr.

    1985-01-01

    Based upon recent development of practical isolation techniques for eosinophils, labeling and in vivo imaging of eosinophils has been achieved. Isolation of cells was performed utilizing a Percoll density gradient. The eosinophils were subsequently labeled by a modified /sup 111/In-oxine method. Migration of eosinophils in response to intradermal ear-pinna injections of SEA (soluble schistosoma egg antigen), S. mansoni eggs, E. coli, and turpentine was followed with gamma-ray camera imaging from 4 to 48 h. Maximal localization, determined by Gamma 11 data processing, occurred by 4-h post-injection of radiolabel. SEA and S. mansoni eggs provided a greater stimulus for localization than E. coli or turpentine. Neutrophils did not preferentially accumulate. Tissue distribution of labeled eosinophils was greatest in the spleen, followed by liver and bone. /sup 111/In-labeled-eosinophil scans are sensitive to parasitic infections, although somewhat nonspecific.

  1. Serial in vivo imaging of the porcine heart after percutaneous, intramyocardially injected 111In-labeled human mesenchymal stromal cells

    DEFF Research Database (Denmark)

    Lyngbaek, Stig; Ripa, Rasmus S; Haack-Sørensen, Mandana;

    2010-01-01

    This pilot trial aimed to investigate the utilization of (111)In-labeling of mesenchymal stromal cells (MSC) for in vivo tracking after intramyocardial transplantation in a xenotransplantation model with gender mismatched cells. Human male MSC were expanded ex vivo and labeled with (111)In...

  2. Serial in vivo imaging of the porcine heart after percutaneous, intramyocardially injected (111)In-labeled human mesenchymal stromal cells

    DEFF Research Database (Denmark)

    Lyngbæk, Stig; Ripa, Rasmus Sejersten; Haack-Sørensen, Mandana;

    2009-01-01

    This pilot trial aimed to investigate the utilization of (111)In-labeling of mesenchymal stromal cells (MSC) for in vivo tracking after intramyocardial transplantation in a xenotransplantation model with gender mismatched cells. Human male MSC were expanded ex vivo and labeled with (111)In...

  3. Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters

    Science.gov (United States)

    Slastnikova, Tatiana A; Rosenkranz, Andrey A; Morozova, Natalia B; Vorontsova, Maria S; Petriev, Vasiliy M; Lupanova, Tatiana N; Ulasov, Alexey V; Zalutsky, Michael R; Yakubovskaya, Raisa I; Sobolev, Alexander S

    2017-01-01

    Purpose Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111In for cancer therapy. Methods Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111In in high specific activity. Cytotoxicity of the 111In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111In-labeled MNT in B16-F1 melanoma tumor-bearing mice. Results The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111In by serial imaging and significant tumor growth delay (82% growth inhibition) were found. Conclusion The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111In-NOTA–MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111In-NOTA–MNT suggests further applications of the MNT delivery strategy should be explored. PMID:28138237

  4. Quantification of the distribution of /sup 111/In-labelled platelets in organs

    Energy Technology Data Exchange (ETDEWEB)

    van Reenen, O.; Loetter, M.G.; Heyns, A.P.; de Kock, F.; Herbst, C.; Kotze, H.; Pieters, H.; Minnaar, P.C.; Badenhorst, P.N.

    1982-02-01

    A simple and practical approach to the in vivo quantification of /sup 111/indium-oxine labelled blood platelets with a scintillation camera and computer assisted imaging system was evaluated. Radioactivity of the 172 and 247 keV energies was measured in a phantom at various source distances from the collimator and the accuracy of anterior and posterior mode measurements compared with that of the geometrical mean (GM) method, with and without correction for Compton scatter (CS). Organ radioactivity, expressed as a percentage of whole body radioactivity, was determined in vivo in five baboons and the accuracy of the methods verified by post mortem quantification in the animals. Measurement in the anterior mode significantly overestimates hepatic and underestimates splenic radioactivity; posterior mode quantification reverses these results. Correction with the GM method made the accuracy and reproducibility very acceptable. Further correction for anterior-posterior attenuation and/or CS did not improve results materially. The GM method could readily be applied in five human subjects. This study shows that the GM method is an accurate and practical method for the in vivo quantification of organ and regional distribution of /sup 111/In-labelled platelets.

  5. Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters

    Directory of Open Access Journals (Sweden)

    Slastnikova TA

    2017-01-01

    Full Text Available Tatiana A Slastnikova,1,* Andrey A Rosenkranz,1,2,* Natalia B Morozova,3 Maria S Vorontsova,3 Vasiliy M Petriev,4,5 Tatiana N Lupanova,1 Alexey V Ulasov,1 Michael R Zalutsky,6 Raisa I Yakubovskaya,3 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 2Department of Biophysics, Biological Faculty, Lomonosov Moscow State University, 3Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow, 4National Medical Research Radiological Center, Russian Ministry of Health Care, Obninsk, Moscow Region, 5Department of Nuclear Medicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute, Moscow, Russia; 6Department of Radiology, Duke University Medical Center, Durham, NC, USA *These authors contributed equally to this work Purpose: Modular nanotransporters (MNTs are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111In for cancer therapy.Methods: Three MNTs developed to target either melanocortin receptor-1 (MC1R, folate receptor (FR, or epidermal growth factor receptor (EGFR that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111In in high specific activity. Cytotoxicity of the 111In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1. In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111In-labeled MNT in B16-F1 melanoma tumor

  6. Review cyclic peptides on a merry-go-round; towards drug design.

    Science.gov (United States)

    Tapeinou, Anthi; Matsoukas, Minos-Timotheos; Simal, Carmen; Tselios, Theodore

    2015-09-01

    Peptides and proteins are attractive initial leads for the rational design of bioactive molecules. Several natural cyclic peptides have recently emerged as templates for drug design due to their resistance to chemical or enzymatic hydrolysis and high selectivity to receptors. The development of practical protocols that mimic the power of nature's strategies remains paramount for the advancement of novel peptide-based drugs. The de novo design of peptide mimetics (nonpeptide molecules or cyclic peptides) for the synthesis of linear or cyclic peptides has enhanced the progress of therapeutics and diverse areas of science and technology. In the case of metabolically unstable peptide ligands, the rational design and synthesis of cyclic peptide analogues has turned into an alternative approach for improved biological activity.

  7. Simulation-based Discovery of Cyclic Peptide Nanotubes

    Science.gov (United States)

    Ruiz Pestana, Luis A.

    Today, there is a growing need for environmentally friendly synthetic membranes with selective transport capabilities to address some of society's most pressing issues, such as carbon dioxide pollution, or access to clean water. While conventional membranes cannot stand up to the challenge, thin nanocomposite membranes, where vertically aligned subnanometer pores (e.g. nanotubes) are embedded in a thin polymeric film, promise to overcome some of the current limitations, namely, achieving a monodisperse distribution of subnanometer size pores, vertical pore alignment across the membrane thickness, and tunability of the pore surface chemistry. Self-assembled cyclic peptide nanotubes (CPNs), are particularly promising as selective nanopores because the pore size can be controlled at the subnanometer level, exhibit high chemical design flexibility, and display remarkable mechanical stability. In addition, when conjugated with polymer chains, the cyclic peptides can co-assemble in block copolymer domains to form nanoporous thin films. CPNs are thus well positioned to tackle persistent challenges in molecular separation applications. However, our poor understanding of the physics underlying their remarkable properties prevents the rational design and implementation of CPNs in technologically relevant membranes. In this dissertation, we use a simulation-based approach, in particular molecular dynamics (MD) simulations, to investigate the critical knowledge gaps hindering the implementation of CPNs. Computational mechanical tests show that, despite the weak nature of the stabilizing hydrogen bonds and the small cross section, CPNs display a Young's modulus of approximately 20 GPa and a maximum strength of around 1 GPa, placing them among the strongest proteinaceous materials known. Simulations of the self-assembly process reveal that CPNs grow by self-similar coarsening, contrary to other low-dimensional peptide systems, such as amyloids, that are believed to grow through

  8. Self-assembling properties of all γ-cyclic peptides containing sugar amino acid residues.

    Science.gov (United States)

    Guerra, Arcadio; Brea, Roberto J; Amorín, Manuel; Castedo, Luis; Granja, Juan R

    2012-11-28

    In this study, a novel dimer-forming cyclic peptide composed exclusively by cyclic γ-amino acids with a saccharide-like outer surface is described. The antiparallel β-sheet type hydrogen bonding interactions responsible for the large association constant in non-polar solvents constitute a suitable model for a novel class of self-assembling peptide nanotubes.

  9. Investigation of the interaction between HIV-1 DNA and cyclic peptides by electrospray ionization mass spectrometry

    Institute of Scientific and Technical Information of China (English)

    Yi Quan Liu; Hui Hui Li; Yun Hua Ye; Gu Yuan

    2009-01-01

    The interaction between HIV-I DNA and five cyclic peptides (CPI-CP5) was investigated using electrospray ionization mass spectrometry (ESI-MS). It revealed that CPI [c(Ala-Tyr-Leu-Ala-Gly)] and CP4 [c(Pro-D-Tyr-Leu-D-Ala-Gly)] have the higher binding affinity with the duplex DNA among the five cyclic peptides.

  10. Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound.

    Directory of Open Access Journals (Sweden)

    Feng-Yi Yang

    Full Text Available The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted (111In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D induced by focused ultrasound (FUS. An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM 8401 cells was developed in this study. (111In-labeled human atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of (111In-AP-1 Lipo-Dox or (111In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05. Combining sonication with drugs significantly increased the tumor-to-normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of (111In-AP-1 Lipo-Dox with sonication. The (111In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.

  11. Combinatorial Library Screening Coupled to Mass Spectrometry to Identify Valuable Cyclic Peptides.

    Science.gov (United States)

    Camperi, Silvia A; Giudicessi, Silvana L; Martínez-Ceron, María C; Gurevich-Messina, Juan M; Saavedra, Soledad L; Acosta, Gerardo; Cascone, Osvaldo; Erra-Balsells, Rosa; Albericio, Fernando

    2016-06-02

    Combinatorial library screening coupled to mass spectrometry (MS) analysis is a practical approach to identify useful peptides. Cyclic peptides can have high biological activity, selectivity, and affinity for target proteins, and high stability against proteolytic degradation. Here we describe two strategies to prepare combinatorial libraries suitable for MS analysis to accelerate the discovery of cyclic peptide structures. Both approaches use ChemMatrix resin and the linker 4-hydroxymethylbenzoic acid. One strategy involves the synthesis of a one-bead-two-peptides library in which each bead contains both the cyclic peptide and its linear counterpart to facilitate MS analysis. The other protocol is based on the synthesis of a cyclic depsipeptide library in which a glycolamidic ester group is incorporated by adding glycolic acid. After library screening, the ring is opened and the peptide is released simultaneously for subsequent MS analysis. © 2016 by John Wiley & Sons, Inc.

  12. Study of (Cyclic Peptide)-Polymer Conjugate Assemblies by Small-Angle Neutron Scattering.

    Science.gov (United States)

    Koh, Ming Liang; FitzGerald, Paul A; Warr, Gregory G; Jolliffe, Katrina A; Perrier, Sébastien

    2016-12-19

    We present a fundamental study into the self-assembly of (cyclic peptide)-polymer conjugates as a versatile supramolecular motif to engineer nanotubes with defined structure and dimensions, as characterised in solution using small-angle neutron scattering (SANS). This work demonstrates the ability of the grafted polymer to stabilise and/or promote the formation of unaggregated nanotubes by the direct comparison to the unconjugated cyclic peptide precursor. This ideal case permitted a further study into the growth mechanism of self-assembling cyclic peptides, allowing an estimation of the cooperativity. Furthermore, we show the dependency of the nanostructure on the polymer and peptide chemical functionality in solvent mixtures that vary in the ability to compete with the intermolecular associations between cyclic peptides and ability to solvate the polymer shell.

  13. Comparative distribution study of /sup 111/In-labelled DTPA and TTHA monoclonal antibody conjugates in a choriocarcinoma xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Buckley, R.G.; Barnett, P.; Searle, F.; Pedley, R.; Boden, J.A.

    1986-11-01

    Conjugates of the chelating agents DTPA and TTHA with a monoclonal anti-HCG were prepared. The tissue distribution of the /sup 111/In-Labelled conjugates and also /sup 111/In-citrate was studied in mice bearing human choriocarcinoma xenografts. The antibody conjugates both gave high liver and spleen radionuclide accumulation. Elevated femur levels were observed for the TTHA conjugate and /sup 111/In-citrate. Generally the DTPA conjugate showed the highest tumor-tissue ratios, although its tumor/blood ratio was lower than the other two materials. The results infer that the DTPA conjugate has the greatest utility as an imaging agent but that it would require a background subtraction technique.

  14. Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products

    Science.gov (United States)

    This article reviews the emergence of cyclic sulfamidates as versatile intermediatesfor the synthesis of unnatural amino acids, chalcogen peptides, modified sugars, drugs and drug candidates, and important natural products.

  15. Modulating Charge Transfer Through Cyclic D,L α-Peptide Self-Assembly

    OpenAIRE

    Horne, W. Seth; Ashkenasy, Nurit; Ghadiri, M. Reza

    2005-01-01

    We describe a concise solid support-based synthetic method for the preparation of cyclic D,L α-peptides bearing 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) side chains. Studies of the structural and photoluminescence properties of these molecules in solution show that the hydrogen bond directed self-assembly of the cyclic D,L α-peptide backbone promotes intermolecular NDI excimer formation. The efficiency of NDI charge transfer in the resulting supramolecular assemblies is shown to depen...

  16. Exploitation of the Ornithine Effect Enhances Characterization of Stapled and Cyclic Peptides

    Science.gov (United States)

    Crittenden, Christopher M.; Parker, W. Ryan; Jenner, Zachary B.; Bruns, Kerry A.; Akin, Lucas D.; McGee, William M.; Ciccimaro, Eugene; Brodbelt, Jennifer S.

    2016-05-01

    A method to facilitate the characterization of stapled or cyclic peptides is reported via an arginine-selective derivatization strategy coupled with MS/MS analysis. Arginine residues are converted to ornithine residues through a deguanidination reaction that installs a highly selectively cleavable site in peptides. Upon activation by CID or UVPD, the ornithine residue cyclizes to promote cleavage of the adjacent amide bond. This Arg-specific process offers a unique strategy for site-selective ring opening of stapled and cyclic peptides. Upon activation of each derivatized peptide, site-specific backbone cleavage at the ornithine residue results in two complementary products: the lactam ring-containing portion of the peptide and the amine-containing portion. The deguanidination process not only provides a specific marker site that initiates fragmentation of the peptide but also offers a means to unlock the staple and differentiate isobaric stapled peptides.

  17. Modulating charge transfer through cyclic D,L-alpha-peptide self-assembly.

    Science.gov (United States)

    Horne, W Seth; Ashkenasy, Nurit; Ghadiri, M Reza

    2005-02-04

    We describe a concise, solid support-based synthetic method for the preparation of cyclic d,l-alpha-peptides bearing 1,4,5,8-naphthalenetetracarboxylic acid diimide (NDI) side chains. Studies of the structural and photoluminescence properties of these molecules in solution show that the hydrogen bond-directed self-assembly of the cyclic d,l-alpha-peptide backbone promotes intermolecular NDI excimer formation. The efficiency of NDI charge transfer in the resulting supramolecular assemblies is shown to depend on the length of the linker between the NDI and the peptide backbone, the distal NDI substituent, and the number of NDIs incorporated in a given structure. The design rationale and synthetic strategies described here should provide a basic blueprint for a series of self-assembling cyclic d,l-alpha-peptide nanotubes with interesting optical and electronic properties.

  18. Modulating Charge Transfer Through Cyclic D,L α-Peptide Self-Assembly

    Science.gov (United States)

    Horne, W. Seth; Ashkenasy, Nurit; Ghadiri, M. Reza

    2007-01-01

    We describe a concise solid support-based synthetic method for the preparation of cyclic D,L α-peptides bearing 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) side chains. Studies of the structural and photoluminescence properties of these molecules in solution show that the hydrogen bond directed self-assembly of the cyclic D,L α-peptide backbone promotes intermolecular NDI excimer formation. The efficiency of NDI charge transfer in the resulting supramolecular assemblies is shown to depend on the length of the linker between the NDI and the peptide backbone, the distal NDI substituent, and the number of NDIs incorporated in a given structure. The design rationale and synthetic strategies described here should provide a basic blueprint for a series of self-assembling cyclic D,L α-peptide nanotubes with interesting optical and electronic properties. PMID:15624124

  19. Antifungal cyclic peptides from the marine sponge Microscleroderma herdmani

    Science.gov (United States)

    Screening natural product extracts from National Cancer Institute Open Repository for antifungal discovery afforded hits for bioassay-guided fractionation. Upon LC-MS analysis of column fractions with antifungal activities to generate information on chemical structure, two new cyclic hexapeptides, m...

  20. Factors that restrict intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE)

    DEFF Research Database (Denmark)

    Ouyang, Hui; Chen, Weiqing; Andersen, Thomas E;

    2009-01-01

    The objective of this study was to determine the relative importance of metabolism by cytochrome P450 (CYP) enzymes versus efflux by P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, OMCA-DADLE) of the opioid peptide DADLE (H......-gp), not metabolic enzymes (e.g., CYP 3A, esterases), restrict the permeation of peptide prodrugs across the rat intestinal mucosa....

  1. Pretargetted imaging of colorectal cancer recurrences using an 111In-labelled bivalent hapten and a bispecific antibody conjugate.

    Science.gov (United States)

    Chetanneau, A; Barbet, J; Peltier, P; Le Doussal, J M; Gruaz-Guyon, A; Bernard, A M; Resche, I; Rouvier, E; Bourguet, P; Delaage, M

    1994-12-01

    In 11 patients recurrence of colorectal cancer was suspected by a rise in serum carcinoembryonic antigen (CEA) (nine cases), by a subocclusive clinical situation (one case) or by endoscopy (on an anastomosis, one case). Two-step tumour targetting was performed by a first injection of 0.1 mg kg-1 of unlabelled bispecific antibody conjugate (an anti-CEA Fab' fragment chemically coupled to an anti-diethylene triamine pentaacetate (DTPA)-indium fragment) followed 4 to 5 days later by injection of the bivalent DTPA hapten labelled with 5 to 8 mCi 111In. Planar scintigraphy, single photon emission computed tomographic (SPECT) 360 degrees acquisitions and whole-body scans were obtained 4.5 and 24 h after injection of the radiolabelled hapten. Biodistribution was determined for eight patients at 48 h. The final diagnosis was confirmed histologically in nine patients (eight by second-look surgery, one by laparotomy). Overall, results were one true negative (1-year follow-up) and 10 true positive; however, for the three large liver metastases (3 to 6 cm), only the periphery of the metastasis had high uptake compared to normal liver. For pelvic recurrences, immunoscintigraphic (IS) contrast was better for small tumours. The highest tumour uptake was found for a 1 cm diameter pelvic recurrence (7.2% i.d. kg-1). Mean tumour-to-blood ratios were 6.4. Thus, this two-step tumour targetting technique, which uses a bispecific antibody conjugate and an 111In-labelled bivalent hapten injected sequentially without chasing the excess bispecific antibody, provided satisfactory results in this preliminary clinical trial for detection of recurrent colorectal cancers.

  2. The binding mechanism of a peptidic cyclic serine protease inhibitor

    DEFF Research Database (Denmark)

    Jiang, Longguang; Svane, Anna S P; Sørensen, Hans Peter

    2011-01-01

    Serine proteases are classical objects for studies of catalytic and inhibitory mechanisms as well as interesting as therapeutic targets. Since small-molecule serine protease inhibitors generally suffer from specificity problems, peptidic inhibitors, isolated from phage-displayed peptide libraries...... inhibitory mechanism and an unusually high specificity. Using a number of modified variants of upain-1, we characterised the upain-1-urokinase-type plasminogen activator complex using X-ray crystal structure analysis, determined a model of the peptide in solution by NMR spectroscopy, and analysed binding...... kinetics and thermodynamics by surface plasmon resonance and isothermal titration calorimetry. We found that upain-1 changes both main-chain conformation and side-chain orientations as it binds to the protease, in particular its Trp3 residue and the surrounding backbone. The properties of upain-1...

  3. Molecular pom poms from self-assembling α,γ-cyclic peptides.

    Science.gov (United States)

    Panciera, Michele; Amorín, Manuel; Granja, Juan R

    2014-08-11

    The hierarchical self-assembly properties of a dimer-forming cyclic peptide that bears a nicotinic acid moiety to form molecular pom-pom-like structures are described. This dimeric assembly self organizes into spherical structures that can encapsulate small organic molecules owing to its porosity and it can also facilitate metal deposition on its surface directed by the pyridine moiety.

  4. Psychrophilin A and cycloaspeptide D, novel cyclic peptides from the psychrotolerant fungus Penicillium ribeum

    DEFF Research Database (Denmark)

    Dalsgaard, Petur; Larsen, Thomas Ostenfeld; Frydenvang, K.;

    2004-01-01

    and 2D NMR techniques, HREIMS, tandem mass spectrometry (ESMS/MS), and X-ray crystallography. The amino acid residues of psychrophilin A (1) and cycloaspeptide D (2) were all found to possess the L configuration by Marfey's method. Psychrophilin A (1) is the first natural cyclic peptide containing...

  5. Psychrophilin A and cycloaspeptide D, novel cyclic peptides from the psychrotolerant fungus Penicillium ribeum

    DEFF Research Database (Denmark)

    Dalsgaard, Petur Weihe; Larsen, Thomas Ostenfeld; Frydenvang, Karla Andrea;

    2004-01-01

    and 2D NMR techniques, HREIMS, tandem mass spectrometry (ESMS/MS), and X-ray crystallography. The amino acid residues of psychrophilin A (1) and cycloaspeptide D (2) were all found to possess the l configuration by Marfey's method. Psychrophilin A (1) is the first natural cyclic peptide containing...

  6. Cyclic peptide inhibitors of the β-sliding clamp in Staphylococcus aureus

    DEFF Research Database (Denmark)

    Kjelstrup, Susanne; Hansen, Paula Melo Paulon; Thomsen, Line Elnif;

    2013-01-01

    Interaction between pairs of Staphylococcus aureus replication proteins was detected in an Escherichia coli based two-hybrid analysis. A reverse two-hybrid system was constructed for selection of compounds that hindered interaction between interacting protein pairs. A number of cyclic peptides...

  7. Strong combined gene-environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis

    DEFF Research Database (Denmark)

    Pedersen, Line Merete Blak; Jacobsen, Søren; Garred, Peter;

    2007-01-01

    To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs)....

  8. Anti-cyclic citrullinated peptide (anti-CCP) antibodies with brucellosis.

    Science.gov (United States)

    Kisacik, Bunyamin; Dag, Muhammet Said; Pehlivan, Yavuz; Ugurlu, Kenan; Mercan, Ozge Kaya; Aydinli, Musa; Devay, Seda Duygulu; Sayarlioglu, Mehmet; Onat, Ahmet Mesut

    2014-06-01

    Anti-cyclic citrullinated peptide (anti-CCP) was positive in 11.5 % and rheumatoid factor was positive in 8.8 % of the patients with Brucella. After a comparative evaluation, we have found out that there was not a statistical significance concerning the anti-CCP levels between the patients with brucellosis and healthy control.

  9. Total synthesis, structure, and oral absorption of a thiazole cyclic peptide, sanguinamide A

    DEFF Research Database (Denmark)

    Nielsen, Daniel S; Hoang, Huy N; Lohman, Rink-Jan;

    2012-01-01

    The first total synthesis and three-dimensional solution structure are reported for sanguinamide A, a thiazole-containing cyclic peptide from the sea slug H. sanguineus. Solution phase fragment synthesis, solid phase fragment assembly, and solution macrocyclization were combined to give (1) in 10...

  10. Cyclic peptide inhibitors of the β-sliding clamp in Staphylococcus aureus

    DEFF Research Database (Denmark)

    Kjelstrup, Susanne; Hansen, Paula Melo Paulon; Thomsen, Line Elnif;

    2013-01-01

    Interaction between pairs of Staphylococcus aureus replication proteins was detected in an Escherichia coli based two-hybrid analysis. A reverse two-hybrid system was constructed for selection of compounds that hindered interaction between interacting protein pairs. A number of cyclic peptides......, from a library generated by the split intein-mediated circular ligation of peptides and proteins technology, were found to interfere with dimerization of the β-sliding clamp of the replisome. Two 8-mer peptides were analyzed in more detail. Both inhibited DNA replication, led to SOS induction, altered...

  11. A Selective Cyclic Peptidic Human SIRT5 Inhibitor

    Directory of Open Access Journals (Sweden)

    Jiajia Liu

    2016-09-01

    Full Text Available In the current study, we discovered that a side chain-to-side chain cyclic pentapeptide harboring a central Nε-carboxyethyl-thiocarbamoyl-lysine residue behaved as a strong and selective (versus human SIRT1/2/3/6 inhibitor against human SIRT5-catalyzed deacylation reaction. This compound was also found to be proteolytically much more stable than its linear counterpart. This compound could be a valuable lead for developing stronger, selective, metabolically stable, and cell permeable human SIRT5 inhibitors.

  12. Control of lipolysis by natriuretic peptides and cyclic GMP.

    Science.gov (United States)

    Lafontan, Max; Moro, Cédric; Berlan, Michel; Crampes, François; Sengenes, Coralie; Galitzky, Jean

    2008-01-01

    Human fat cell lipolysis was, until recently, thought to be mediated exclusively by a cAMP-dependent protein kinase (PKA)-regulated pathway under the control of catecholamines and insulin. We have shown that atrial- and B-type natriuretic peptides (ANP and BNP respectively) stimulate lipolysis in human fat cells through a cGMP-dependent protein kinase (PKG) signaling pathway independent of cAMP production and PKA activity. Pharmacological or physiological (exercise) increases in plasma ANP levels stimulate lipid mobilization in humans. This pathway becomes important during chronic treatment with beta-adrenoceptor antagonists, which inhibit catecholamine-induced lipolysis but enhance cardiac ANP release. These findings have metabolic implications and point to potential problems when natriuretic peptide secretion is altered or during therapeutic use of recombinant BNP.

  13. Discovery and design of cyclic peptides as dengue virus inhibitors through structure-based molecular docking

    Institute of Scientific and Technical Information of China (English)

    Sobia Idrees; Usman Ali Ashfaq

    2014-01-01

    Objective:To find potential peptide inhibitors against theNS2B/NS3 protease ofDENV which in turn, can inhibit the viral replication inside host cell.Methods:Cyclic peptides were designed having combination of positively charged amino acids usingChemSketch software and were converted to3D structures.DENVNS3 protein structure was retrieved fromProteinDataBank (PDB) usingPDBId:2FOM.DENVNS3 and cylic peptides were docked usingMOE software after structural optimization.Results:Through molecular docking it was revealed that most of the peptides bound deeply in the binding pocket ofDENVNS2B/NS3 protease an had interactions with catalytic triad.Peptide2 successfully blocked the catalytic triad ofNS2B/NS3 protease. Peptide1, ,4 and6 also had potential interactions with active residues of theNS2B/NS3 protease while all other peptides were in close contact with the active sites ofNS2B/NS3 protease thus, these peptides can serve as a potential drug candidate to stop viral replication.Conclusions:Thus, it can be concluded from the study that these peptides could serve as important inhibitors to inhibit the viral replication and need further in-vitro investigations to confirm their efficacy.

  14. Design of cyclic peptides that bind protein surfaces with antibody-like affinity.

    Science.gov (United States)

    Millward, Steven W; Fiacco, Stephen; Austin, Ryan J; Roberts, Richard W

    2007-09-21

    There is a pressing need for new molecular tools to target protein surfaces with high affinity and specificity. Here, we describe cyclic messenger RNA display with a trillion-member covalent peptide macrocycle library. Using this library, we have designed a number of high-affinity, redox-insensitive, cyclic peptides that target the signaling protein G alpha i1. In addition to cyclization, our library construction took advantage of an expanded genetic code, utilizing nonsense suppression to insert N-methylphenylalanine as a 21st amino acid. The designed macrocycles exhibit several intriguing features. First, the core motif seen in all of the selected variants is the same and shares an identical context with respect to the macrocyclic scaffold, consistent with the idea that selection simultaneously optimizes both the cyclization chemistry and the structural placement of the binding epitope. Second, detailed characterization of one molecule, cyclic G alpha i binding peptide (cycGiBP), demonstrates substantially enhanced proteolytic stability relative to that of the parent linear molecule. Third and perhaps most important, the cycGiBP peptide binds the target with very high affinity ( K i approximately 2.1 nM), similar to those of many of the best monoclonal antibodies and higher than that of the betagamma heterodimer, an endogenous G alpha i1 ligand. Overall the work provides a general route to design novel, low-molecular-weight, high-affinity ligands that target protein surfaces.

  15. Cyclic Peptide-Decorated Self-Assembled Nanohybrids for Selective Recognition and Detection of Multivalent RNAs.

    Science.gov (United States)

    Choi, Jun Shik; Han, So-hee; Kim, Hyoseok; Lim, Yong-Beom

    2016-03-16

    Although there has been substantial advancement in the development of nanostructures, the development of self-assembled nanostructures that can selectively recognize multivalent targets has been very difficult. Here we show the proof of concept that topology-controlled peptide nanoassemblies can selectively recognize and detect a multivalent RNA target. We compared the differential behaviors of peptides in a linear or cyclic topology in terms of peptide-gold nanoparticle hybrid nanostructure formation, conformational stabilization, monovalent and multivalent RNA binding in vitro, and multivalent RNA recognition in live cells. When the topology-dependent selectivity amplification of the cyclic peptide hybrids is combined with the noninvasive nature of dark-field microscopy, the cellular localization of the viral Rev response element (RRE) RNA can be monitored in situ. Because intracellular interactions are often mediated by overlapping binding partners with weak affinity, the topology-controlled peptide assemblies can provide a versatile means to convert weak ligands into multivalent ligands with high affinity and selectivity.

  16. A new and convenient method for purification of {sup 86}Y using a Sr(II) selective resin and comparison of biodistribution of {sup 86}Y and {sup 111}In labeled Herceptin{sup TM}

    Energy Technology Data Exchange (ETDEWEB)

    Garmestani, Kayhan; Milenic, Diane E.; Plascjak, Paul S.; Brechbiel, Martin W. E-mail: martinwb@mail.nih.gov

    2002-07-01

    A simple and rapid procedure was developed for purification of cyclotron produced {sup 86}Y via the {sup 86}Sr(p,n) {sup 86}Y reaction. A commercially available Sr(II) selective resin was used to separate {sup 86}Y from the cyclotron irradiated Sr(II) target with a recovery of the enriched Sr(II) target while yielding a 75-80% recovery of {sup 86}Y suitable for radiolabeling either proteins or peptides. To demonstrate the utility of this methodology, the anti-HER2 monoclonal antibody Herceptin{sup TM} was radiolabeled with the purified {sup 86}Y and compared to {sup 111}In labeled Herceptin{sup TM}. The biodistribution study demonstrated that {sup 111}In-Herceptin{sup TM}, while a suitable surrogate for {sup 90}Y in the major organs, did not parallel the uptake of {sup 86}Y-Herceptin{sup TM} in the bone, and thus may not accurately predict the level of {sup 90}Y accumulation in the bone for clinical RIT applications. This result exemplifies the requirement of employing appropriate matched pair isotopes for imaging and therapy to insure that dosimetry considerations may be addressed accurately.

  17. Cyclic peptides-assisted trans- port of metal ions across liquid-organic membrane

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The formation of alkali and alkaline-earth metal picrate complexes with cyclo(Pro-Gly)n ionophores (1, n = 3; 2, n = 4) can facilitate the migration of metal ions across a bulk liquid CH2Cl2 membrane. The migration behavior was studied by measuring the solution absorption at 356 nm, using a UV/Vis spectrophotometer, and the rates can be determined by comparing the initial absorption of donor solutions with the absorption of the corresponding receiver solutions as the function of time. It was found that cyclic peptide 1 shows higher transport activity for the studied alkali and alkaline-earth metal ions than compound 2, which is related to the backbone flexibility of the cyclic peptides. The findings in this work suggest that the rate of ionophore-facilitated ion transport depends not only on the ability of complex forma-tion in aqueous phase, but also on the ability of complex dissociation in organic phase.

  18. Natriuretic peptides modify Pseudomonas fluorescens cytotoxicity by regulating cyclic nucleotides and modifying LPS structure

    Directory of Open Access Journals (Sweden)

    Feuilloley Marc GJ

    2008-07-01

    Full Text Available Abstract Background Nervous tissues express various communication molecules including natriuretic peptides, i.e. Brain Natriuretic Peptide (BNP and C-type Natriuretic Peptide (CNP. These molecules share structural similarities with cyclic antibacterial peptides. CNP and to a lesser extent BNP can modify the cytotoxicity of the opportunistic pathogen Pseudomonas aeruginosa. The psychrotrophic environmental species Pseudomonas fluorescens also binds to and kills neurons and glial cells, cell types that both produce natriuretic peptides. In the present study, we investigated the sensitivity of Pseudomonas fluorescens to natriuretic peptides and evaluated the distribution and variability of putative natriuretic peptide-dependent sensor systems in the Pseudomonas genus. Results Neither BNP nor CNP modified P. fluorescens MF37 growth or cultivability. However, pre-treatment of P. fluorescens MF37 with BNP or CNP provoked a decrease of the apoptotic effect of the bacterium on glial cells and an increase of its necrotic activity. By homology with eukaryotes, where natriuretic peptides act through receptors coupled to cyclases, we observed that cell-permeable stable analogues of cyclic AMP (dbcAMP and cyclic GMP (8BcGMP mimicked the effect of BNP and CNP on bacteria. Intra-bacterial concentrations of cAMP and cGMP were measured to study the involvement of bacterial cyclases in the regulation of P. fluorescens cytotoxicity by BNP or CNP. BNP provoked an increase (+49% of the cAMP concentration in P. fluorescens, and CNP increased the intra-bacterial concentrations of cGMP (+136%. The effect of BNP and CNP on the virulence of P. fluorescens was independent of the potential of the bacteria to bind to glial cells. Conversely, LPS extracted from MF37 pre-treated with dbcAMP showed a higher necrotic activity than the LPS from untreated or 8BcGMP-pre-treated bacteria. Capillary electrophoresis analysis suggests that these different effects of the LPS may be due

  19. In silico study of amphiphilic nanotubes based on cyclic peptides in polar and non-polar solvent

    DEFF Research Database (Denmark)

    Vijayakumar, Vinodhkumar; Vijayaraj, Ramadoss; Peters, Günther H.J.

    2016-01-01

    The stability of cyclic peptide assemblies (CPs) forming a macromolecular nanotube structure was investigated in solvents of different polarity using computational methods. The stability and structure of the complexes were studied using traditional molecular dynamics (MD). Energy of dissociation ...

  20. An Efficient Method for the In Vitro Production of Azol(in)e-Based Cyclic Peptides**

    Science.gov (United States)

    Houssen, Wael E; Bent, Andrew F; McEwan, Andrew R; Pieiller, Nathalie; Tabudravu, Jioji; Koehnke, Jesko; Mann, Greg; Adaba, Rosemary I; Thomas, Louise; Hawas, Usama W; Liu, Huanting; Schwarz-Linek, Ulrich; Smith, Margaret C M; Naismith, James H; Jaspars, Marcel

    2014-01-01

    Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6–9 residues representing 11 out of the 20 canonical amino acids. PMID:25331823

  1. An efficient method for the in vitro production of azol(in)e-based cyclic peptides.

    Science.gov (United States)

    Houssen, Wael E; Bent, Andrew F; McEwan, Andrew R; Pieiller, Nathalie; Tabudravu, Jioji; Koehnke, Jesko; Mann, Greg; Adaba, Rosemary I; Thomas, Louise; Hawas, Usama W; Liu, Huanting; Schwarz-Linek, Ulrich; Smith, Margaret C M; Naismith, James H; Jaspars, Marcel

    2014-12-15

    Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6-9 residues representing 11 out of the 20 canonical amino acids.

  2. Jatrophidin I, a cyclic peptide from Brazilian Jatropha curcas L.: isolation, characterization, conformational studies and biological activity.

    Science.gov (United States)

    Altei, Wanessa F; Picchi, Douglas G; Abissi, Barbara M; Giesel, Guilherme M; Flausino, Otavio; Reboud-Ravaux, Michèle; Verli, Hugo; Crusca, Edson; Silveira, Edilberto R; Cilli, Eduardo M; Bolzani, Vanderlan S

    2014-11-01

    A cyclic peptide, jatrophidin I, was isolated from the latex of Jatropha curcas L. Its structure was elucidated by extensive 2D NMR spectroscopic analysis, with additional conformational studies performed using Molecular Dynamics/Simulated Annealing (MD/SA). Jatrophidin I had moderate protease inhibition activity when compared with pepstatin A; however, the peptide was inactive in antimalarial, cytotoxic and antioxidant assays.

  3. Peptide macrocycles featuring a backbone secondary amine: a convenient strategy for the synthesis of lipidated cyclic and bicyclic peptides on solid support.

    Science.gov (United States)

    Oddo, Alberto; Münzker, Lena; Hansen, Paul R

    2015-05-15

    A convenient strategy for the on-resin synthesis of macrocyclic peptides (3- to 13-mers) via intramolecular halide substitution by a diamino acid is described. The method is compatible with standard Fmoc/tBu SPPS and affords a tail-to-side-chain macrocyclic peptide featuring an endocyclic secondary amine. This functional group is still reactive toward acylation, allowing for the continuation of the synthesis. An application to the synthesis of lipidated cyclic and bicyclic antimicrobial peptides is presented.

  4. Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery.

    Science.gov (United States)

    Qian, Ziqing; LaRochelle, Jonathan R; Jiang, Bisheng; Lian, Wenlong; Hard, Ryan L; Selner, Nicholas G; Luechapanichkul, Rinrada; Barrios, Amy M; Pei, Dehua

    2014-06-24

    Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR4 was 4-12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape.

  5. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy

    Science.gov (United States)

    Chan, Lai Yue; Craik, David J.; Daly, Norelle L.

    2016-01-01

    Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers. PMID:27734947

  6. Cyclic peptide inhibitors of the β-sliding clamp in Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Susanne Kjelstrup

    Full Text Available Interaction between pairs of Staphylococcus aureus replication proteins was detected in an Escherichia coli based two-hybrid analysis. A reverse two-hybrid system was constructed for selection of compounds that hindered interaction between interacting protein pairs. A number of cyclic peptides, from a library generated by the split intein-mediated circular ligation of peptides and proteins technology, were found to interfere with dimerization of the β-sliding clamp of the replisome. Two 8-mer peptides were analyzed in more detail. Both inhibited DNA replication, led to SOS induction, altered cell morphology and cell death. The peptides were active when added to bacterial cultures indicating that they could traverse the bacterial membrane to find their intracellular target. Peptide specificity was confirmed by overproduction of the putative target (DnaN which resulted in resistance. The minimum inhibitory concentration was ∼50 μg/ml for S. aureus cells. These compounds may serve as lead candidates for future development into novel classes of antibiotics as well as provide information on the function of the S. aureus replication process.

  7. Atrial natriuretic peptide receptor heterogeneity and effects on cyclic GMP accumulation

    Energy Technology Data Exchange (ETDEWEB)

    Leitman, D.C.

    1988-01-01

    The effects of atrial natriuretic peptide (ANP), oxytocin (OT) and vasopressin (AVP) on guanylate cyclase activity and cyclic GMP accumulation were examined, since these hormones appear to be intimately associated with blood pressure and intravascular volume homeostasis. ANP was found to increase cyclic GMP accumulation in ten cell culture systems, which were derived from blood vessels, adrenal cortex, kidney, lung, testes and mammary gland. ANP receptors were characterized in intact cultured cells using {sup 125}I-ANP{sub 8-33}. Specific {sup 125}I-ANP binding was saturable and of high affinity. Scratchard analysis of the binding data for all cell types exhibited a straight line, indicating that these cells possessed a single class of binding sites. Despite the presence of linear Scatchard plots, these studies demonstrated that cultured cells possess two functionally and physically distinct ANP-binding sites. Most of the ANP-binding sites in cultured cells have a molecular size of 66,000 daltons under reducing conditions. The identification of cultured cell types in which hormones (ANP and oxytocin) regulate guanylate cyclase activity and increase cyclic GMP synthesis will provide valuable systems to determine the mechanisms of hormone-receptor coupling to guanylate cyclase and the cellular processes regulated by cyclic GMP.

  8. Drug conjugation to cyclic peptide-polymer self-assembling nanotubes.

    Science.gov (United States)

    Blunden, Bianca M; Chapman, Robert; Danial, Maarten; Lu, Hongxu; Jolliffe, Katrina A; Perrier, Sébastien; Stenzel, Martina H

    2014-09-26

    We show for the first time how polymeric nanotubes (NTs) based on self-assembled conjugates of polymers and cyclic peptides can be used as an efficient drug carrier. RAPTA-C, a ruthenium-based anticancer drug, was conjugated to a statistical co-polymer based on poly(2-hydroxyethyl acrylate) (pHEA) and poly(2-chloroethyl methacrylate) (pCEMA), which formed the shell of the NTs. Self-assembly into nanotubes (length 200-500 nm) led to structures exhibiting high activity against cancer cells.

  9. Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides.

    Science.gov (United States)

    Hermans, Stefan J; Ascher, David B; Hancock, Nancy C; Holien, Jessica K; Michell, Belinda J; Chai, Siew Yeen; Morton, Craig J; Parker, Michael W

    2015-02-01

    Insulin-regulated aminopeptidase (IRAP or oxytocinase) is a membrane-bound zinc-metallopeptidase that cleaves neuroactive peptides in the brain and produces memory enhancing effects when inhibited. We have determined the crystal structure of human IRAP revealing a closed, four domain arrangement with a large, mostly buried cavity abutting the active site. The structure reveals that the GAMEN exopeptidase loop adopts a very different conformation from other aminopeptidases, thus explaining IRAP's unique specificity for cyclic peptides such as oxytocin and vasopressin. Computational docking of a series of IRAP-specific cognitive enhancers into the crystal structure provides a molecular basis for their structure-activity relationships and demonstrates that the structure will be a powerful tool in the development of new classes of cognitive enhancers for treating a variety of memory disorders such as Alzheimer's disease.

  10. Spectroscopic Identification of Cyclic Imide b2-Ions from Peptides Containing Gln and Asn Residues

    Science.gov (United States)

    Grzetic, Josipa; Oomens, Jos

    2013-08-01

    In mass-spectrometry based peptide sequencing, formation of b- and y-type fragments by cleavage of the amide C-N bond constitutes the main dissociation pathway of protonated peptides under low-energy collision induced dissociation (CID). The structure of the b 2 fragment ion from peptides containing glutamine (Gln) and asparagine (Asn) residues is investigated here by infrared ion spectroscopy using the free electron laser FELIX. The spectra are compared with theoretical spectra calculated using density functional theory for different possible isomeric structures as well as to experimental spectra of synthesized model systems. The spectra unambiguously show that the b2-ions do not possess the common oxazolone structure, nor do they possess the alternative diketopiperazine structure. Instead, cyclic imide structures are formed through nucleophilic attack by the amide nitrogen atom of the Gln and Asn side chains. The alternative pathway involving nucleophilic attack from the side-chain amide oxygen atom leading to cyclic isoimide structures, which had been suggested by several authors, can clearly be excluded based on the present IR spectra. This mechanism is perhaps surprising as the amide oxygen atom is considered to be the better nucleophile; however, computations show that the products formed via attack by the amide nitrogen are considerably lower in energy. Hence, b2-ions with Asn or Gln in the second position form structures with a five-membered succinimide or a six-membered glutarimide ring, respectively. b2-Ions formed from peptides with Asn in the first position are spectroscopically shown to possess the classical oxazolone structure.

  11. Continuum modeling investigation of gigahertz oscillators based on a C60 fullerene inside cyclic peptide nanotubes

    Science.gov (United States)

    Sadeghi, F.; Ansari, R.; Darvizeh, M.

    2016-02-01

    Research concerning the fabrication of nano-oscillators with operating frequency in the gigahertz (GHz) range has become a focal point in recent years. In this paper, a new type of GHz oscillators is introduced based on a C60 fullerene inside a cyclic peptide nanotube (CPN). To study the dynamic behavior of such nano-oscillators, using the continuum approximation in conjunction with the 6-12 Lennard-Jones (LJ) potential function, analytical expressions are derived to determine the van der Waals (vdW) potential energy and interaction force between the two interacting molecules. Employing Newton's second law, the equation of motion is solved numerically to arrive at the telescopic oscillatory motion of a C60 fullerene inside CPNs. It is shown that the fullerene molecule exhibits different kinds of oscillation inside peptide nanotubes which are sensitive to the system parameters. Furthermore, for the precise evaluation of the oscillation frequency, a novel semi-analytical expression is proposed based on the conservation of the mechanical energy principle. Numerical results are presented to comprehensively study the effects of the number of peptide units and initial conditions (initial separation distance and velocity) on the oscillatory behavior of C60 -CPN oscillators. It is found out that for peptide nanotubes comprised of one unit, the maximum achievable frequency is obtained when the inner core oscillates with respect to its preferred positions located outside the tube, while for other numbers of peptide units, such frequency is obtained when the inner core oscillates with respect to the preferred positions situated in the space between the two first or the two last units. It is further found out that four peptide units are sufficient to obtain the optimal frequency.

  12. Anti-cyclic citrullinated peptide antibodies in children with Juvenile Idiopathic Arthritis

    Science.gov (United States)

    Hamooda, Mohamed; Fouad, Hala; Galal, Nermeen; Sewelam, Nadia; Megahed, Dina

    2016-01-01

    Aim The purpose of present study was to access the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with Juvenile Idiopathic Arthritis (JIA), and to investigate the clinical significance and diagnostic value of the anti-CCP antibodies in correlation with age, sex & activity. Methods This case-control study was performed on 50 patients with JIA in addition to 40 sex and age-matched children as a control group. The participants were recruited from rheumatology Outpatient Clinic of Cairo University Specialized Pediatric Hospital. Patients were subjected to full history taking, clinical examination, routine laboratory investigations and x-rays on involved joints. Both patients and controls underwent assay of anti-CCP antibodies by AxSYM Anti-CCP IgG Microparticle Enzyme Immunoassay (MEIA) which is a semi-quantitative determination of the IgG class of autoantibodies specific to cyclic citrullinated peptide (CCP) in patients’ serum or plasma. Data were analyzed using Mann-Whitney U test, ANOVA, and independent-samples t-test by SPSS version 15. Results Anti-CCP positivity was identified amongst patients with JIA, particularly those JIA patients experiencing RF positive polyarticular disease onset. Above all, it is important that anti-CCP positivity and bone erosions, degree of joint damage, and ESR levels were significantly correlated. Conclusion Anti-CCP could be utilized as a valuable marker in the polyarticular form of JIA to direct early, and could be aggressive therapeutic intervention. PMID:27790341

  13. Synthesis and antifungal activities of glycosylated derivatives of the cyclic peptide fungicide caspofungin.

    Science.gov (United States)

    Guo, Junxiang; Hu, Honggang; Zhao, Qingjie; Wang, Ting; Zou, Yan; Yu, Shichong; Wu, Qiuye; Guo, Zhongwu

    2012-08-01

    Diseases caused by systemic fungal infections have become a significant clinical problem in recent decades. A series of glycosyl derivatives of the approved cyclic peptide antifungal drug caspofungin conjugated with β-D-glucopyranose, β-D-galactopyranose, β-D-xylopyranose, β-L-rhamnopyranose, β-maltose and β-lactose units were designed, synthesized, and evaluated as new potential antifungal drugs. The compounds were obtained by coupling the corresponding glycosyl amines to the free primary amino groups of caspofungin through a bifunctional glutaryl linker. In contrast to caspofungin, these glycosylated derivatives are soluble in water, but are not hygroscopic and moreover, are more stable than caspofungin under high humidity and temperature. CD studies showed that glycosylation has very little impact on the conformation of the cyclic peptide of caspofungin. In vitro antifungal tests against seven human pathogenic fungi revealed that the caspofungin-monosaccharide conjugates, but not the disaccharide conjugates, have increased antifungal activities against the majority of tested fungus species relative to caspofungin. The β-D-glucopyranosyl derivative 2 a showed the strongest and broadest antifungal activity, providing a lead for further studies.

  14. Rgg protein structure-function and inhibition by cyclic peptide compounds.

    Science.gov (United States)

    Parashar, Vijay; Aggarwal, Chaitanya; Federle, Michael J; Neiditch, Matthew B

    2015-04-21

    Peptide pheromone cell-cell signaling (quorum sensing) regulates the expression of diverse developmental phenotypes (including virulence) in Firmicutes, which includes common human pathogens, e.g., Streptococcus pyogenes and Streptococcus pneumoniae. Cytoplasmic transcription factors known as "Rgg proteins" are peptide pheromone receptors ubiquitous in Firmicutes. Here we present X-ray crystal structures of a Streptococcus Rgg protein alone and in complex with a tight-binding signaling antagonist, the cyclic undecapeptide cyclosporin A. To our knowledge, these represent the first Rgg protein X-ray crystal structures. Based on the results of extensive structure-function analysis, we reveal the peptide pheromone-binding site and the mechanism by which cyclosporin A inhibits activation of the peptide pheromone receptor. Guided by the Rgg-cyclosporin A complex structure, we predicted that the nonimmunosuppressive cyclosporin A analog valspodar would inhibit Rgg activation. Indeed, we found that, like cyclosporin A, valspodar inhibits peptide pheromone activation of conserved Rgg proteins in medically relevant Streptococcus species. Finally, the crystal structures presented here revealed that the Rgg protein DNA-binding domains are covalently linked across their dimerization interface by a disulfide bond formed by a highly conserved cysteine. The DNA-binding domain dimerization interface observed in our structures is essentially identical to the interfaces previously described for other members of the XRE DNA-binding domain family, but the presence of an intermolecular disulfide bond buried in this interface appears to be unique. We hypothesize that this disulfide bond may, under the right conditions, affect Rgg monomer-dimer equilibrium, stabilize Rgg conformation, or serve as a redox-sensitive switch.

  15. Cyclic Constraints on Conformational Flexibility in γ-PEPTIDES: Conformation-Specific IR and UV Spectroscopy

    Science.gov (United States)

    Walsh, Patrick S.; Kusaka, Ryoji; Zwier, Timothy S.; Fisher, Brian F.; Gellman, Samuel H.

    2013-06-01

    Spectroscopic studies of flexible peptides in the gas phase can provide insight to their inherent structural preferences in the absence of solvent. Recently, there has been increased attention paid to synthetic foldamers containing non-natural residues that can be specifically engineered to robustly form particular secondary structures. These engineered peptides have potential in therapeutic drug design because they are resistant to enzymatic degradation. Specifically, the Gellman group has synthesized a γ-peptide with a six membered cyclic constraint in the γ^{4}-γ^{3} position and an ethyl group at the γ^{2} position (γ_{ACHC}). The three stereocenters have a well-defined chirality [S,S,S]. These two features constrain the relative orientation of adjacent amide groups, thereby favoring a particular "pitch" to the turn. Solution phase results indicate that constrained γ-peptides induce the formation of a 14-helix. Ac-γ_{ACHC}-NHBz, its monohydrate and Ac-γ_{ACHC}-γ_{ACHC}-NHBz have been studied using ultraviolet (UV) and infrared (IR) double-resonance methods to obtain conformation-specific spectra under jet-cooled conditions in the gas phase. IR spectra in the hydride stretch (3300-3750 cm^{-1}), amide I/II and OH bend (1400-1800 cm^{-1}) were recorded and compared to predictions using density functional methods (DFT) and harmonic frequency calculations. We will compare the present results on constrained γ-peptides with corresponding results on unconstrained analogs. Data obtained for the monohydrated water cluster of Ac-γ_{ACHC}-NHBz will also be presented, including assignment of the water bend fundamental, which appears in the midst of transitions due to the amide II vibrations. L. Guo, W. Zhang, A. G. Reidenbach, M. W. Giuliano, I. A. Guzei, L. C. Spencer and S. H. Gellman Angew. Chem. Int. Ed. 2011, 50, 5843-5846

  16. Gamma scintigraphy of {sup 111}In-labelled branched chain polypeptides (BCP) with a poly(L-lysine) backbone in mice with mammary carcinoma. Effect of charge on biodistribution and tumour imaging potential

    Energy Technology Data Exchange (ETDEWEB)

    Pimm, M.V.; Gribben, S.J. [University of Nottingham (United Kingdom); Perkins, A.C.; Mezo, G.; Gaal, D.; Hudecz, F.

    1995-11-01

    Radiolabelled synthetic branched chain polypeptides (BCP) represent a new and novel range of materials with potential as radiopharmaceuticals. Preliminary imaging studies have been undertaken with {sup 111}In-labelled BCP in mice with subcutaneously transplanted mammary carcinoma. Four polypeptides each with a poly(L-lysine) backbone and side chains of DL-alanine residues were studied. These were AK, which is polycationic, EAK which is amphoteric, having additional glutamic acid residues at the end of the side chains, and AcEAK (anionic) and SucEAK (highly polyanionic) where the terminal glutamic acid amino groups were acetylated or succinylated respectively. Radiolabelling was achieved by previous conjugation with DTPA. Serial images up to 48 hours showed marked retention of {sup 111}In-labelled polycationic AK and polyanionic SucEAK in the liver and spleen, with renal uptake also being visible in the case of AK. {sup 111}In-labelled EAK and AcEAK showed longer blood survival with some liver uptake, but tumour uptake was also visualized by 24 hours with both of these polypeptides. These studies demonstrate the feasibility of using {sup 111}In-labelled synthetic branched chain polypeptides as radiopharmaceuticals for gamma scintigraphy and the visualization of tumours by modification of the side chain structure. These materials warrant further study. (author).

  17. Diminished oligomerization in the synthesis of new anti-angiogenic cyclic peptide using solution instead of solid-phase cyclization.

    Science.gov (United States)

    Rubio, Sandra; Clarhaut, Jonathan; Péraudeau, Elodie; Vincenzi, Marian; Soum, Claire; Rossi, Filomena; Guillon, Jean; Papot, Sébastien; Ronga, Luisa

    2016-05-01

    The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2. CBO-P23M was prepared using in solution cyclization, therefore reducing the peptide cyclodimerization occurred during solid-phase cyclization. The cyclic dimer of CBO-P23M, which was obtained as the main side product during synthesis of the corresponding monomer, was also isolated and investigated. Both peptides markedly reduce VEGF-A-induced phosphorylation of VEGFR-2 and Erk1/2. Moreover, they exhibit anti-angiogenic activity in an in vitro morphogenesis study. Therefore CBO-P23M and CBO-P23M dimer appear as attractive candidates for the development of novel angiogenesis inhibitors for the treatment of cancer and other angiogenesis-related diseases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 368-375, 2016.

  18. In vitro detection of mdr1 mRNA in murine leukemia cells with {sup 111}In-labeled oligonucleotide

    Energy Technology Data Exchange (ETDEWEB)

    Bai Jingming; Yokoyama, Kunihiko; Kinuya, Seigo; Michigishi, Takatoshi; Tonami, Norihisa [Kanazawa University Graduate School of Medical Sciences, Department of Biotracer Medicine (Nuclear Medicine), Kanazawa (Japan); Shiba, Kazuhiro [Kanazawa University, Radioisotope Center, Kanazawa (Japan); Matsushita, Ryo [Kanazawa University, Laboratory for Development of Medicine, Faculty of Pharmaceutical Sciences, Kanazawa (Japan); Nomura, Masaaki [Kanazawa University Hospital, Hospital Pharmacy, Kanazawa (Japan)

    2004-11-01

    The feasibility of intracellular mdr1 mRNA expression detection with radiolabeled antisense oligonucleotide (ODN) was investigated in the murine leukemia cell line, P388/S, and its subclonal, adriamycin-resistant cell line, P388/R. The expression level of mdr1 mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Existence of the multidrug resistance (MDR) phenomenon was assessed via cellular uptake of {sup 99m}Tc-sestamibi (MIBI), a known substrate for P-glycoprotein. A 15-mer phosphorothioate antisense ODN complementary to the sequences located at -1 to 14 of mdr1 mRNA and its corresponding sense ODN were conjugated with the cyclic anhydride of diethylene triamine penta-acetic acid (cDTPA) via an amino group linked to the terminal phosphate at the 5' end at pH 8-9. The DTPA-ODN complexes at concentrations of 0.1-17.4 {mu}Mwere reacted with {sup 111}InCl{sub 3} at pH 5 for 1 h. The hybridization affinity of labeled ODN was evaluated with size-exclusion high-performance liquid chromatography following incubation with the complementary sequence. Cellular uptake of labeled ODN was examined in vitro. Furthermore, enhancing effects of synthetic lipid carriers (Transfast) on transmembrane delivery of ODN were assessed. P388/R cells displayed intense mdr1 mRNA expression in comparison with P388/S cells. {sup 99m}Tc-MIBI uptake in P388/S cells was higher than that in P388/R cells. Specific radioactivity up to 1,634 MBq/nmol was achieved via elevation of added radioactivity relative to ODN molar amount. The hybridization affinity of antisense {sup 111}In-ODN was preserved at approximately 85% irrespective of specific activity. Cellular uptake of antisense {sup 111}In-ODN did not differ from that of sense {sup 111}In-ODN in either P388/S cells or P388/R cells. However, lipid carrier incorporation significantly increased transmembrane delivery of {sup 111}In-ODN; moreover, specific uptake of antisense {sup 111}In-ODN was demonstrated in P388/R

  19. Anti-Cyclic Citrullinated Peptide Antibody-Positive Meningoencephalitis in the Preclinical Period of Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Tomoya Shibahara

    2016-07-01

    Full Text Available Rheumatoid meningoencephalitis (RM is a rare complication of rheumatoid arthritis (RA. This report describes a 63-year-old man with complaints of high-grade fever, headache, and vomiting for several days before admission. Both his serum and cerebrospinal fluid were positive for anti-cyclic citrullinated peptide (CCP antibody and rheumatoid factor, and contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging (MRI showed abnormal gadolinium enhancement of the meninges and high-intensity lesions in the subarachnoid spaces. The patient was diagnosed with RM despite lack of signs suggesting RA. His symptoms drastically improved with intravenous infusion of high-dose methylprednisolone. Two months later, he developed RA. The findings in this patient suggest that RM could develop prior to the onset of RA. Anti-CCP antibody and MRI findings may be useful for the diagnosis of RM, regardless of RA history.

  20. Factors that restrict the intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE)

    DEFF Research Database (Denmark)

    Ouyang, Hui; Chen, Weiqing; Andersen, Thomas E;

    2009-01-01

    inactive or substantially less active than PSC-833 in increasing the P(B) values of these prodrugs. These data suggest that, while P-gp plays a role, other factors (e.g., substrate activity for other efflux transporters and/or for metabolic enzymes) may contribute to restricting the permeation of AOA......The objective of this study was to elucidate the role of P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, and OMCA-DADLE) of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). In the Caco-2 cell model, the high P......(app,BL-to-AP)/P(app,AP-to-BL) ratios of AOA-DADLE, CA-DADLE, and OMCA-DADLE (71-117) were significantly decreased by including known P-gp inhibitors, GF-12098, cyclosporine (CyA), or PSC-833, in the incubation media, suggesting that P-gp is restricting the AP-to-BL permeation of these cyclic prodrugs. In the in situ perfused rat...

  1. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis

    NARCIS (Netherlands)

    Kroot, EJJA; de Jong, BAW; van Leeuwen, MA; Swinkels, H; van den Hoogen, FHJ; van't Hof, M; van de Putte, LBA; van Rijswijk, MH; van Venrooij, WJ; van Riel, PLCM

    2000-01-01

    Objective. To study the predictive value of anti-cyclic citrullinated peptide antibody (anti-CCP) in patients with recent-onset rheumatoid arthritis (RA). Methods. Outcome in terms of physical disability (Health Assessment Questionnaire) and radiologic damage (modified Sharp method) over 3-year and

  2. Two cyclic peptides produced by the endophytic fungus # 2221 from Castaniopsisfissa on the south China sea coast

    Institute of Scientific and Technical Information of China (English)

    Wen Qing YIN; Jie Ming ZOU; Zhi Gang SHE; L. L. P. Vrijmoed; E. B. Gareth Jones; Yong Cheng LIN

    2005-01-01

    New cyclic peptides 1 and 2 were isolated from the endophytic fungus #2221 from Castaniopsisfissa on the south China sea coast. By 2D NMR methods and chiral HPLC technique,their structures were elucidated as cyclo (L-Val-L-Leu-L-Val-L-Leu) and cyclo(L-Leu-L-Ala-L-Leu-L-Ala), respectively.

  3. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides

    DEFF Research Database (Denmark)

    Pedersen, Line Merete Blak; Jacobsen, Søren; Klarlund, Mette;

    2006-01-01

    The aim of this study was to evaluate new and previously hypothesised non-genetic risk factors for serologic subtypes of rheumatoid arthritis (RA) defined by the presence or absence of auto-antibodies to cyclic citrullinated peptides (CCP). In a national case-control study, we included 515 patients...

  4. Profiling anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Tebo Anne E

    2012-08-01

    Full Text Available Abstract Background Anti-citrullinated protein/peptide antibodies (ACPA, have high specificity for rheumatoid arthritis (RA. Some children with juvenile idiopathic arthritis (JIA, phenotypically resemble RA and test positive for rheumatoid factor (RF a characteristic biomarker of RA. We investigated the prevalence of ACPA and its relationship to other serologic markers associated with RA in a well-characterized JIA cohort. Methods Cases were 334 children with JIA, 30 of whom had RF + polyarticular JIA. Sera from all cases and 50 healthy pediatric controls were investigated by ELISA at a single time point for anti-cyclic citrullinated peptide (anti-CCP IgG, RF IgM, IgA and IgG, anti-RA33 IgG, and antinuclear antibodies (ANA. Comparisons between cases and controls were made using Chi-square or Fisher exact tests and T-tests. Results The prevalence of RF was 8% among controls, and 12% among cases (ns. The prevalence of ACPA was 2% in controls and 14.3% in cases (OR 8.2, p Conclusions ACPAs are detectable in 14% of children with JIA. Children with positive ACPA but negative RF are frequent, and may define a distinct subset of children with JIA. ACPA testing should be included in the classification of JIA.

  5. Highly sensitive SERS analysis of the cyclic Arg-Gly-Asp peptide ligands of cells using nanogap antennas.

    Science.gov (United States)

    Portela, Alejandro; Yano, Taka-Aki; Santschi, Christian; Martin, Olivier J F; Tabata, Hitoshi; Hara, Masahiko

    2017-02-01

    The cyclic RGD (cRGD) peptide ligands of cells have become widely used for treating several cancers. We report a highly sensitive analysis of c(RGDfC) using surface enhanced Raman spectroscopy (SERS) using single dimer nanogap antennas in aqueous environment. Good agreement between characteristic peaks of the SERS and the Raman spectra of bulk c(RGDfC) with its peptide's constituents were observed. The exhibited blinking of the SERS spectra and synchronization of intensity fluctuations, suggest that the SERS spectra acquired from single dimer nanogap antennas was dominated by the spectrum of single to a few molecules. SERS spectra of c(RGDfC) could be used to detect at the nanoscale, the cells' transmembrane proteins binding to its ligand. SERS of cyclic RGD on nanogap antenna.

  6. Comparison of yttrium and indium complexes of DOTA-BA and DOTA-MBA: models for (90)Y- and (111)In-labeled DOTA-biomolecule conjugates.

    Science.gov (United States)

    Liu, Shuang; Pietryka, John; Ellars, Charles E; Edwards, D Scott

    2002-01-01

    Yttrium and indium complexes of 1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecylacetylbenzylamine (DOTA-BA) and 1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecylacetyl-R-(+)-alpha-methylbenzylamine (DOTA-MBA) were prepared in order to study solution structures of (90)Y- and (111)In-labeled DOTA-biomolecule conjugates. (90)Y and (111)In complexes M(L) (M = (90)Y and (111)In; L = DOTA-BA and DOTA-MBA) were prepared from the reaction of MCl(3) with DOTA-BA and DOTA-MBA, respectively, in ammonium acetate buffer. A reverse phase HPLC method revealed that both (90)Y and (111)In complexes show only one radiometric peak in their radio-HPLC chromatograms. It was also found that (111)In(DOTA-BA) and (111)In(DOTA-MBA) are more hydrophilic than their corresponding (90)Y analogues, suggesting different coordination spheres in (111)In and (90)Y complexes of the same DOTA conjugate. Complexes M(L) (M = Y and In; L = DOTA-BA and DOTA-MBA) were prepared and characterized by HPLC, LC-MS, and NMR ((1)H and (13)C) methods. The HPLC concordance experiments for (90)Y(DOTA-MBA)/Y(DOTA-MBA) and (111)In(DOTA-MBA)/In(DOTA-MBA) show that the same complex is prepared at both tracer and macroscopic levels. The NMR data ((1)H and (13)C) clearly demonstrates that Y(DOTA-BA) and Y(DOTA-MBA) exist in solution as one predominant isomer. VT NMR data ((1)H and (13)C) show that In(DOTA-BA) and In(DOTA-MBA) are fluxional at room temperature while Y(DOTA-BA) and Y(DOTA-MBA) become fluxional only at elevated temperatures. The fluxionality of these complexes is due to rapid rotation of acetate/acetamide chelating arms and inversion of ethylenic groups of the macrocyclic ring.

  7. Synthesis of linear and cyclic peptide-PEG-lipids for stabilization and targeting of cationic liposome-DNA complexes.

    Science.gov (United States)

    Ewert, Kai K; Kotamraju, Venkata Ramana; Majzoub, Ramsey N; Steffes, Victoria M; Wonder, Emily A; Teesalu, Tambet; Ruoslahti, Erkki; Safinya, Cyrus R

    2016-03-15

    Because nucleic acids (NAs) have immense potential value as therapeutics, the development of safe and effective synthetic NA vectors continues to attract much attention. In vivo applications of NA vectors require stabilized, nanometer-scale particles, but the commonly used approaches of steric stabilization with a polymer coat (e.g., PEGylation; PEG=poly(ethylene glycol)) interfere with attachment to cells, uptake, and endosomal escape. Conjugation of peptides to PEG-lipids can improve cell attachment and uptake for cationic liposome-DNA (CL-DNA) complexes. We present several synthetic approaches to peptide-PEG-lipids and discuss their merits and drawbacks. A lipid-PEG-amine building block served as the common key intermediate in all synthetic routes. Assembling the entire peptide-PEG-lipid by manual solid phase peptide synthesis (employing a lipid-PEG-carboxylic acid) allowed gram-scale synthesis but is mostly applicable to linear peptides connected via their N-terminus. Conjugation via thiol-maleimide or strain-promoted (copper-free) azide-alkyne cycloaddition chemistry is highly amenable to on-demand preparation of peptide-PEG-lipids, and the appropriate PEG-lipid precursors are available in a single chemical step from the lipid-PEG-amine building block. Azide-alkyne cycloaddition is especially suitable for disulfide-bridged peptides such as iRGD (cyclic CRGDKGPDC). Added at 10 mol% of a cationic/neutral lipid mixture, the peptide-PEG-lipids stabilize the size of CL-DNA complexes. They also affect cell attachment and uptake of nanoparticles in a peptide-dependent manner, thereby providing a platform for preparing stabilized, affinity-targeted CL-DNA nanoparticles.

  8. Exploring the dynamic behaviors and transport properties of gas molecules in a transmembrane cyclic peptide nanotube.

    Science.gov (United States)

    Li, Rui; Fan, Jianfen; Li, Hui; Yan, Xiliang; Yu, Yi

    2013-12-05

    The dynamic behaviors and transport properties of O2, CO2, and NH3 molecules through a transmembrane cyclic peptide nanotube (CPNT) of 8×cyclo-(WL)4/POPE have been investigated by steered molecular dynamics (SMD) simulations and adaptive biasing force (ABF) samplings. Different external forces are needed for three gas molecules to enter the channel. The periodic change of the pulling force curve for a gas traveling through the channel mainly arises from the regular and periodic arrangement of the composed CP subunits of the CPNT. Radial distribution functions (RDFs) between gas and water disclose the density decrease of channel water, which strongly aggravates the discontinuity of H-bond formation between a gas molecule and the neighboring water. Compared to hardly any H-bond formation between CO2 (or O2) and the framework of the CPNT, NH3 can form abundant H-bonds with the carbonyl/amide groups of the CPNT, leading to a fierce competition to NH3-water H-bonded interactions. In addition to direct H-bonded interactions, all three gases can form water bridges with the tube. The potential profile of mean force coincides with the occurring probability of a gas molecule along the tube axis. The energy barriers at two mouths of the CPNT elucidate the phenomenon that CO2 and O2 are thoroughly confined in the narrow lumen while NH3 can easily go outside the tube. Intermolecular interactions of each gas with channel water and the CPNT framework and the formation of H-bonds and water bridges illuminate the different gas translocation behaviors. The results uncover interesting and comprehensive mechanisms underlying the permeation characteristics of three gas molecules traveling through a transmembrane CPNT.

  9. Synthesis of a chiral amino acid with bicyclo[1.1.1]pentane moiety and its incorporation into linear and cyclic antimicrobial peptides.

    Science.gov (United States)

    Pritz, Stephan; Pätzel, Michael; Szeimies, Günter; Dathe, Margitta; Bienert, Michael

    2007-06-01

    The synthesis of the lipophilic chiral amino acid 1 bearing the bicyclo[1.1.1]pentane moiety is described. Linear and cyclic hexapeptides of the type Arg-Arg-Xaa-Yaa-Arg-Phe containing 1 instead of one or two tryptophan residues are prepared by solid phase peptide synthesis and the antimicrobial and hemolytic activity of the peptides obtained are discussed.

  10. Spectroscopic Identification of Cyclic Imide b2-Ions from Peptides Containing Gln and Asn Residues

    NARCIS (Netherlands)

    J. Grzetic; J. Oomens

    2013-01-01

    In mass-spectrometry based peptide sequencing, formation of b- and y-type fragments by cleavage of the amide C-N bond constitutes the main dissociation pathway of protonated peptides under low-energy collision induced dissociation (CID). The structure of the b (2) fragment ion from peptides containi

  11. Pharmacophore refinement of gpIIb/IIIa antagonists based on comparative studies of antiadhesive cyclic and acyclic RGD peptides

    Science.gov (United States)

    Müller, Gerhard; Gurrath, Marion; Kessler, Horst

    1994-12-01

    Structurally guided design approaches to low-molecular-weight platelet aggregation antagonists addressing the platelet-associated heterodimeric cell surface receptor gpIIb/IIIa rely on comparative studies of an ensemble of conformationally and biologically characterized compounds, since no high-resolution structure of the receptor system is available. We report a classical indirect and comparative pharmacophore refinement approach based on a series of small cyclic Arg-Gly-Asp (RGD) peptides as gpIIb/IIIa-fibrinogen interaction antagonists. These peptides have previously been investigated as potent and selective tumor cell adhesion inhibitors. The definition of geometrical descriptors classifying the RGD peptide conformations and their subsequent analysis over selected RGD- and RXD-containing protein structures allows for a correlation of distinct structural features for platelet aggregation inhibition. An almost parallel alignment of the Arg and Asp side chains was identified by a vector analysis as being present in all active cyclic hexa-and pentapeptides. This orientation is induced mainly by the constraint of backbone cyclization and is not of any covalent tripeptide-inherent origin, which was rationalized by a 500 ps high-energy MD simulation of a sequentially related linear model peptide. The incorporation of the recognition tripeptide Arg-Gly-Asp into the cyclic peptide templates acted as a filter mechanism, restricting the otherwise free torsional relation of both side chains to a parallel orientation. Based on the derived results, several detailed features of the receptor binding site could be deduced in terms of receptor complementarity. These findings should govern the design of next-generation compounds with enhanced activities. Furthermore, the complementary stereochemical characteristics of the substrate can be used as boundary conditions for pseudoreceptor modelling studies that are capable of reconstructing a hypothetical binding pocket

  12. RHEUMATOID FACTOR AND ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODIES IN PATIENTS WITH PSORIATIC ARTHRITIS

    Directory of Open Access Journals (Sweden)

    V. V. Badokin

    2011-01-01

    Full Text Available Objective: to define the clinical value of rheumatoid factor (RF and anti-cyclic citrullinated peptide antibodies (anti-CCP in early psori- atic arthritis (PA. Subjects and methods. Fifty-six patients (32 females and 24 males with early PA with a mean duration of 12±6.7 months were studied. The examinees' age ranged from 18 to 76 years (mean age 44±15.5 years. Mean psoriasis duration was 12.5±2.2 years. RF IgM was determined using a high-sensitive nephelometric method on a BN Pro-Spec analyzer (Siemens, Germany and serum anti-CCP concentra- tions were measured by immunochemiluminescence on a COBAS e411 analyzer (Roche, Switzerland. Group 1 included 10 patients with anti-CCP and/or RF (a study group; Group 2 comprised 46 patients without anti-CCP and RF (a control group. Results. There was anti-CCP in 7 (12.5% of the patients with early PA, RF in 8 (14.3%, both of them in 5 (9%. The study group had a severer course of PA accompanied by polyarthritis, inflamed distal interphalangeal joints, axial arthritis, dactylitis, enthesitis, and, in some cases spondylitis and sacroiliitis. In groups 1 and 2, the number of tender joints was 17.6±4 and 10±1.5, respectively (p = 0.04; that of swollen ones, 12.6±1.5 and 7.0±1.1 (p = 0.02; DAS28 index, 5.9±1.7 and 4.5±1.5 (p = 0.02; ESR, 34.5±5.9 and 22±2.3 (p = 0.04, high-sensitive C reactive protein, 70±25.3 and 24.9±5.0 (p = 0.06; and Sharp ratio, 68.7±14.3 and 21.3±3.8 (p < 0.004. Conclusion. In patients with early PA, anti-CCP and RF were encountered with an approximately equal frequency; at the same time, they were associated with polyarthritis, high disease activity, and an erosive process. 

  13. Synthesis of a highly hydrophobic cyclic decapeptide by solid-phase synthesis of linear peptide and cyclization in solution

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A general method was described to synthesize a highly hydrophobic cyclic peptide,cyclo[LWLWLWLWLQ]where underlines indicate D-configuration of the amino acid,by a two-step solid-phase/solution synthesis strategy.The linear decapeptide was assembled by standard Boc chemistry on solid-phase and subsequently cyclized in solution with high efficiency and reproducibility. In subsequent purification by semi-preparative HPLC,50%(v/v) DMF/H_2O was employed as the solvent to overcome the difficulty of solubilizat...

  14. Transmembrane delivery of anticancer drugs through self-assembly of cyclic peptide nanotubes

    Science.gov (United States)

    Chen, Jian; Zhang, Bei; Xia, Fei; Xie, Yunchang; Jiang, Sifan; Su, Rui; Lu, Yi; Wu, Wei

    2016-03-01

    Breaking the natural barriers of cell membranes achieves fast entry of therapeutics, which leads to enhanced efficacy and helps overcome multiple drug resistance. Herein, transmembrane delivery of a series of small molecule anticancer drugs was achieved by the construction of artificial transmembrane nanochannels formed by self-assembly of cyclic peptide (cyclo[Gln-(d-Leu-Trp)4-d-Leu], CP) nanotubes (CPNTs) in the lipid bilayers. Our in vitro study in liposomes indicated that the transport of molecules with sizes smaller than 1.0 nm, which is the internal diameter of the CPNTs, could be significantly enhanced by CPNTs in a size-selective and dose-dependent manner. Facilitated uptake of 5-fluorouracil (5-FU) was also confirmed in the BEL7402 cell line. On the contrary, CPs could facilitate neither the transport across liposomal membranes nor the uptake by cell lines of cytarabine, a counterevidence drug with a size of 1.1 nm. CPs had a very weak anticancer efficacy, but could significantly reduce the IC50 of 5-FU in BEL7402, HeLa and S180 cell lines. Analysis by a q test revealed that a combination of 5-FU and CP had a synergistic effect in BEL7402 at all CP levels, in S180 at CP levels higher than 64 μg mL-1, but not in HeLa, where an additive effect was observed. Temporarily, intratumoral injection is believed to be the best way for CP administration. In vivo imaging using 125I radio-labelled CP confirmed that CPNPTs were completely localized in the tumor tissues, and translocation to other tissues was negligible. In vivo anticancer efficacy was studied in the grafted S180 solid tumor model in mice, and the results indicated that tumor growth was greatly inhibited by the combinatory use of 5-FU and CP, and a synergistic effect was observed at CP doses of 0.25 mg per kg bw. It is concluded that facilitated transmembrane delivery of anticancer drugs with sizes smaller than 1.0 nm was achieved, and the synergistic anticancer effect was confirmed both in cell lines

  15. Brain-natriuretic peptide and cyclic guanosine monophosphate as biomarkers of myxomatous mitral valve disease in dogs

    DEFF Research Database (Denmark)

    Moesgaard, Sophia Gry; Falk, Bo Torkel; Teerlink, Tom;

    2011-01-01

    Elevations in the plasma concentrations of natriuretic peptides correlate with increased severity of myxomatous mitral valve disease (MMVD) in dogs. This study correlates the severity of MMVD with the plasma concentrations of the biomarkers N-terminal fragment of the pro-brain-natriuretic peptide...... (NT-proBNP) and its second messenger, cyclic guanosine monophosphate (cGMP). Furthermore, the l-arginine:asymmetric dimethylarginine (ADMA) ratio was measured as an index of nitric oxide availability. The study included 75 dogs sub-divided into five groups based on severity of MMVD as assessed...... by clinical examination and echocardiography. Plasma NT-proBNP and cGMP concentrations increased with increasing valve dysfunction and were significantly elevated in dogs with heart failure. The cGMP:NT-proBNP ratio decreased significantly in dogs with heart failure, suggesting the development of natriuretic...

  16. Evaluation of single amino acid chelate derivatives and regioselective radiolabelling of a cyclic peptide for the urokinase plasminogen activator receptor

    Energy Technology Data Exchange (ETDEWEB)

    Armstrong, Andrea F.; Lemon, Jennifer A. [McMaster Institute for Applied Radiation Sciences, McMaster University, ON, L8S 4M1 (Canada); Czorny, Shannon K. [McMaster Institute for Applied Radiation Sciences, McMaster University, ON, L8S 4M1 (Canada); Juravinski Cancer Centre, Hamilton, ON, L8V 5C2 (Canada); Singh, Gurmit [Juravinski Cancer Centre, Hamilton, ON, L8V 5C2 (Canada); Valliant, John F. [Department of Chemistry, McMaster University, Hamilton, ON, L8S 4M1 (Canada); Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, ON, L8S 4M1 (Canada)], E-mail: valliant@mcmaster.ca

    2009-11-15

    Introduction: The aim of this work was to investigate the relative radiolabelling kinetics and affinity of a series of ligands for the [{sup 99m}Tc(CO){sub 3}]{sup +} core, both in the absence and in the presence of competing donors. This information was used to select a suitable ligand for radiolabelling complex peptide-based targeting vectors in high yield under mild conditions. Methods: A series of {alpha}-N-Fmoc-protected lysine derivatives bearing two heterocyclic donor groups at the {epsilon}-amine (, 2-pyridyl; , quinolyl; , 6-methoxy-2-pyridyl; 1d, 2-thiazolyl; 1e, N-methylimidazolyl; , 3-pyridyl) were synthesized and labelled with {sup 99m}Tc. A resin-capture purification strategy for the separation of residual ligand from the radiolabelled product was also developed. The binding affinities of targeted peptides 4, 5a and 5b for uPAR were determined using flow cytometry. Results: Variable temperature radiolabelling reactions using - and [{sup 99m}Tc(CO){sub 3}]{sup +} revealed optimal kinetics and good selectivity for compounds and 1d; in the case of , 1d, and 1e, the labelling can be conducted at ambient temperature. The utility of this class of ligands was further demonstrated by the radiolabelling of a cyclic peptide that is known to target the serine protease receptor uPAR; essentially quantitative incorporation of {sup 99m}Tc occurred exclusively at the SAAC site, despite the presence of a His residue, and without disruption of the disulfide bond. Conclusion: A series of single amino acid chelate (SAAC) ligands have been evaluated for their ability to incorporate {sup 99m}Tc into peptides. The lead agent to emerge from this work is the thiazole SAAC derivative 1d which has demonstrated the ability to regioselectively label the widest range of peptides.

  17. The biosynthesis of Caryophyllaceae-like cyclic peptides in Saponaria vaccaria L. from DNA-encoded precursors.

    Science.gov (United States)

    Condie, Janet A; Nowak, Goska; Reed, Darwin W; Balsevich, J John; Reaney, Martin J T; Arnison, Paul G; Covello, Patrick S

    2011-08-01

    Cyclic peptides (CPs) are produced in a very wide range of taxa. Their biosynthesis generally involves either non-ribosomal peptide synthases or ribosome-dependent production of precursor peptides. Plants within the Caryophyllaceae and certain other families produce CPs which generally consist of 5-9 proteinogenic amino acids. The biological roles for these CPs in the plant are not very clear, but many of them have activity in mammalian systems. There is currently very little known about the biosynthesis of CPs in the Caryophyllaceae. A collection of expressed sequence tags from developing seeds of Saponaria vaccaria was investigated for information about CP biosynthesis. This revealed genes that appeared to encode CP precursors which are subsequently cyclized to mature CPs. This was tested and confirmed by the expression of a cDNA encoding a putative precursor of the CP segetalin A in transformed S. vaccaria roots. Similarly, extracts of developing S. vaccaria seeds were shown to catalyze the production of segetalin A from the same putative (synthetic) precursor. Moreover, the presence in S. vaccaria seeds of two segetalins, J [cyclo(FGTHGLPAP)] and K [cyclo(GRVKA)], which was predicted by sequence analysis, was confirmed by liquid chromatography/mass spectrometry. Sequence analysis also predicts the presence of similar CP precursor genes in Dianthus caryophyllus and Citrus spp. The data support the ribosome-dependent biosynthesis of Caryophyllaceae-like CPs in the Caryophyllaceae and Rutaceae.

  18. Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability.

    Science.gov (United States)

    Laksitorini, Marlyn D; Kiptoo, Paul K; On, Ngoc H; Thliveris, James A; Miller, Donald W; Siahaan, Teruna J

    2015-03-01

    It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood-brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., (14) C-mannitol, gadolinium-diethylenetriaminepentacetate (Gd-DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin-Darby canine kidney cell monolayers in a concentration-dependent manner (IC50 = 0.3 mM) with a maximal response at 0.4 mM. Under the current experimental conditions, ADTC5 improved the delivery of (14) C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain.

  19. Cyclic RGD peptide incorporation on phage major coat proteins for improved internalization by HeLa cells.

    Science.gov (United States)

    Choi, Dong Shin; Jin, Hyo-Eon; Yoo, So Young; Lee, Seung-Wuk

    2014-02-19

    Delivering therapeutic materials or imaging reagents into specific tumor tissues is critically important for development of novel cancer therapeutics and diagnostics. Genetically engineered phages possess promising structural features to develop cancer therapeutic materials. For cancer targeting purposes, we developed a novel engineered phage that expressed cyclic RGD (cRGD) peptides on the pVIII major coat protein using recombinant DNA technology. Using a type 88 phage engineering approach, which inserts a new gene to express additional major coat protein in the noncoding region of the phage genome, we incorporated an additional pVIII major coat protein with relatively bulky cRGD and assembled heterogeneous major coat proteins on the F88.4 phage surfaces. With IPTG control, we could tune different numbers of cRGD peptide displayed on the phage particles up to 140 copies. The resulting phage with cRGD on the recombinant pVIII protein exhibited enhanced internalization efficiency into HeLa cells in a ligand density and conformational structure dependent manner when comparing with the M13 phages modified with either linear RGD on pVIII or cRGD on pIII. Our cRGD peptide engineered phage could be useful for cancer therapy or diagnostic purposes after further modifying the phage with drug molecules or contrast reagents in the future.

  20. Radiolabelled peptides for oncological diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Laverman, Peter; Boerman, Otto C.; Oyen, Wim J.G. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands); Sosabowski, Jane K. [Queen Mary University of London, Centre for Molecular Oncology, Barts Cancer Institute, London (United Kingdom)

    2012-02-15

    Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The {sup 111}In-labelled somatostatin analogue octreotide (OctreoScan trademark) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours. (orig.)

  1. Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain.

    Science.gov (United States)

    Alaofi, Ahmed; On, Ngoc; Kiptoo, Paul; Williams, Todd D; Miller, Donald W; Siahaan, Teruna J

    2016-02-01

    The aim of this study is to evaluate the effect of peptide cyclization on the blood-brain barrier (BBB) modulatory activity and plasma stability of His-Ala-Val peptides, which are derived from the extracellular 1 domain of human E-cadherin. The activities to modulate the intercellular junctions by linear HAV4 (Ac-SHAVAS-NH2), cyclic cHAVc1 (Cyclo(1,8)Ac-CSHAVASC-NH2), and cyclic cHAVc3 (Cyclo(1,6)Ac-CSHAVC-NH2) were compared in in vitro and in vivo BBB models. Linear HAV4 and cyclic cHAVc1 have the same junction modulatory activities as assessed by in vitro MDCK monolayer model and in situ rat brain perfusion model. In contrast, cyclic cHAVc3 was more effective than linear HAV4 in modulating MDCK cell monolayers and in improving in vivo brain delivery of Gd-DTPA on i.v. administration in Balb/c mice. Cyclic cHAVc3 (t1/2 = 12.95 h) has better plasma stability compared with linear HAV4 (t1/2 = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2-4 h) compared with HAV4 (<1 h). Both HAV4 and cHAVc3 peptides also enhanced the in vivo brain delivery of IRdye800cw-PEG (25 kDa) as detected by near IR imaging. The result showed that cyclic cHAVc3 peptide had better activity and plasma stability than linear HAV4 peptide.

  2. A cyclic undecamer peptide mimics a turn in folded Alzheimer amyloid β and elicits antibodies against oligomeric and fibrillar amyloid and plaques.

    Directory of Open Access Journals (Sweden)

    Peter Hoogerhout

    Full Text Available The 39- to 42-residue amyloid β (Aβ peptide is deposited in extracellular fibrillar plaques in the brain of patients suffering from Alzheimer's Disease (AD. Vaccination with these peptides seems to be a promising approach to reduce the plaque load but results in a dominant antibody response directed against the N-terminus. Antibodies against the N-terminus will capture Aβ immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded Aβ, which might have a physiologically relevant function. Therefore, we have targeted an immune response on a conformational neo-epitope in misfolded amyloid that is formed in advance of Aβ-aggregation. A tetanus toxoid-conjugate of the 11-meric cyclic peptide Aβ(22-28-YNGK' elicited specific antibodies in Balb/c mice. These antibodies bound strongly to the homologous cyclic peptide-bovine serum albumin conjugate, but not to the homologous linear peptide-conjugate, as detected in vitro by enzyme-linked immunosorbent assay. The antibodies also bound--although more weakly--to Aβ(1-42 oligomers as well as fibrils in this assay. Finally, the antibodies recognized Aβ deposits in AD mouse and human brain tissue as established by immunohistological staining. We propose that the cyclic peptide conjugate might provide a lead towards a vaccine that could be administered before the onset of AD symptoms. Further investigation of this hypothesis requires immunization of transgenic AD model mice.

  3. Synthesis and Antibody Recognition of Cyclic Epitope Peptides, Together with Their Dimer and Conjugated Derivatives Based on Residues 9-22 of Herpes Simplex Virus Type 1 Glycoprotein D

    NARCIS (Netherlands)

    Jakab, Annamaria; Schlosser, Gitta; Feijlbrief, Matty; Welling-Wester, Sytske; Manea, Marilena; Vila-Perello, Miquel; Andreu, David; Ferenc Hudecz, [No Value; Mezo, Gabor

    2009-01-01

    The synthesis of new cyclic peptides comprising the 9-22 epitope (9)LKMADPNRFRGKDL(22) sequence derived from HSV gD-1 is reported. In addition, we describe procedures for the preparation of cyclic peptide dimers and conjugates with an oligotuftsin derivative carrier. The binding of a monoclonal anti

  4. Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors.

    Science.gov (United States)

    Gerona-Navarro, Guillermo; Yoel-Rodríguez; Mujtaba, Shiraz; Frasca, Antonio; Patel, Jigneshkumar; Zeng, Lei; Plotnikov, Alexander N; Osman, Roman; Zhou, Ming-Ming

    2011-02-23

    The CREB binding protein (CBP) is a human transcriptional coactivator consisting of several conserved functional modules, which interacts with distinct transcription factors including nuclear receptors, CREB, and STAT proteins. Despite the importance of CBP in transcriptional regulation, many questions regarding the role of its particular domains in CBP functions remain unanswered. Therefore, developing small molecules capable of selectively modulating a single domain of CBP is of invaluable aid at unraveling its prominent activities. Here we report the design, synthesis, and biological evaluation of conformationally restricted peptides as novel modulators for the acetyl-lysine binding bromodomain (BRD) of CBP. Utilizing a target structure-guided and computer-aided rational design approach, we developed a series of cyclic peptides with affinity for CBP BRD significantly greater than those of its biological ligands, including lysine-acetylated histones and tumor suppressor p53. The best cyclopeptide of the series exhibited a K(d) of 8.0 μM, representing a 24-fold improvement in affinity over that of the linear lysine 382-acetylated p53 peptide. This lead peptide is highly selective for CBP BRD over BRDs from other transcriptional proteins. Cell-based functional assays carried out in colorectal carcinoma HCT116 cells further demonstrated the efficacy of this compound to modulate p53 stability and function in response to DNA damage. Our results strongly argue that these CBP modulators can effectively inhibit p53 transcriptional activity by blocking p53K382ac binding to CBP BRD and promoting p53 instability by changes of its post-translational modification states, a different mechanism than that of the p53 inhibitors reported to date.

  5. Cross-reactive binding of cyclic peptides to an anti-TGFalpha antibody Fab fragment: an X-ray structural and thermodynamic analysis.

    Science.gov (United States)

    Hahn, M; Winkler, D; Welfle, K; Misselwitz, R; Welfle, H; Wessner, H; Zahn, G; Scholz, C; Seifert, M; Harkins, R; Schneider-Mergener, J; Höhne, W

    2001-11-23

    The monoclonal antibody tAb2 binds the N-terminal sequence of transforming growth factor alpha, VVSHFND. With the help of combinatorial peptide libraries it is possible to find homologous peptides that bind tAb2 with an affinity similar to that of the epitope. The conformational flexibility of short peptides can be constrained by cyclization in order to improve their affinity to the antibody and their stability towards proteolysis. Two cyclic peptides which are cross-reactive binders for tAb2 were selected earlier using combinatorial peptide libraries. One is cyclized by an amide bond between the N-alpha group and the side-chain of the last residue (cyclo-SHFNEYE), and the other by a disulfide bridge (cyclo-CSHFNDYC). The complex structures of tAb2 with the linear epitope peptide VVSHFND and with cyclo-SHFNEYE were determined by X-ray diffraction. Both peptides show a similar conformation and binding pattern in the complex. The linear peptide SHFNEYE does not bind tAb2, but cyclo-SHFNEYE is stabilized in a loop conformation suitable for binding. Hence the cyclization counteracts the exchange of aspartate in the epitope sequence to glutamate. Isothermal titration calorimetry was used to characterize the binding energetics of tAb2 with the two cyclic peptides and the epitope peptide. The binding reactions are enthalpically driven with an unfavorable entropic contribution under all measured conditions. The association reactions are characterized by negative DeltaC(p) changes and by the uptake of one proton per binding site. A putative candidate for proton uptake during binding is the histidine residue in each of the peptides. Hydrogen bonds and the putative formation of an electrostatic pair between the protonated histidine and a carboxy group may contribute markedly to the favorable enthalpy of complex formation. Implications to cyclization of peptides for stabilization are discussed.

  6. A Cell-Based Approach for the Biosynthesis/Screening of Cyclic Peptide Libraries against Bacterial Toxins

    Energy Technology Data Exchange (ETDEWEB)

    Camarero, J A; Kimura, R; Woo, Y; Cantor, J; Steenblock, E

    2007-10-24

    Available methods for developing and screening small drug-like molecules able to knockout toxins or pathogenic microorganisms have some limitations. In order to be useful, these new methods must provide high-throughput analysis and identify specific binders in a short period of time. To meet this need, we are developing an approach that uses living cells to generate libraries of small biomolecules, which are then screened inside the cell for activity. Our group is using this new, combined approach to find highly specific ligands capable of disabling anthrax Lethal Factor (LF) as proof of principle. Key to our approach is the development of a method for the biosynthesis of libraries of cyclic peptides, and an efficient screening process that can be carried out inside the cell.

  7. Co-assembly of cyclic peptide nanotubes and block copolymers in thin films: controlling the kinetic pathway

    Science.gov (United States)

    Zhang, Chen; Xu, Ting

    2015-09-01

    Directed co-assembly of polymer-conjugated cyclic peptide nanotubes (CPNs) and block copolymers in thin films is a viable approach to fabricate sub-nanometer porous membranes without synthesizing nanotubes with identical length and vertical alignment. Here we show that the process is pathway dependent and successful co-assembly requires eliminating CPNs larger than 100 nm in solution. Optimizing polymer-solvent interactions can improve conjugate dispersion to a certain extent, but this limits thin film fabrication. Introduction of a trace amount of hydrogen-bond blockers, such as trifluoroacetic acid by vapor absorption, is more effective to reduce CPN aggregation in solution and circumvents issues of solvent immiscibility. This study provides critical insights into guided assemblies within nanoscopic frameworks toward sub-nanometer porous membranes.Directed co-assembly of polymer-conjugated cyclic peptide nanotubes (CPNs) and block copolymers in thin films is a viable approach to fabricate sub-nanometer porous membranes without synthesizing nanotubes with identical length and vertical alignment. Here we show that the process is pathway dependent and successful co-assembly requires eliminating CPNs larger than 100 nm in solution. Optimizing polymer-solvent interactions can improve conjugate dispersion to a certain extent, but this limits thin film fabrication. Introduction of a trace amount of hydrogen-bond blockers, such as trifluoroacetic acid by vapor absorption, is more effective to reduce CPN aggregation in solution and circumvents issues of solvent immiscibility. This study provides critical insights into guided assemblies within nanoscopic frameworks toward sub-nanometer porous membranes. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03915k

  8. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis

    NARCIS (Netherlands)

    Berglin, E.; Padyukov, L.; Sundin, U.; Hallmans, G.; Stenlund, H.; Venrooij, W.J.W. van; Klareskog, L.; Dahlqvist, S.R.

    2004-01-01

    Antibodies against cyclic citrullinated peptide (CCP) and rheumatoid factors (RFs) have been demonstrated to predate the onset of rheumatoid arthritis ( RA) by years. A nested case control study was performed within the Northern Sweden Health and Disease study cohort to analyse the presence of share

  9. Peptide-22 and Cyclic RGD Functionalized Liposomes for Glioma Targeting Drug Delivery Overcoming BBB and BBTB.

    Science.gov (United States)

    Chen, Cuitian; Duan, Ziqing; Yuan, Yan; Li, Ruixiang; Pang, Liang; Liang, Jianming; Xu, Xinchun; Wang, Jianxin

    2017-02-22

    Chemotherapy outcomes for the treatment of glioma remain unsatisfied due to the inefficient drug transport across BBB/BBTB and poor drug accumulation in the tumor site. Nanocarriers functionalized with different targeting ligands are considered as one of the most promising alternatives. However, few studies were reported to compare the targeting efficiency of the ligands and develop nanoparticles to realize BBB/BBTB crossing and brain tumor targeting simultaneously. In this study, six peptide-based ligands (Angiopep-2, T7, Peptide-22, c(RGDfK), D-SP5 and Pep-1), widely used for brain delivery, were selected to decorate liposomes, respectively, so as to compare their targeting ability to BBB or BBTB. Based on the in vitro cellular uptake results on BCECs and HUVECs, Peptide-22 and c(RGDfK) were picked to construct a BBB/BBTB dual-crossing, glioma-targeting liposomal drug delivery system c(RGDfK)/Pep-22-DOX-LP. In vitro cellular uptake demonstrated that the synergetic effect of c(RGDfK) and Peptide-22 could significantly increase the internalization of liposomes on U87 cells. In vivo imaging further verified that c(RGDfK)/Pep-22-LP exhibited higher brain tumor distribution than single ligand modified liposomes. The median survival time of glioma-bearing mice treated with c(RGDfK)/Pep-22-DOX-LP (39.5 days) was significantly prolonged than those treated with free doxorubicin or other controls. In conclusion, the c(RGDfK) and Peptide-22 dual-modified liposome was constructed based on the targeting ability screening of various ligands. The system could effectively overcome BBB/BBTB barriers, target to tumor cells and inhibit the growth of glioma, which proved its potential for improving the efficacy of chemotherapeutics for glioma therapy.

  10. Sulfonation of Tyrosine as a Method to Improve Biodistribution of Peptide-Based Radiotracers: Novel (18)F-Labelled Cyclic RGD Analogues.

    Science.gov (United States)

    Haskali, Mohammad Baqir; Denoyer, Delphine; Noonan, Wayne; Cullinane, Carleen; Rangger, Christine; Pouliot, Normand; Haubner, Roland; Roselt, Peter D; Hicks, Rodney J; Hutton, Craig A

    2017-02-13

    The labeling of peptides with positron emitting radionuclides has long held the promise of a wide range of PET agents possessing high affinity and selectivity. Not surprisingly, controlling the biodistribution of these agents has proven to be a major challenge in their successful application. Modification of peptide hydrophilicity in order to increase renal clearance has been a common endeavor to improve overall biodistribution. Herein, we examine the effect of site-specific sulfonation of tyrosine moieties in cyclic(RGDyK) peptides as a means to enhance their hydrophilicity and improve their biodistribution. The novel sulfonated cyclic(RGDyK) peptides were conjugated directly to 4-nitrophenyl 2-[18F]fluoropropionate and the biodistribution of the radiolabeled peptides was compared with that of their non-sulfonated, clinically relevant counterparts, [18F]GalactoRGD and [18F]FPPRGD2. Site-specific sulfonation of the tyrosine residues was shown to increase hydrophilicity and improve biodistribution of the RGD peptides, despite contributing just 79 Da towards the MW, compared with 189 Da for both the 'Galacto' and mini-PEG moieties, suggesting this may be a broadly applicable approach to enhancing biodistribution of radiolabelled peptides.

  11. REVIEW: Role of cyclic AMP signaling in the production and function of the incretin hormone glucagon-like peptide-1

    Science.gov (United States)

    Yu, Zhiwen; Jin, Tianru

    2008-01-01

    Pancreatic cells express the proglucagon gene (gcg) and thereby produce the peptide hormone glucagon, which stimulates hepatic glucose production and thereby increases blood glucose levels. The same gcg gene is also expressed in the intestinal endocrine L cells and certain neural cells in the brain. In the gut, gcg expression leads to the production of glucagon-like peptide-1 (GLP-1). This incretin hormone stimulates insulin secretion when blood glucose level is high. In addition, GLP-1 stimulates pancreatic cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. Today, a long-term effective GLP-1 receptor agonist has been developed as a drug in treating diabetes and potentially other metabolic disorders. Extensive investigations have shown that the expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP signaling, and the crosstalk between PKA and Wnt signaling pathway, are also involved in cAMP-stimulated gcg expression and GLP-1 production. Furthermore, functions of GLP-1 in pancreatic cells are mainly mediated by cAMP-PKA, cAMP-Epac and Wnt signaling pathways as well.

  12. Molecular determinants and interaction data of cyclic peptide inhibitor with the extracellular domain of TrkB receptor

    Directory of Open Access Journals (Sweden)

    Nitin Chitranshi

    2016-03-01

    Full Text Available TrkB is a high affinity receptor for the brain derived neurotrophic factor (BDNF and its phosphorylation stimulates activation of several intracellular signalling pathways linked to cellular growth, differentiation and maintenance. Identification of various activators and inhibitors of the TrkB receptor and greater understanding their binding mechanisms is critical to elucidate the biochemical and pharmacological pathways and analyse various protein crystallization studies. The data presented here is related to the research article entitled “Brain Derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3β (GSK3β signalling” [1]. Cyclotraxin B (CTXB is a disulphide bridge linked cyclic peptide molecule that interacts with TrkB receptor and inhibits the BDNF/TrkB downstream signalling. This article reports for the first time binding mechanism and interaction parameters of CTXB with the TrkB receptor. The molecular model of CTXB has been generated and it’s docking with TrkB domain carried out to determine the critical residues involved in the protein peptide interaction.

  13. Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis.

    Science.gov (United States)

    Thell, Kathrin; Hellinger, Roland; Sahin, Emine; Michenthaler, Paul; Gold-Binder, Markus; Haider, Thomas; Kuttke, Mario; Liutkevičiūtė, Zita; Göransson, Ulf; Gründemann, Carsten; Schabbauer, Gernot; Gruber, Christian W

    2016-04-12

    Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by auto-reactive T cells that induce demyelination and neuronal degradation. Treatment options are still limited and several MS medications need to be administered by parenteral application but are modestly effective. Oral active drugs such as fingolimod have been weighed down by safety concerns. Consequently, there is a demand for novel, especially orally active therapeutics. Nature offers an abundance of compounds for drug discovery. Recently, the circular plant peptide kalata B1 was shown to silence T-cell proliferation in vitro in an IL-2-dependent mechanism. Owing to this promising effect, we aimed to determine in vivo activity of the cyclotide [T20K]kalata B1 using the MS mouse model experimental autoimmune encephalomyelitis (EAE). Treatment of mice with the cyclotide resulted in a significant delay and diminished symptoms of EAE by oral administration. Cyclotide application substantially impeded disease progression and did not exhibit adverse effects. Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs. Considering their stable structural topology and oral activity, cyclotides are candidates as peptide therapeutics for pharmaceutical drug development for treatment of T-cell-mediated disorders.

  14. The Cyclic Antibacterial Peptide Enterocin AS-48: Isolation, Mode of Action, and Possible Food Applications

    Directory of Open Access Journals (Sweden)

    María José Grande Burgos

    2014-12-01

    Full Text Available Enterocin AS-48 is a circular bacteriocin produced by Enterococcus. It contains a 70 amino acid-residue chain circularized by a head-to-tail peptide bond. The conformation of enterocin AS-48 is arranged into five alpha-helices with a compact globular structure. Enterocin AS-48 has a wide inhibitory spectrum on Gram-positive bacteria. Sensitivity of Gram-negative bacteria increases in combination with outer-membrane permeabilizing treatments. Eukaryotic cells are bacteriocin-resistant. This cationic peptide inserts into bacterial membranes and causes membrane permeabilization, leading ultimately to cell death. Microarray analysis revealed sets of up-regulated and down-regulated genes in Bacillus cereus cells treated with sublethal bacteriocin concentration. Enterocin AS-48 can be purified in two steps or prepared as lyophilized powder from cultures in whey-based substrates. The potential applications of enterocin AS-48 as a food biopreservative have been corroborated against foodborne pathogens and/or toxigenic bacteria (Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus, Escherichia coli, Salmonella enterica and spoilage bacteria (Alicyclobacillus acidoterrestris, Bacillus spp., Paenibacillus spp., Geobacillus stearothermophilus, Brochothrix thermosphacta, Staphylococcus carnosus, Lactobacillus sakei and other spoilage lactic acid bacteria. The efficacy of enterocin AS-48 in food systems increases greatly in combination with chemical preservatives, essential oils, phenolic compounds, and physico-chemical treatments such as sublethal heat, high-intensity pulsed-electric fields or high hydrostatic pressure.

  15. The Cyclic Antibacterial Peptide Enterocin AS-48: Isolation, Mode of Action, and Possible Food Applications

    Science.gov (United States)

    Grande Burgos, María José; Pérez Pulido, Rubén; López Aguayo, María del Carmen; Gálvez, Antonio; Lucas, Rosario

    2014-01-01

    Enterocin AS-48 is a circular bacteriocin produced by Enterococcus. It contains a 70 amino acid-residue chain circularized by a head-to-tail peptide bond. The conformation of enterocin AS-48 is arranged into five alpha-helices with a compact globular structure. Enterocin AS-48 has a wide inhibitory spectrum on Gram-positive bacteria. Sensitivity of Gram-negative bacteria increases in combination with outer-membrane permeabilizing treatments. Eukaryotic cells are bacteriocin-resistant. This cationic peptide inserts into bacterial membranes and causes membrane permeabilization, leading ultimately to cell death. Microarray analysis revealed sets of up-regulated and down-regulated genes in Bacillus cereus cells treated with sublethal bacteriocin concentration. Enterocin AS-48 can be purified in two steps or prepared as lyophilized powder from cultures in whey-based substrates. The potential applications of enterocin AS-48 as a food biopreservative have been corroborated against foodborne pathogens and/or toxigenic bacteria (Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus, Escherichia coli, Salmonella enterica) and spoilage bacteria (Alicyclobacillus acidoterrestris, Bacillus spp., Paenibacillus spp., Geobacillus stearothermophilus, Brochothrix thermosphacta, Staphylococcus carnosus, Lactobacillus sakei and other spoilage lactic acid bacteria). The efficacy of enterocin AS-48 in food systems increases greatly in combination with chemical preservatives, essential oils, phenolic compounds, and physico-chemical treatments such as sublethal heat, high-intensity pulsed-electric fields or high hydrostatic pressure. PMID:25493478

  16. Dynamic PET and Optical Imaging and Compartment Modeling using a Dual-labeled Cyclic RGD Peptide Probe

    Directory of Open Access Journals (Sweden)

    Lei Zhu, Ning Guo, Quanzheng Li, Ying Ma, Orit Jacboson, Seulki Lee, Hak Soo Choi, James R. Mansfield, Gang Niu, Xiaoyuan Chen

    2012-01-01

    Full Text Available Purpose: The aim of this study is to determine if dynamic optical imaging could provide comparable kinetic parameters to that of dynamic PET imaging by a near-infrared dye/64Cu dual-labeled cyclic RGD peptide.Methods: The integrin αvβ3 binding RGD peptide was conjugated with a macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA for copper labeling and PET imaging and a near-infrared dye ZW-1 for optical imaging. The in vitro biological activity of RGD-C(DOTA-ZW-1 was characterized by cell staining and receptor binding assay. Sixty-min dynamic PET and optical imaging were acquired on a MDA-MB-435 tumor model. Singular value decomposition (SVD method was applied to compute the dynamic optical signal from the two-dimensional optical projection images. Compartment models were used to quantitatively analyze and compare the dynamic optical and PET data.Results: The dual-labeled probe 64Cu-RGD-C(DOTA-ZW-1 showed integrin specific binding in vitro and in vivo. The binding potential (Bp derived from dynamic optical imaging (1.762 ± 0.020 is comparable to that from dynamic PET (1.752 ± 0.026.Conclusion: The signal un-mixing process using SVD improved the accuracy of kinetic modeling of 2D dynamic optical data. Our results demonstrate that 2D dynamic optical imaging with SVD analysis could achieve comparable quantitative results as dynamic PET imaging in preclinical xenograft models.

  17. Blocking TNF-α by combination of TNF-α- and TNFR-binding cyclic peptide ameliorates the severity of TNBS-induced colitis in rats.

    Science.gov (United States)

    Yin, Bingjiao; Hu, Xin; Wang, Jing; Liang, Huifang; Li, Xiaoyan; Niu, Nin; Li, Baihua; Jiang, Xiaodan; Li, Zhuoya

    2011-04-10

    Tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of Crohn's disease. TNF antagonists are effectively used to treat these patients, although the efficiency of different antagonists varies. In the present study we combined TNF-α binding cyclic peptide (TBCP) and TNFR1 binding cyclic peptide (TRBCP) to treat TNBS-induced colitis in rats for one week. The symptoms of colitis including bloody diarrhea, rectal prolapse, and a profound and sustained weight loss were significantly ameliorated and the colon inflammatory damage, both macroscopic and histological scores, MPO activity, and NO production were markedly decreased in rats by neutralization of TNF-α and blocking TNFR1, as compared with those in rats treated with irrelevant peptide or normal saline (Prats treated with both TBCP and TRBCP were also down-regulated (Prats treated with irrelevant peptide or normal saline. These findings suggest that the combination of TNF-α- and TNFR1-binding peptide effectively improves the symptoms of TNBS-induced colitis and alleviates colonic pathological damages in rats. This combination may be a potent candidate for clinical treatment of the inflammatory bowel disease.

  18. Anti-cyclic Citrullinated Peptide Antibody (Anti-CCP and Diagnostic Value for Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Mehmet Agilli

    2014-02-01

    Full Text Available Rheumatoid arthritis (RA is an inflammatory multisystem disease of unknown etiology characterized by chronic destructive synovitis. It and #8217;s prevalence is about 1% all over the world. Serologic markers are also important beside some clinical situations upon RA diagnosis. Today, the most commonly used laboratory test is rheumatoid factor (RF in patients with suspected RA. RF is sensitive but not a specific biomarker for diagnosing RA. Early diagnosis of RA is essential to prevent of progressive joint damage. In recent years, anticyclic citrullinated peptide/protein antibody (anti-CCP attracts the attention as a remarkable biomarker for early diagnosis. Anti-CCP which is a family of anti-citrullinated protein antibodies (ACPA family, showed quite satisfactory specificity in the diagnosis of RA. Due to the prescence of ACPA was included to 2010 RA diagnostic criteria, in a manner of speaking, importance of anti-CCP was registered. [TAF Prev Med Bull 2014; 13(1.000: 83-88

  19. Marine sponge cyclic peptide theonellamide A disrupts lipid bilayer integrity without forming distinct membrane pores.

    Science.gov (United States)

    Espiritu, Rafael Atillo; Cornelio, Kimberly; Kinoshita, Masanao; Matsumori, Nobuaki; Murata, Michio; Nishimura, Shinichi; Kakeya, Hideaki; Yoshida, Minoru; Matsunaga, Shigeki

    2016-06-01

    Theonellamides (TNMs) are antifungal and cytotoxic bicyclic dodecapeptides derived from the marine sponge Theonella sp. These peptides specifically bind to 3β-hydroxysterols, resulting in 1,3-β-D-glucan overproduction and membrane damage in yeasts. The inclusion of cholesterol or ergosterol in phosphatidylcholine membranes significantly enhanced the membrane affinity of theonellamide A (TNM-A) because of its direct interaction with 3β-hydroxyl groups of sterols. To better understand TNM-induced membrane alterations, we investigated the effects of TNM-A on liposome morphology. (31)P nuclear magnetic resonance (NMR) and dynamic light scattering (DLS) measurements revealed that the premixing of TNM-A with lipids induced smaller vesicle formation. When giant unilamellar vesicles were incubated with exogenously added TNM-A, confocal micrographs showed dynamic changes in membrane morphology, which were more frequently observed in cholesterol-containing than sterol-free liposomes. In conjunction with our previous data, these results suggest that the membrane action of TNM-A proceeds in two steps: 1) TNM-A binds to the membrane surface through direct interaction with sterols and 2) accumulated TNM-A modifies the local membrane curvature in a concentration-dependent manner, resulting in dramatic membrane morphological changes and membrane disruption.

  20. Circulating anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis and chronic obstructive pulmonary disease.

    Science.gov (United States)

    Yang, Deng-Ho; Tu, Chuan-Chou; Wang, Shou-Cheng; Wei, Cheng-Chung; Cheng, Ya-Wen

    2014-07-01

    Anti-cyclic citrullinated peptide (anti-CCP) antibody is highly specific for diagnosing rheumatoid arthritis (RA). Cigarette smoking is a lifestyle and environmental factor associated with anti-CCP production and is strongly associated with chronic obstructive pulmonary disease (COPD). This study assessed levels of anti-CCP antibodies and rheumatoid factor (RF) among patients with RA and COPD. The study sample comprised 63 patients with RA and 70 patients with COPD, all of whom underwent assessment of anti-CCP antibody and RF levels. Testing revealed that 54.2% of RA patients and 0% of COPD patients were positive for anti-CCP antibodies. Additionally, 82.5% of RA patients and 42% of COPD patients were positive for RF. Among RA patients, levels of anti-CCP antibodies were higher among smokers than among nonsmokers (242.7 ± 128.3 vs. 68.1 ± 112.1, P < 0.001). COPD patients had low titers of RF but were negative for anti-CCP antibodies. The presence of anti-CCP antibodies was a reliable serologic marker in RA diagnosis and was associated with cigarette smoking.

  1. Association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope and smoking status in Brazilian patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Michel Alexandre Yazbek

    2011-01-01

    Full Text Available INTRODUCTION: Epstein-Barr virus exposure appears to be an environmental trigger for rheumatoid arthritis that interacts with other risk factors. Relationships among anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status have been observed in patients with rheumatoid arthritis from different populations. OBJECTIVE: To perform an association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status in Brazilian patients with rheumatoid arthritis. METHODS: In a case-control study, 140 rheumatoid arthritis patients and 143 healthy volunteers who were matched for age, sex, and ethnicity were recruited. Anti-Epstein-Barr nuclear antigen-1 antibodies and anti-cyclic citrullinated peptide antibodies were examined using an enzyme-linked immunosorbent assay, and shared epitope alleles were identified by genotyping. Smoking information was collected from all subjects. A comparative analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status was performed in the patient group. Logistic regression analysis models were used to analyze the risk of rheumatoid arthritis. RESULTS: Anti-Epstein-Barr nuclear antigen-1 antibodies were not associated with anti-cyclic citrullinated peptide antibodies, shared epitope alleles, or smoking status. Anti-cyclic citrullinated peptide antibody positivity was significantly higher in smoking patients with shared epitope alleles (OR = 3.82. In a multivariate logistic regression analysis using stepwise selection, only anti-cyclic citrullinated peptide antibodies were found to be independently associated with rheumatoid arthritis (OR = 247.9. CONCLUSION: Anti-Epstein-Barr nuclear antigen-1 antibodies did not increase the risk of rheumatoid arthritis and were not associated with the rheumatoid arthritis risk factors studied. Smoking

  2. The clinical significance of antibody determination to cyclic citrullinated peptides in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Stamenković Bojana

    2012-01-01

    Full Text Available Introduction. Anti-citrullinated peptides antibodies (ACPA are present in 80% of sera of rheumatoid arthritis (RA patients with high specificity for diagnosis and prediction for the development of early erosive arthritis. A few studies have reported a low frequency ACPA in systemic sclerosis (SSc patients with the presence of arthritis. Objective. The aim of our study was to determine the frequency of ACPA in systemic sclerosis (SSc patients, their correlation with clinical manifestations and radiographic features. Methods. The study included 82 patients with SSc, mean age 54.4 years, 59 with the limited (lSSc and 23 with the diffuse (dSSc form of the disease. The control group included 28 healthy age and sex matched subjects. ACPA and rheumatoid factor (RF were determined in all SSc patients and healthy subjects in whom standard radiography of hands and wrists was also done. Results. The presence of ACPA was detected in 11 (13.4% of SSc patients. Their level was not increased in any of the controls. Positive RF was found in 15.9% of SSc patients. Arthritis was present in 17.1%, as well as marginal bone erosions. There was a statistically significant association between positive ACPA and arthritis (p<0.0001 and positive ACPA and marginal bone erosions (p=0.0002. Conclusion. The research confirmed the correlation between ACPA with clinical signs of arthritis and radiographic damage of hand joints. ACPA is a useful diagnostic marker in the identification of SSc patients with arthritis and anatomic bone damage enabling the use of adequate therapy in order to prevent joint damage and poor quality of life.

  3. Peptídeos cíclicos de biomassa vegetal: características, diversidade, biossíntese e atividades biológicas Cyclic peptide from plant biomass: chemical features and diversity, biosynthesis and biological activities

    Directory of Open Access Journals (Sweden)

    Douglas Gatte Picchi

    2009-01-01

    Full Text Available Natural peptides are outstanding as the most promising macromolecules in the search for new drugs, especially those of cyclic nature. The higher plants revealed a very peculiar composition of their cyclic peptides, which distinguish themselves by a "head-to-tail" cyclization. It is possible to define two groups of cyclic peptides from plant biomass. Those called in this review as Eucyclopeptides formed by 2-12 amino acid, and Cyclotides considered as circular polypeptides, composed of 29-37 amino acid that retain three disulfides bridges in an arrangement known as cyclic cystine knot. Searching for plant peptides should form into a subject for scientific research in the forefront of great importance for bioprospecting natural products macromolecular.

  4. Significance of Anti-cyclic Citrullinated Peptide Autoantibodies in Immune-mediated Inflammatory Skin Disorders with and without Arthritis

    Science.gov (United States)

    Grover, Chander; Kashyap, Bineeta; Daulatabad, Deepashree; Dhawan, Amit; Kaur, Iqbal R

    2016-01-01

    Background: Anti-cyclic citrullinated peptides (CCPs) are autoantibodies directed against citrullinated peptides. Rheumatoid factor (RF), an antibody against the Fc portion of IgG, is known to form immune complexes and contribute to the etiopathogenesis of various skin disorders. C-reactive protein (CRP), an acute-phase protein, increases following secretion of interleukin-6 from macrophages and T cells. Anti-CCP, RF, and CRP are well-established immune-markers, their diagnostic potential in immune-mediated skin disorders remains less widely studied. Aims and Objectives: To determine the correlation between anti-CCP, RF, and CRP in immune-mediated inflammatory skin diseases. Materials and Methods: About 61 clinically diagnosed cases of various immune-mediated skin diseases (psoriasis [n = 38], connective tissue diseases such as systemic lupus erythematosus and systemic sclerosis [n = 14], and immunobullous disorders including pemphigus vulgaris and pemphigus foliaceus [n = 9]) were included in the study. These patients were subclassified on the basis of presence or absence of arthritis. Arthritis was present in nine cases of psoriasis and seven connective tissue disorder patients. Detection of serum anti-CCP was done using enzyme-linked immunosorbent assay, whereas CRP and RF levels were detected using latex agglutination technique. Results: Of the 61 specimens, 14.75% had elevated serum anti-CCP levels. RF and CRP levels were elevated in 18.03% and 39.34% specimens, respectively. RF was elevated in 13.16% of inflammatory and 42.88% of connective tissue disorders, whereas anti-CCP was raised in 10.53% of inflammatory and 35.71% of connective tissue disorders. CRP positivity was highest in connective tissue disorders (50%), followed by 39.47% in inflammatory and 22.22% in immunobullous conditions. In none of the immunobullous patients, anti-CCP or RF levels were found to be elevated. Association of the presence of arthritis with elevated anti-CCP was found to be

  5. Usefulness of anti-cyclic citrullinate peptide antibody determination in synovial fluid analysis of patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    G. Valesini

    2011-09-01

    Full Text Available Objective: To assess the role of anti-cyclic citrullinated peptide (CCP antibody detection in synovial fluid (SF of RA patients compared to OA patients. Methods: We evaluated in 25 RA subjects and 14 OA patients, presenting a knee-joint effusion, the main clinical and laboratory parameters including the number of painful and/or swollen joints, Ritchie index, morning stiffness, ESR, CRP and analysis of SF obtained by therapeutic arthrocentesis. IgG anti-CCP (ELISA, rheumatoid factor (RF and total IgG (nephelometry method were measured in SF and paired serum samples. Results: We found anti-CCP antibodies and RF in 64% (16/25 and 60% (15/25 of RA sera, respectively; 72% (18/25 of RA patients were positive for anti-CCP antibodies or RF. We found a higher SF/serum ratio for anti-CCP (p<0.004 compared to that for total IgG. The calculation of anti-CCP concentration as IgG anti-CCP (units/total IgG (g L-1 revealed higher values in SF than in serum (p<0.046 in RA patients. Among these, correlation analysis showed that anti-CCP/total IgG values in SF correlated with the relative concentration of serum anti-CCP/total IgG (rs=0.842; p<0.00001 and serum anti-CCP antibody levels (rs=0.799; p<0.0001. We did not find any correlation between SF anti-CCP levels and the main characteristics of SF as well as the clinical or laboratory parameters. Conclusion: Our study give evidence for a preferential production of anti-CCP antibodies at RA joint level, confirming the pathogenetic role of these autoantibodies. Moreover, SF determination of anti-CCP, corrected for the total amount of the corresponding immunoglobulin, may be helpful as diagnostic tool in selected cases.

  6. Evaluation of a new DTPA-derivative chelator: comparative biodistribution and imaging studies of [sup 111]In-labeled B3 monoclonal antibody in athymic mice bearing human epidermoid carcinoma xenografts. [Diethylenetriaminpentaacetic acid

    Energy Technology Data Exchange (ETDEWEB)

    Camera, L.; Kinuya, S.; Garmestani, K.; Pai, L.H.; Brechbiel, M.W.; Gansow, O.A.; Paik, C.H.; Pastan, I.; Carrasquillo, J.A. (National Cancer Inst., Bethesda, MD (United States))

    1993-11-01

    Biodistribution and imaging characteristics of monoclonal antibody (MAb) B3 conjugated to either the 2-(p-isothiocvanatobenzyl)-cyclohexyl-DTPA (CHX-B) or 2-(p-isothiocyanatobenzyl)-6-methyl-DTPA (1B4M) and labeled with [sup 111]In, were evalulated in nude mice bearing A431 human epidermoid carcinoma xenografts. MAb B3, is a murine IgG1k reacting with a carbohydrate antigen abundantly expressed by most carcinomas. Both [sup 111]In-(CHX-B)-B3 and [sup 111]In-(1B4M)-B3 showed good tumor targeting with peak values observed at 72 h with 27.6 [+-] 7.6 and 25.4 [+-] 1.7% ID/g, respectively (P > 0.05). High tumor-to-organ ratios were also observed and, confirmed by the imaging results. In particular, tumor-to liver ratios increased from 5.0 [+-] 0.9 at 24 h to 9.2 [+-] 2.0 at 168 h for [sup 111]In-(CHX-B)-B3 and from 4.5 [+-] 0.6 to 8.9 [+-] 3.5 for [sup 111]In-(1B4M)-B3. This was mainly the result of low liver accumulation of both [sup 111]In-(CHX-B)-B3 and [sup 111]In-(1B4M)-B3, with only 2.48 [+-] 0.46 and 2.5 [+-] 0.9% ID/g at 168h, respectively (P > 0.05). Our findings indicate that either CHX-B or 1B4M can be successfully used for [sup 111]In-labeling of MAbs and that [sup 111]In-B3 may represent a promising radioimmunoimaging agent. (Author).

  7. Anti-Cyclic Citrullinated Peptide (Anti-CCP) and Anti-Mutated Citrullinated Vimentin (Anti-MCV) Relation with Extra-Articular Manifestations in Rheumatoid Arthritis

    OpenAIRE

    2014-01-01

    We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group (P = 0.40 and P = 0.91, resp.). Making an analysis of individual manifestations, rheum...

  8. Potent μ-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[D-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation.

    Science.gov (United States)

    Li, Yangmei; Cazares, Margret; Wu, Jinhua; Houghten, Richard A; Toll, Laurence; Dooley, Colette

    2016-02-11

    To optimize the structure of a μ-opioid receptor ligand, analogs H-Tyr-c[D-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity was tested. The analog containing a Phe(3) was identified as not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at D-Lys(2)-Xxx(3) is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity toward the μ-opioid receptor.

  9. Onset of polyarticular juvenile idiopathic arthritis with both anti-cyclic citrullinated peptide antibodies and rheumatoid factor in a 3-year-old girl

    Directory of Open Access Journals (Sweden)

    Yasui Kozo

    2012-12-01

    Full Text Available Abstract This report describes 3 year old girl with the unusual presentation of polyarticular juvenile idiopathic arthritis (JIA with anti-cyclic citrullinated peptide (anti-CCP antibodies and a positive rheumatoid factor (RF. She was initially treated with a nonsteroidal anti-inflammatory drug (NSAID; ibuprofen followed by methotrexate (MTX, 10 mg/m2/week and prednisolone (0.25 mg/kg/day, but these treatments were ineffective. Administration of tocilizumab, a humanized antihuman interleukin-6 receptor monoclonal antibody, promptly improved her clinical manifestations, and she has been in complete remission (DAS28

  10. Peptide Macrocycles Featuring a Backbone Secondary Amine: A Convenient Strategy for the Synthesis of Lipidated Cyclic and Bicyclic Peptides on Solid Support

    DEFF Research Database (Denmark)

    Oddo, Alberto; Münzker, Lena; Hansen, Paul Robert

    2015-01-01

    A convenient strategy for the on-resin synthesis of macrocyclic peptides (3- to 13-mers) via intramolecular halide substitution by a diamino acid is described. The method is compatible with standard Fmoc/tBu SPPS and affords a tail-to-side-chain macrocyclic peptide featuring an endocyclic secondary...

  11. Targeting human prostate cancer with 111In-labeled D2B IgG, F(ab')2 and Fab fragments in nude mice with PSMA-expressing xenografts.

    Science.gov (United States)

    Lütje, Susanne; van Rij, Catharina M; Franssen, Gerben M; Fracasso, Giulio; Helfrich, Wijnand; Eek, Annemarie; Oyen, Wim J; Colombatti, Marco; Boerman, Otto C

    2015-01-01

    D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab')2 and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing subcutaneous prostate cancer xenografts. The optimal time point for imaging was determined in biodistribution and microSPECT imaging studies with (111)In-D2B IgG, (111)In-capromab pendetide, (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments in mice with PSMA-expressing LNCaP and PSMA-negative PC3 tumors at several time points after injection. All (111)In-labeled antibody formats specifically accumulated in the LNCaP tumors, with highest uptake of (111)In-D2B IgG and (111)In-capromab pendetide at 168 h p.i. (94.8 ± 19.2% injected dose per gram (ID/g) and 16.7 ± 2.2% ID/g, respectively), whereas uptake of (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments peaked at 24 h p.i. (12.1 ± 3.0% ID/g and 15.1 ± 2.9% ID/g, respectively). Maximum LNCaP tumor-to-blood ratios were 13.0 ± 2.3 (168 h p.i.), 6.2 ± 0.7 (24 h p.i.), 23.0 ± 4.0 (24 h p.i.) and 4.5 ± 0.6 (168 h p.i.) for (111)In-D2B IgG, (111)In-F(ab')2, (111)In-Fab and (111)In-capromab pendetide, respectively. LNCaP tumors were clearly visualized with microSPECT with all antibody formats. This study demonstrates the feasibility of D2B IgG, F(ab')2 and Fab fragments for targeting PSMA-expressing prostate cancer xenografts.

  12. Ammonia inhibits the C-type natriuretic peptide-dependent cyclic GMP synthesis and calcium accumulation in a rat brain endothelial cell line.

    Science.gov (United States)

    Konopacka, Agnieszka; Zielińska, Magdalena; Albrecht, Jan

    2008-05-01

    Recently we reported a decrease of C-type natriuretic peptide (CNP)-dependent, natriuretic peptide receptor 2 (NPR2)-mediated cyclic GMP (cGMP) synthesis in a non-neuronal compartment of cerebral cortical slices of hyperammonemic rats [Zielińska, M., Fresko, I., Konopacka, A., Felipo, V., Albrecht, J., 2007. Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices. Neurotoxicology 28, 1260-1263]. Here we accounted for the possible involvement of cerebral capillary endothelial cells in this response by measuring the effect of ammonia on the CNP-mediated cGMP formation and intracellular calcium ([Ca2+]i) accumulation in a rat cerebral endothelial cell line (RBE-4). We first established that stimulation of cGMP synthesis in RBE-4 cells was coupled to protein kinase G (PKG)-mediated Ca2+ influx from the medium which was inhibited by an L-type channel blocker nimodipine. Ammonia treatment (1h, 5mM NH4Cl) evoked a substantial decrease of CNP-stimulated cGMP synthesis which was related to a decreased binding of CNP to NPR2 receptors, and depressed the CNP-dependent [Ca2+]i accumulation in these cells. Ammonia also abolished the CNP-dependent Ca2+ accumulation in the absence of Na+. In cells incubated with ammonia in the absence of Ca2+ a slight CNP-dependent increase of [Ca2+]i was observed, most likely representing Ca2+ release from intracellular stores. Depression of CNP-dependent cGMP-mediated [Ca2+]i accumulation may contribute to cerebral vascular endothelial dysfunction associated with hyperammonemia or hepatic encephalopathy.

  13. Examining the meaning of the peptide transfer free energy obtained from blocked (Gly)_n and cyclic-diglycine model compounds

    CERN Document Server

    Asthagiri, D; Weber, V

    2013-01-01

    In experiments, the free energy of transferring the peptide group from water to an osmolyte solution is obtained using the transfer free energy of (Gly)_n with the added assumption that a constant incremental change in free energy with n implies that each additional unit makes an independent contribution to the free energy. Here we test this assumption and uncover its limitations. Together with results for cyclic-diglycine, we show that, in principle, it is not possible to obtain a peptide group transfer free energy that is independent of the model system. We calculate the hydration free energy of acetyl-(Gly)_n-methyl amide (n=1..7) peptides modeled in the extended conformation in water and osmolyte solutions and find that the hydration free energy is linear in n, suggestive of independent, additive group-contributions. To probe the observed linearity further, we study the hydration of the solute bereft of water molecules in the first hydration shell. This conditioned solute arises naturally in the theoretic...

  14. Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

    Directory of Open Access Journals (Sweden)

    Ryota Kirikoshi

    2017-02-01

    Full Text Available The Asn-Gly-Arg (NGR motif and its deamidation product isoAsp-Gly-Arg (isoDGR have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH2CO-NGRC]-NH2, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H2PO4− ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8 continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H2PO4− ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH2 group on the five-membered ring, was shown to easily undergo NH3 elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation.

  15. Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain.

    Science.gov (United States)

    Kirikoshi, Ryota; Manabe, Noriyoshi; Takahashi, Ohgi

    2017-02-16

    The Asn-Gly-Arg (NGR) motif and its deamidation product isoAsp-Gly-Arg (isoDGR) have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH₂CO-NGRC]-NH₂, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H₂PO₄(-) ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8) continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H₂PO₄(-) ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH₂ group on the five-membered ring, was shown to easily undergo NH₃ elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation.

  16. Gas-phase doubly charged complexes of cyclic peptides with copper in +1, +2 and +3 formal oxidation states: formation, structures and electron capture dissociation.

    Science.gov (United States)

    Afonso, Carlos; Tabet, Jean-Claude; Giorgi, Gianluca; Tureček, František

    2012-02-01

    Copper complexes with a cyclic D-His-β-Ala-L-His-L-Lys and all-L-His-β-Ala-His-Lys peptides were generated by electrospray which were doubly charged ions that had different formal oxidation states of Cu(I), Cu(II) and Cu(III) and different protonation states of the peptide ligands. Electron capture dissociation showed no substantial differences between the D-His and L-His complexes. All complexes underwent peptide cross-ring cleavages upon electron capture. The modes of ring cleavage depended on the formal oxidation state of the Cu ion and peptide protonation. Density functional theory (DFT) calculations, using the B3LYP with an effective core potential at Cu and M06-2X functionals, identified several precursor ion structures in which the Cu ion was threecoordinated to pentacoordinated by the His and Lys side-chain groups and the peptide amide or enolimine groups. The electronic structure of the formally Cu(III) complexes pointed to an effective Cu(I) oxidation state with the other charge residing in the peptide ligand. The relative energies of isomeric complexes of the [Cu(c-HAHK + H)](2+) and [Cu(c-HAHK - H)](2+) type with closed electronic shells followed similar orders when treated by the B3LYP and M06-2X functionals. Large differences between relative energies calculated by these methods were obtained for open-shell complexes of the [Cu(c-HAHK)](2+) type. Charge reduction resulted in lowering the coordination numbers for some Cu complexes that depended on the singlet or triplet spin state being formed. For [Cu(c-HAHK - H)](2+) complexes, solution H/D exchange involved only the N-H protons, resulting in the exchange of up to seven protons, as established by ultra-high mass resolution measurements. Contrasting the experiments, DFT calculations found the lowest energy structures for the gas-phase ions that were deprotonated at the peptide C(α) positions.

  17. Hormonal Neuroendocrine and Vasoconstrictor Peptide Responses of Ball Game and Cyclic Sport Elite Athletes by Treadmill Test.

    Directory of Open Access Journals (Sweden)

    Anna Protzner

    Full Text Available Our objective was to evaluate complex hormonal response in ball game and cyclic sport elite athletes through an incremental treadmill test, since, so far, variables in experimental procedures have often hampered comparisons of data.We determined anthropometric data, heart rate, maximal oxygen uptake, workload, plasma levels of lactate, adrenaline, noradrenaline, dopamine, cortisol, angiontensinogen and endothelin in control (n = 6, soccer (n = 8, handball (n = 12, kayaking (n = 9 and triathlon (n = 9 groups based on a Bruce protocol through a maximal exercise type of spiroergometric test.We obtained significant increases for adrenaline, 2.9- and 3.9-fold by comparing the normalized means for soccer players and kayakers and soccer players and triathletes after/before test, respectively. For noradrenaline, we observed an even stronger, three-time significant difference between each type of ball game and cyclic sport activity.Exercise related adrenaline and noradrenaline changes were more pronounced than dopamine plasma level changes and revealed an opportunity to differentiate cyclic and ball game activities and control group upon these parameters. Normalization of concentration ratios of the monitored compounds by the corresponding maximal oxygen uptake reflected better the differences in the response level of adrenaline, noradrenaline, dopamine and cortisol.

  18. Functionalization of Ruthenium(II) terpyridine complexes with cyclic RGD pep-tides to target integrin receptors in cancer cells

    NARCIS (Netherlands)

    Hahn, Eva M.; Estrada Ortiz, Natalia; Han, Jiaying; Ferreira, Vera F. C.; Kapp, Tobias G.; Correia, Joao D. G.; Casini, Angela; Kuehn, Fritz E.

    2016-01-01

    The lack of selectivity for cancer cells and the resulting negative impact on healthy tissue is a severe drawback of actual cancer chemotherapy. Tethering of cytotoxic drugs to targeting vectors such as peptides, which recognize receptors overexpressed on the surface of tumor cells, is one possible

  19. The Diagnostic Utility of Anti-cyclic Citrullinated Peptide Antibodies, Matrix Metalloproteinase-3, Rheumatoid Factor, Erythrocyte Sedimentation Rate, and C-reactive Protein in Patients with Erosive and Non-erosive Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    O. Shovman

    2005-01-01

    Full Text Available Objective: To compare the diagnostic utility of laboratory variables, including matrix metalloproteinase-3 (MMP-3, anti-cyclic citrullinated peptide (CCP antibodies, rheumatoid factor (RF, erythrocyte sedimentation rate (ESR, and C-reactive protein (CRP in patients with erosive and non-erosive rheumatoid arthritis (RA.

  20. Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation

    Directory of Open Access Journals (Sweden)

    Pero Stephanie C

    2007-09-01

    Full Text Available Abstract Background Human growth factor receptor bound protein 7 (Grb7 is an adapter protein that mediates the coupling of tyrosine kinases with their downstream signaling pathways. Grb7 is frequently overexpressed in invasive and metastatic human cancers and is implicated in cancer progression via its interaction with the ErbB2 receptor and focal adhesion kinase (FAK that play critical roles in cell proliferation and migration. It is thus a prime target for the development of novel anti-cancer therapies. Recently, an inhibitory peptide (G7-18NATE has been developed which binds specifically to the Grb7 SH2 domain and is able to attenuate cancer cell proliferation and migration in various cancer cell lines. Results As a first step towards understanding how Grb7 may be inhibited by G7-18NATE, we solved the crystal structure of the Grb7 SH2 domain to 2.1 Å resolution. We describe the details of the peptide binding site underlying target specificity, as well as the dimer interface of Grb 7 SH2. Dimer formation of Grb7 was determined to be in the μM range using analytical ultracentrifugation for both full-length Grb7 and the SH2 domain alone, suggesting the SH2 domain forms the basis of a physiological dimer. ITC measurements of the interaction of the G7-18NATE peptide with the Grb7 SH2 domain revealed that it binds with a binding affinity of Kd = ~35.7 μM and NMR spectroscopy titration experiments revealed that peptide binding causes perturbations to both the ligand binding surface of the Grb7 SH2 domain as well as to the dimer interface, suggesting that dimerisation of Grb7 is impacted on by peptide binding. Conclusion Together the data allow us to propose a model of the Grb7 SH2 domain/G7-18NATE interaction and to rationalize the basis for the observed binding specificity and affinity. We propose that the current study will assist with the development of second generation Grb7 SH2 domain inhibitors, potentially leading to novel inhibitors of

  1. Utility of 11C-donepezil and 11C-methionine for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: Comparison to autologous 111In-labelled leukocytes, 18F-FDG, and 99mTc-MPD

    DEFF Research Database (Denmark)

    Afzelius, Pia; Alstrup, Aage Kristian Olsen; Schønheyer, Henrik C.

    2016-01-01

    The aim of this study was to compare 11C-methionine and 11C-donepezil positron emission tomography (PET) with 111In-labeled leukocyte and 99mTc-MDP single-photon emission computed tomography (SPECT), and 18F-fluorodeoxyglucose (18F-FDG) PET to improve detection of osteomyelitis. The tracers...... a sequential scan protocol with 18F-FDG, 11C-methionine, 11C-donepezil, 99mTc- methylene diphosphonate (MDP), and 111In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 22 osteomyelitis...... lesions, 5 lesions characterized as abscesses and pulmonary abscesses in one pig. By comparing the 22 osteomyelitic lesions, 18F-FDG accumulated in 100%, 111In-leukocytes in 86%, 11C-methionine in 86%, 11C-donepezil in 63%, and 99mTc-MDP in none. Overall, 18F-FDG PET was slightly superior to 111In...

  2. Utility of 11C-methionine and 11C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous 111In-labelled leukocytes, 99mTc-DPD, and 18F-FDG

    Science.gov (United States)

    Afzelius, Pia; Alstrup, Aage KO; Schønheyder, Henrik C; Borghammer, Per; Jensen, Svend B; Bender, Dirk; Nielsen, Ole L

    2016-01-01

    The aim of this study was to compare 11C-methionine and 11C-donepezil positron emission tomography (PET) with 111In-labeled leukocyte and 99mTc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and 18F-fluorodeoxyglucose (18F-FDG) PET to improve detection of osteomyelitis. The tracers’ diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, 11C-methionine and 11C-donepezil PET, 99mTc-DPD and 111In-labelled leukocytes scintigraphy, and 18F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, 18F-FDG accumulated in 100%, 111In-leukocytes in 79%, 11C-methionine in 79%, 11C-donepezil in 58%, and 99mTc-DPD in none. Overall, 18F-FDG PET was superior to 111In-leukocyte SPECT and 11C-methionine in marking infectious lesions. PMID:28078182

  3. Utility of (11)C-methionine and (11)C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous (111)In-labelled leukocytes, (99m) Tc-DPD, and (18)F-FDG.

    Science.gov (United States)

    Afzelius, Pia; Alstrup, Aage Ko; Schønheyder, Henrik C; Borghammer, Per; Jensen, Svend B; Bender, Dirk; Nielsen, Ole L

    2016-01-01

    The aim of this study was to compare (11)C-methionine and (11)C-donepezil positron emission tomography (PET) with (111)In-labeled leukocyte and (99m) Tc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and (18)F-fluorodeoxyglucose ((18)F-FDG) PET to improve detection of osteomyelitis. The tracers' diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m) Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, (18)F-FDG accumulated in 100%, (111)In-leukocytes in 79%, (11)C-methionine in 79%, (11)C-donepezil in 58%, and (99m) Tc-DPD in none. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT and (11)C-methionine in marking infectious lesions.

  4. Structure determination of a flexible cyclic peptide based on NMR and MD simulation 3J-coupling.

    Science.gov (United States)

    Gattin, Zrinka; Zaugg, Judith; van Gunsteren, Wilfred F

    2010-03-15

    Molecular dynamics (MD) simulations, in which experimental values such as nuclear Overhauser effects (NOEs), dipolar couplings, (3)J-coupling constants or crystallographic structure factors are used to bias the values of specific molecular properties towards experimental ones, are often carried out to study the structure refinement of peptides and proteins. However, (3)J-coupling constants are usually not employed because of the multiplicity of torsional angle values (phi) corresponding to each (3)J-coupling constant value. Here, we apply the method of adaptively enforced restraining using a local-elevation (LE) biasing potential energy function in which a memory function penalizes conformations in case both the average and the current (3)J-values deviate from the experimental target value. Then, the molecule is forced to sample other parts of the conformational space, thereby being able to cross high energy barriers and to bring the simulated average close to the measured value. Herein, we show the applicability of this method in structure refinement of a cyclo-beta-tetrapeptide by enforcing the (3)J-value restraining with LE on twelve backbone torsional angles. The resulting structural ensemble satisfies the experimental (3)J-coupling data better than the NMR model structure derived using conventional single-structure refinement based on these data. Thus, application of local-elevation search MD simulation in combination with biasing towards (3)J-coupling makes it possible to use (3)J-couplings quantitatively in structure determination of peptides.

  5. Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide that binds the Tat-transactivating response element (TAR RNA.

    Directory of Open Access Journals (Sweden)

    Matthew S Lalonde

    2011-05-01

    Full Text Available The RNA response element TAR plays a critical role in HIV replication by providing a binding site for the recruitment of the viral transactivator protein Tat. Using a structure-guided approach, we have developed a series of conformationally-constrained cyclic peptides that act as structural mimics of the Tat RNA binding region and block Tat-TAR interactions at nanomolar concentrations in vitro. Here we show that these compounds block Tat-dependent transcription in cell-free systems and in cell-based reporter assays. The compounds are also cell permeable, have low toxicity, and inhibit replication of diverse HIV-1 strains, including both CXCR4-tropic and CCR5-tropic primary HIV-1 isolates of the divergent subtypes A, B, C, D and CRF01_AE. In human peripheral blood mononuclear cells, the cyclic peptidomimetic L50 exhibited an IC(50 ∼250 nM. Surprisingly, inhibition of LTR-driven HIV-1 transcription could not account for the full antiviral activity. Timed drug-addition experiments revealed that L-50 has a bi-phasic inhibition curve with the first phase occurring after HIV-1 entry into the host cell and during the initiation of HIV-1 reverse transcription. The second phase coincides with inhibition of HIV-1 transcription. Reconstituted reverse transcription assays confirm that HIV-1 (- strand strong stop DNA synthesis is blocked by L50-TAR RNA interactions in-vitro. These findings are consistent with genetic evidence that TAR plays critical roles both during reverse transcription and during HIV gene expression. Our results suggest that antiviral drugs targeting TAR RNA might be highly effective due to a dual inhibitory mechanism.

  6. Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis

    Science.gov (United States)

    Ponce-Guarneros, Manuel; Mejía, Mayra; Juárez-Contreras, Pablo; Corona-Sánchez, Esther Guadalupe; Rodríguez-Hernández, Tania Marlen; Salazar-Páramo, Mario; Cardona-Muñoz, Ernesto German; Celis, Alfredo; González-Lopez, Laura

    2015-01-01

    Objective. To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2) are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD). Methods. In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT) were compared with 42 RA without lung involvement (RA only). Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified. Results. Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, P < 0.001). In the logistic regression analysis after adjustment for age, disease duration (DD), smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX) treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers (P = 0.003) and + RF (P = 0.002). In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers (P = 0.02) and with fibrosis score DD (P = 0.01), anti-CCP2 titers (P < 0.001), and MTX treatment duration (P < 0.001). Conclusions. Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD. PMID:26090479

  7. Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Alberto Daniel Rocha-Muñoz

    2015-01-01

    Full Text Available Objective. To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2 are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD. Methods. In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT were compared with 42 RA without lung involvement (RA only. Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified. Results. Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, P<0.001. In the logistic regression analysis after adjustment for age, disease duration (DD, smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers (P=0.003 and + RF (P=0.002. In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers (P=0.02 and with fibrosis score DD (P=0.01, anti-CCP2 titers (P<0.001, and MTX treatment duration (P<0.001. Conclusions. Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD.

  8. Anti-cyclic citrullinated peptide (CCP) antibody in patients with wood-smoke-induced chronic obstructive pulmonary disease (COPD) without rheumatoid arthritis.

    Science.gov (United States)

    Sigari, Naseh; Moghimi, Nasrin; Shahraki, Farhad Saber; Mohammadi, Shilan; Roshani, Daem

    2015-01-01

    Citrullination, a post-translational modification of proteins, is increased in inflammatory processes and is known to occur in smokers. It can induce anti-cyclic citrullinated peptide (CCP) antibodies, the most specific serologic marker for rheumatoid arthritis. Thus far, the incidence of autoimmunity in patients with wood-smoke-induced chronic obstructive pulmonary disease (COPD) resulting in anti-CCP production has not been examined. We hypothesise that anti-CCP antibody level in these patients should be higher than that in healthy subjects. A total of 112 non-rheumatoid arthritis patients, including 56 patients with wood-smoke-induced COPD and 56 patients with tobacco-induced COPD, and 56 healthy non-smoker controls were included. The serum anti-CCP antibody levels were measured and compared between the groups and against smoke exposure and clinical characteristics. The mean anti-CCP antibody levels in wood-smoke-induced COPD group were significantly higher than those in tobacco-induced COPD group (p = 0.03) and controls (p = 0.004). Furthermore, 8 (14.2 %) patients with wood-smoke-induced COPD, 4 (7.14 %) with tobacco-induced COPD and 2 (3.57 %) controls exceeded the conventional cut-off of anti-CCP antibody positivity. No relationship was found between the anti-CCP antibody level and age, gender, duration of disease, Pack-years of smoking, and duration of exposure to wood smoke. Moreover, correlations between anti-CCP antibodies and severity of airflow limitation, CAT scores, mMRC scores of dyspnoea, and GOLD staging of COPD severity were not significant. Wood-smoke-induced COPD could significantly increase the anti-CCP antibody level in non-rheumatoid arthritis patients when compared with that in patients with tobacco-induced COPD and healthy controls.

  9. Anti-Cyclic Citrullinated Peptide (Anti-CCP and Anti-Mutated Citrullinated Vimentin (Anti-MCV Relation with Extra-Articular Manifestations in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Laura Gonzalez-Lopez

    2014-01-01

    Full Text Available We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP and anti-mutated citrullinated vimentin antibodies (anti-MCV with the presence of extra-articular (ExRA manifestations in 225 patients with rheumatoid arthritis (RA. Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group (P=0.40 and P=0.91, resp.. Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF; (P=0.01, anti-CCP (P=0.048, and anti-MCV (P=0.02. Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di (r=0.154, P=0.03, erythrocyte sedimentation rate (ESR; (r=0.155, P=0.03, and RF (P=0.254, P<0.001, whereas anti-MCV titres only correlated with RF (r=0.169, P=0.02. On adjusted analysis, ExRA was associated with longer age (P=0.015, longer disease duration (P=0.007, higher DAS-28 score (P=0.002, and higher HAQ-DI score (P=0.007, but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation.

  10. Anti-Cyclic Citrullinated Peptide (Anti-CCP) and Anti-Mutated Citrullinated Vimentin (Anti-MCV) Relation with Extra-Articular Manifestations in Rheumatoid Arthritis

    Science.gov (United States)

    Gonzalez-Lopez, Laura; Rocha-Muñoz, Alberto Daniel; Ponce-Guarneros, Manuel; Flores-Chavez, Alejandra; Salazar-Paramo, Mario; Cardona-Muñoz, Ernesto German; Fajardo-Robledo, Nicte Selene; Zavaleta-Muñiz, Soraya Amali; Garcia-Cobian, Teresa; Gamez-Nava, Jorge Ivan

    2014-01-01

    We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group (P = 0.40 and P = 0.91, resp.). Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF); (P = 0.01), anti-CCP (P = 0.048), and anti-MCV (P = 0.02). Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di) (r = 0.154, P = 0.03), erythrocyte sedimentation rate (ESR); (r = 0.155, P = 0.03), and RF (P = 0.254, P < 0.001), whereas anti-MCV titres only correlated with RF (r = 0.169, P = 0.02). On adjusted analysis, ExRA was associated with longer age (P = 0.015), longer disease duration (P = 0.007), higher DAS-28 score (P = 0.002), and higher HAQ-DI score (P = 0.007), but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation. PMID:24804270

  11. Relation of rheumatoid factor and anti-cyclic citrullinated peptide antibody with disease activity in rheumatoid arthritis: cross-sectional study.

    Science.gov (United States)

    Choe, Jung-Yoon; Bae, Jisuk; Lee, Hwajeong; Bae, Sang-Cheol; Kim, Seong-Kyu

    2013-09-01

    To analyze the association of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) with non-remission and with disease activity measures in rheumatoid arthritis (RA). Cross-sectional study of consecutive RA patients. Non-remission was defined as a disease activity score (DAS28) ≥ 2.6 at study enrollment. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) were additionally measured. Serum titers of RF and anti-CCP were transformed into incremental levels (100/units) and log-transformed levels. Analysis of association with non-remission was done with logistic regression models, with and without adjustment for age, sex, disease duration, and corticoid use. Multiple regression models, raw and similarly adjusted, were used to measure the association of RF and anti-CCP with the disease activity measures. A total of 385 patients were included, of whom 286 (74 %) were not in remission. Log-transformed RF level was associated with an increased risk of non-remission after adjustment (OR = 1.32, 95 % CI 1.04-1.67). This association was especially evident in patients with less than 10 years of disease duration (OR = 1.51, 95 % CI 1.15-1.99) and in those using steroids (OR = 2.06, 95 % CI 1.22-3.48). Serum RF titers and log-transformed RF levels showed a small but significant association with DAS28 score (adjusted beta coefficients 0.002 and 0.18, respectively; both p ≤ 0.01), but neither with SDAI or CDAI nor with anti-CCP antibody. : Log-transformed RF levels might be associated with non-remission in RA, especially in patients with short disease duration or on steroids.

  12. Frequency and diagnostic significance of anti-cyclic citrullinated peptide antibodies (ACCP and anti-modified citrullinated vimentin antibodies (AMCV in children with early juvenile arthritis

    Directory of Open Access Journals (Sweden)

    S O Salugina

    2008-01-01

    Full Text Available Objective. To determine frequency of anti-cyclic citrullinated peptide antibodies (ACCP and anti-modified citrullinated vimentin antibodies (AMCV elevation and their diagnostic significance in children with early juvenile arthritis (JA. Material and methods. ACCP were evaluated in serum of 80 pts with early JA (36 girls, 44 boys, mean age 8,5±5,03 years, AMCV — in 85 pts with early JA (49 girls and 36 boys aged from 1,5 to 16 years (mean age 8,7±4,9 years. Disease duration in all children was less than 6 months. Control group included 54 grown up pts with early rheumatoid arthritis (RA, 27 - with undifferentiated arthritis (UDA and 37 conditionally healthy children. АССР was assessed by immuno-enzyme assay (IEA with commercial kits “Axis Shield Diagnostics" (Great Britain, upper normal limit 5,0 U/ml. AMCV was examined by IEA with commercial kits “Orgentec Diagnostics” (Germany, upper normal limit — 25 U/ml. Results. ACCP was elevated in 7 children with early JA (8,8%. Frequency was higher than in healthy children but lower than in grown up pts with early RA and comparable with UDA. In juvenile rheumatoid arthritis (JRA ACCP were more frequent than in juvenile chronic arthritis (JCA. Concentration was higher in rheumatoid factor (RF positive pts with polyarticular JA. AMCV level was elevated in in 23 (27,1% pts with early JA (more frequent than in healthy donors but less frequent than in grown up pts with early RA and UDA. AMCV was significantly more frequent in JRA than in JCA and in RF positive than in RF negative pts. AMCV concentration in JA was higher than in healthy children but lower than in grown up pts with RA. It was also higher in RF+ than RF- JA. ACCP and AMCV correlated with swollen joint count, tender joint count and RF. AMCV also correlated with ESR and CRP. Conclusion. In pts with early JA ACCP and AMCV are equally or more frequent than RF. In spite of low sensitivity they have high specificity for JRA in contrast

  13. Detection of anti-cyclic citrullinated peptide antibodies in patients with rheumatoid arthritis: the clinical significance%抗环瓜氨酸抗体检测在类风湿关节炎中的临床意义

    Institute of Scientific and Technical Information of China (English)

    殷健; 李婷; 包军; 徐沪济

    2011-01-01

    类风湿关节炎( rheumatoid arthritis,RA)是一种主要累及全身多关节的自身免疫性疾病.目前RA仍具有很高的关节致残率和病死率.早期诊断并进行积极治疗可有效减少关节畸形的可能.近年发现的抗瓜氨酸抗体( anti-citrullinated peptide antibodies,ACPA)可在关节破坏发生前即表现出阳性,该抗体与经典的类风湿因子(rheumatoid factor,RF)相比,在RA的诊断中具有相似的敏感性,但具有更高的特异性.研究发现抗环瓜氨酸抗体(anti-cyclic citrullinated peptide antibodies)在RA的早期诊断、预后判断等方面都有重要意义,并有流行病学证据显示其可能在RA的发病中扮演重要角色.%Rheumatoid arthritis (RA) is an autoimmune disease involving multiple joints, and currently it still leads to high disability rate of the joints and high mortality. Early diagnosis and treatment can effectively reduce joint deformities. The recently discovered anti-citrullinated peptide antibodiesC ACPA) can be detected before damage to the joints occurs. Compared with classical rheumatoid factor (RF) ACPA has higher specificity and similar sensitivity in diagnosing RA. Some studies have showned that anti-cyclic citrullinated peptide antibodies play an important role in the early diagnosis of RA and prediction of prognosis; epidemiological evidences also show that ACPA plays an important role on the pathogenesis of RA.

  14. Use of Galerina marginata genes and proteins for peptide production

    Energy Technology Data Exchange (ETDEWEB)

    Hallen-Adams, Heather E.; Scott-Craig, John S.; Walton, Jonathan D.; Luo, Hong

    2017-03-21

    The present invention relates to compositions and methods comprising genes and peptides associated with cyclic peptides and cyclic peptide production in mushrooms. In particular, the present invention relates to using genes and proteins from Galerina species encoding peptides specifically relating to amatoxins in addition to proteins involved with processing cyclic peptide toxins. In a preferred embodiment, the present invention also relates to methods for making small peptides and small cyclic peptides including peptides similar to amanitin. Further, the present inventions relate to providing kits for making small peptides.

  15. Use of Galerina marginata genes and proteins for peptide production

    Science.gov (United States)

    Hallen-Adams, Heather E.; Scott-Craig, John S.; Walton, Jonathan D.; Luo, Hong

    2016-03-01

    The present invention relates to compositions and methods comprising genes and peptides associated with cyclic peptides and cyclic peptide production in mushrooms. In particular, the present invention relates to using genes and proteins from Galerina species encoding peptides specifically relating to amatoxins in addition to proteins involved with processing cyclic peptide toxins. In a preferred embodiment, the present invention also relates to methods for making small peptides and small cyclic peptides including peptides similar to amanitin. Further, the present inventions relate to providing kits for making small peptides.

  16. Macrophage-inducible C-type lectin is associated with anti-cyclic citrullinated peptide antibodies-positive rheumatoid arthritis in men

    Institute of Scientific and Technical Information of China (English)

    WU Xin-yu; GUO Jian-ping; YIN Fang-rui; LU Xiao-lan; LI Ru; HE Jing; LIU Xu; LI Zhan-guo

    2012-01-01

    Background Macrophage-inducible C-type lectin (MINCLE) is an important member of C-type lectin superfamily,which has been shown evidence for susceptibility to arthritis in animal models.We aimed to investigate the possible association of MINCLE with rheumatoid arthritis (RA) susceptibility in Chinese Hart population.Methods Haplotypes from HapMap database (Chinese Hart Beijing,CHB) were used to select tag-single nucleotide polymorphism (SNP) (r2=0.8) residing in MINCLE gene.A total of 563 patients with RA and 404 healthy controls were TagMan genotyped for SNP rs10841845.Association analyses were performed on the whole data set and on RA subsets based on gender difference and the status of anti-cyclic citrullinated peptide (anti-CCP) antibody in RA patients.Association statistics were calculated by age and sex adjusted logistic regression.Results Overall,MINCLE SNP rs10841845 was not associated with susceptibility to RA.However,following anti-CCP stratification,rs10841845 GG genotypes conferred a significantly protective effects against anti-CCP-positive RA (OR 0.65,95% CI 0.430-0.995,P=0.048).Following gender stratification,SNP rs10841845 G allele appeared to insert its RA protective effect only in male patients,both at allele level (G vs.A OR 0.66,95% CI 0.46-0.93,P=0.018) and at genotype level (GG vs.AA+AG,OR 0.429,95% CI 0.20-0.95,P=0.036).Notably,the male RA protective effect of rs10841845 G allele was only seen in anti-CCP-positive RA (G vs.A:OR 0.64,95% CI 0.43-0.96,P=0.029; GG vs.AA+AG:OR 0.375,95% Cl 0.14-0.94,P=0.038).Furthermore,we observed a significant reduction of Disease Activity Score (DAS) 28 score (3.91±0.70 vs.5.66±0.31,P=0.022) and serum C-reactive protein levels (31.64±24.13 vs.91.80±12.02,P=0.012)in male anti-CCP-positive RA patients carrying rs10841845 GG genotype,compared with patients carrying AA+AG genotypes.Conclusions Our study provides the evidence for a gender specific association between MINCLE rs10841845 and RA

  17. Solution-phase parallel synthesis of a pharmacophore library of HUN-7293 analogues: a general chemical mutagenesis approach to defining structure-function properties of naturally occurring cyclic (depsi)peptides.

    Science.gov (United States)

    Chen, Yan; Bilban, Melitta; Foster, Carolyn A; Boger, Dale L

    2002-05-15

    HUN-7293 (1), a naturally occurring cyclic heptadepsipeptide, is a potent inhibitor of cell adhesion molecule expression (VCAM-1, ICAM-1, E-selectin), the overexpression of which is characteristic of chronic inflammatory diseases. Representative of a general approach to defining structure-function relationships of such cyclic (depsi)peptides, the parallel synthesis and evaluation of a complete library of key HUN-7293 analogues are detailed enlisting solution-phase techniques and simple acid-base liquid-liquid extractions for isolation and purification of intermediates and final products. Significant to the design of the studies and unique to solution-phase techniques, the library was assembled superimposing a divergent synthetic strategy onto a convergent total synthesis. An alanine scan and N-methyl deletion of each residue of the cyclic heptadepsipeptide identified key sites responsible for or contributing to the biological properties. The simultaneous preparation of a complete set of individual residue analogues further simplifying the structure allowed an assessment of each structural feature of 1, providing a detailed account of the structure-function relationships in a single study. Within this pharmacophore library prepared by systematic chemical mutagenesis of the natural product structure, simplified analogues possessing comparable potency and, in some instances, improved selectivity were identified. One potent member of this library proved to be an additional natural product in its own right, which we have come to refer to as HUN-7293B (8), being isolated from the microbial strain F/94-499709.

  18. Prevalência de anticorpos contra peptídeos cíclicos citrulinados na artrite idiopática juvenil The prevalence of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Sandra H. Machado

    2005-12-01

    Full Text Available OBJETIVOS: Avaliar a presença de anticorpos contra peptídeos cíclicos citrulinados em uma coorte de pacientes com artrite idiopática juvenil. MÉTODOS: A presença de anticorpos contra peptídeos cíclicos citrulinados foi avaliada por ensaio imunoenzimático (ELISA no soro de pacientes com artrite idiopática juvenil com idade inferior a 18 anos, acompanhados no ambulatório de reumatologia pediátrica do Hospital de Clínicas de Porto Alegre, com tempo de diagnóstico de doença de, no mínimo, 6 meses. Também foi estudada a presença do fator reumatóide IgM e do fator antinuclear em células Hep-2 RESULTADOS: Foram analisadas amostras séricas de 45 pacientes com artrite idiopática juvenil. A presença de títulos elevados de anticorpos contra peptídeos cíclicos citrulinados foi encontrada somente no soro de uma criança (2%, a qual apresentava quadro de poliartrite com fator reumatóide reagente. CONCLUSÕES: O anticorpo contra peptídeos cíclicos citrulinados pode ser detectado em crianças com artrite idiopática juvenil, mas em freqüência muito inferior aos adultos com artrite reumatóide. Torna-se importante avaliar se anticorpos contra peptídeos cíclicos citrulinados podem identificar os pacientes com artrite idiopática juvenil com potencial de evolução para artrite reumatóide do adulto.OBJECTIVES: To assess the presence of anti-cyclic citrullinated peptide antibodies in a cohort of patients with juvenile idiopathic arthritis. METHODS: Anti-cyclic citrullinated peptide antibodies was tested for with an enzyme linked immunoabsorbent assay (ELISA in serum samples of patients from the Hospital de Clínicas de Porto Alegre, all less than 18 years old and with previous diagnosis for at least 6 months. IgMRF (rheumatoid factor and antinuclear antibodies in Hep-2 cells were also assayed. RESULTS: Serum samples were analyzed from 45 patients. The presence of high levels of anti-cyclic citrullinated peptide antibodies was found

  19. Associação do anticorpo anticitrulina e gravidade da artrite reumatóide Association of anti-cyclic citrullinated peptide antibody and severe rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Aldifran Ferreira da Silva

    2006-06-01

    Full Text Available OBJETIVOS: Avaliar a associação do anticorpo antipeptídeo citrulinado cíclico (anti-CCP com distintos parâmetros clínicos, sorológicos e radiológicos. MÉTODOS: Anti-CCP e fator reumatóide (FR foram pesquisados no soro de 100 pacientes com artrite reumatóide (AR. A atividade da doença foi definida por meio de um índice combinado compreendendo cinco parâmetros: número de juntas inflamadas, número de juntas doloridas, rigidez matinal, escala visual analógica (EVA de dor e velocidade de hemossedimentação (VHS. A capacidade funcional foi medida pelo índice HAQ (Health Assessment Questionnaire e a classe funcional foi determinada mediante aplicação dos critérios revisados do American College of Rheumatology (ACR, de 1991. Erosão e pinçamento articular foram graduados pelo índice de Sharp modificado. A análise estatística empregou os testes do Qui-quadrado, Mann Whitney e Kruskal-Wallis. RESULTADOS: Nenhum dos dois anticorpos demonstrou associação significativa com atividade da doença, sexo, idade de início da doença, presença de nódulos subcutâneos e síndrome de Sjögren. A média de idade foi significativamente menor nos pacientes com AR anti-CCP positivos. A positividade para o FR e anti-CCP foi maior nos pacientes com AR com menos de 50 anos em comparação com os pacientes com mais de 50 anos. A AR de início recente (OBJECTIVE: Evaluate the association of Anti-Cyclic Citrullinated Peptide Antibody (anti-CCP with distinct clinic, serological and radiological parameters. METHODS: anti-CCP and rheumatoid factor (RF were determined in the serum of 100 patients with rheumatoid arthritis (RA. Disease activity was defined by means of a combined index with five parameters: number of swollen joints, number of painful joints, morning stiffness, pain visual analogue scale (VAS, and erythrocyte sedimentation rate (ESR. Functional capacity was measured by (Health Assessment Questionnaire HAQ index and the functional class

  20. Total synthesis of cyclic heptapeptide euryjanicin B

    Institute of Scientific and Technical Information of China (English)

    Chun Mei Zhang; Jun Xiang Guo; Liang Wang; Xiao Yun Chai; Hong Gang Hu; Qiu Ye Wu

    2011-01-01

    The first synthesis of the naturally occurring cyclic peptide euryjanicin B has been achieved. A general method was described to synthesize the cyclic peptide by a two-step solid-phase/solution synthesis strategy. All the amino acids in this study are L-configuration, The linear heptapeptide was assembled by standard Fmoc chemistry on solid-phase and subsequently cyclization was carried out by solution method.

  1. Cyclic derangements

    CERN Document Server

    Assaf, Sami H

    2010-01-01

    A classic problem in enumerative combinatorics is to count the number of derangements, that is, permutations with no fixed point. Inspired by a recent generalization to facet derangements of the hypercube by Gordon and McMahon, we generalize this problem to enumerating derangements in the wreath product of any finite cyclic group with the symmetric group. We also give q- and (q, t)-analogs for cyclic derangements, generalizing results of Brenti and Gessel.

  2. Cartilage oligomeric matrix protein associates differentially with erosions and synovitis and has a different temporal course in cyclic citrullinated peptide antibody (anti-CCP)-positive versus anti-CCP-negative early rheumatoid arthritis

    DEFF Research Database (Denmark)

    Christensen, Anne F; Lindegaard, Hanne; Hørslev-Petersen, Kim;

    2011-01-01

    -suppressive effect. We aimed to compare circulating cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in untreated anti-CCP-positive and anti-CCP-negative RA, and to study the temporal pattern of COMP through 4 years of treatment, including the relationship to imaging and clinical findings......OBJECTIVE: Cyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative rheumatoid arthritis (RA) have been suggested as 2 distinctive disease subsets with respect to disease activity and prognosis. Previously, we proposed that anti-CCP antibodies might have a chondrocyte......-CCP, Health Assessment Questionnaire, visual analog scale scores for pain and global and physician assessment, and magnetic resonance imaging (MRI) of the nondominant hand were recorded at baseline. COMP in serum was measured by ELISA at inclusion and serially through 4 years. RESULTS: Median baseline COMP...

  3. A systematic study of the influence of peptide modification of a gold electrode on the cyclic voltammetry of pseudoazurin from Alcaligenes faecalis strain S-6

    NARCIS (Netherlands)

    Astier, Y; Bond, AM; Wijma, HJ; Canters, GW; Hill, HAO; Davis, JJ

    2004-01-01

    The influence of peptide-protein interactions on the electrochemistry of copper-containing pseudoazurin from Alcaligenes faecalis strain S-6 has been investigated by covalently binding cysteine-containing hexapeptides to a gold electrode surface. The hexapeptides contain three cysteines in the same

  4. Optimization of a siRNA Carrier Modified with a pH-Sensitive Cationic Lipid and a Cyclic RGD Peptide for Efficiently Targeting Tumor Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Tomoya Hada

    2015-09-01

    Full Text Available In recent years, anti-angiogenic therapy has attracted much interest because it is a versatile approach to treating most types of tumors, and therefore would be expected to be applicable for various cancers. Severe adverse events in patients treated with currently available anti-angiogenic therapeutics have, however, been reported, and these are caused by their inhibitory effects in normal tissue. To achieve an efficient anti-angiogenic therapy with minimal toxicity, a drug delivery system (DDS specific to tumor endothelial cells (TECs is needed. Cyclic RGD (cRGD is a well-known ligand against αVβ3 integrin that is expressed at high levels in the cell surface of TECs. To address this issue, we previously developed a cyclic RGD-equipped liposomal DDS (RGD-MEND in which small interfering RNA (siRNA was encapsulated. However, in the previous study, details of the preparation steps were not thoroughly examined. In this paper, to produce the most efficient delivery of therapeutic TECs, we explored optimum preparation conditions and components of the RGD-MEND. The cellular uptake and silencing ability of the RGD-MEND were investigated as a function of ligand density, poly(ethyleneglycol linker length, and lipid composition. As a result, a knockdown efficiency that was five-fold higher than that of the previously reported one (ED50, from 4.0 to 0.75 mg/kg was achieved.

  5. Cyclic Voltammetry.

    Science.gov (United States)

    Evans, Dennis H.; And Others

    1983-01-01

    Cyclic voltammetry is a simple experiment that has become popular in chemical research because it can provide useful information about redox reactions in a form which is easily obtained and interpreted. Discusses principles of the method and illustrates its use in the study of four electrode reactions. (Author/JN)

  6. Cyclic multiverses

    CERN Document Server

    Marosek, Konrad; Balcerzak, Adam

    2015-01-01

    Starting with the idea of regularization of singularities due to the variability of the fundamental constants in cosmology we first study the cyclic universe models. We find two models of oscillating mass density and pressure regularized by varying gravitational constant $G$. Then, we extend this idea onto the multiverse containing cyclic individual universes with either growing or decreasing entropy though leaving the net entropy constant. In order to get the key idea, we consider the doubleverse with the same geometrical evolution of the two "parallel" universes with their physical evolution (physical coupling constants $c(t)$ and $G(t)$) being different. An interesting point is that there is a possibility to exchange the universes at the point of maximum expansion -- the fact which was already noticed in quantum cosmology. Similar scenario is also possible within the framework of Brans-Dicke theory.

  7. Uncoupling of collagen II metabolism in newly diagnosed, untreated rheumatoid arthritis is linked to inflammation and antibodies against cyclic citrullinated peptides

    DEFF Research Database (Denmark)

    Christensen, Anne Friesgaard; Hørslev-Petersen, Kim; Christgau, Stephan;

    2010-01-01

    Objective. To investigate the relationship between markers of collagen 11 synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naive to disease-modifying antirheumatic drugs....... Methods. One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the crosslinked C......-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PHANP and CTX-II measurements. Results. PIIANP was low...

  8. Intrinsic Folding Proclivities in Cyclic β-Peptide Building Blocks: Configuration and Heteroatom Effects Analyzed by Conformer-Selective Spectroscopy and Quantum Chemistry.

    Science.gov (United States)

    Alauddin, Mohammad; Gloaguen, Eric; Brenner, Valérie; Tardivel, Benjamin; Mons, Michel; Zehnacker-Rentien, Anne; Declerck, Valérie; Aitken, David J

    2015-11-09

    This work describes the use of conformer-selective laser spectroscopy following supersonic expansion to probe the local folding proclivities of four-membered ring cyclic β-amino acid building blocks. Emphasis is placed on stereochemical effects as well as on the structural changes induced by the replacement of a carbon atom of the cycle by a nitrogen atom. The amide A IR spectra are obtained and interpreted with the help of quantum chemistry structure calculations. Results provide evidence that the building block with a trans-substituted cyclobutane ring has a predilection to form strong C8 hydrogen bonds. Nitrogen-atom substitution in the ring induces the formation of the hydrazino turn, with a related but distinct hydrogen-bonding network: the structure is best viewed as a bifurcated C8/C5 bond with the N heteroatom lone electron pair playing a significant acceptor role, which supports recent observations on the hydrazino turn structure in solution. Surprisingly, this study shows that the cis-substituted cyclobutane ring derivative also gives rise predominantly to a C8 hydrogen bond, although weaker than in the two former cases, a feature that is not often encountered for this building block.

  9. Imaging tumors with peptide-based radioligands

    Energy Technology Data Exchange (ETDEWEB)

    Behr, T. M.; Gotthardt, M.; Barth, A.; Behe, M. [Philipps-University of Marburg, Dept. of Nuclear Medicine, Marburg (Germany)

    2001-06-01

    Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over)-expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review aims to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. In {sup 111}In-DTPA-(D-Phe{sup 1})-octreotide is the first and only radio peptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), it was postulated the expression of the corresponding (i.e. cholecystokinin (CCK-)-B) receptor type in human MTC. This receptor is also widely expressed on human small-cell lung. Indeed, {sup 111}In-labeled DTPA

  10. Cyclic multiverses

    Science.gov (United States)

    Marosek, Konrad; Dąbrowski, Mariusz P.; Balcerzak, Adam

    2016-09-01

    Using the idea of regularization of singularities due to the variability of the fundamental constants in cosmology we study the cyclic universe models. We find two models of oscillating and non-singular mass density and pressure (`non-singular' bounce) regularized by varying gravitational constant G despite the scale factor evolution is oscillating and having sharp turning points (`singular' bounce). Both violating (big-bang) and non-violating (phantom) null energy condition models appear. Then, we extend this idea on to the multiverse containing cyclic individual universes with either growing or decreasing entropy though leaving the net entropy constant. In order to get an insight into the key idea, we consider the doubleverse with the same geometrical evolution of the two `parallel' universes with their physical evolution [physical coupling constants c(t) and G(t)] being different. An interesting point is that there is a possibility to exchange the universes at the point of maximum expansion - the fact which was already noticed in quantum cosmology. Similar scenario is also possible within the framework of Brans-Dicke theory where varying G(t) is replaced by the dynamical Brans-Dicke field φ(t) though these theories are slightly different.

  11. Comparison of Two Assays to Determine Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis in relation to Other Chronic Inflammatory Rheumatic Diseases: Assaying Anti-Modified Citrullinated Vimentin Antibodies Adds Value to Second-Generation Anti-Citrullinated Cyclic Peptides Testing

    Science.gov (United States)

    Díaz-Toscano, Miriam Lizette; Olivas-Flores, Eva Maria; Zavaleta-Muñiz, Soraya Amali; Gamez-Nava, Jorge Ivan; Cardona-Muñoz, Ernesto German; Ponce-Guarneros, Manuel; Castro-Contreras, Uriel; Nava, Arnulfo; Salazar-Paramo, Mario; Celis, Alfredo; Fajardo-Robledo, Nicte Selene; Corona-Sanchez, Esther Guadalupe; Gonzalez-Lopez, Laura

    2014-01-01

    Determination of anti-citrullinated peptide antibodies (ACPA) plays a relevant role in the diagnosis of rheumatoid arthritis (RA). To date, it is still unclear if the use of several tests for these autoantibodies in the same patient offers additional value as compared to performing only one test. Therefore, we evaluated the performance of using two assays for ACPA: second-generation anti-citrullinated cyclic peptides antibodies (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV) antibodies for the diagnosis of RA. We compared three groups: RA (n = 142), chronic inflammatory disease (CIRD, n = 86), and clinically healthy subjects (CHS, n = 56) to evaluate sensitivity, specificity, predictive values, and likelihood ratios (LR) of these two assays for the presence of RA. A lower frequency of positivity for anti-CCP2 was found in RA (66.2%) as compared with anti-MCV (81.0%). When comparing RA versus other CIRD, sensitivity increased when both assays were performed. This strategy of testing both assays had high specificity and LR+. We conclude that adding the assay of anti-MCV antibodies to the determination of anti-CCP2 increases the sensitivity for detecting seropositive RA. Therefore, we propose the use of both assays in the initial screening of RA in longitudinal studies, including early onset of undifferentiated arthritis. PMID:25025037

  12. Comparison of Two Assays to Determine Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis in relation to Other Chronic Inflammatory Rheumatic Diseases: Assaying Anti-Modified Citrullinated Vimentin Antibodies Adds Value to Second-Generation Anti-Citrullinated Cyclic Peptides Testing

    Directory of Open Access Journals (Sweden)

    Miriam Lizette Díaz-Toscano

    2014-01-01

    Full Text Available Determination of anti-citrullinated peptide antibodies (ACPA plays a relevant role in the diagnosis of rheumatoid arthritis (RA. To date, it is still unclear if the use of several tests for these autoantibodies in the same patient offers additional value as compared to performing only one test. Therefore, we evaluated the performance of using two assays for ACPA: second-generation anti-citrullinated cyclic peptides antibodies (anti-CCP2 and anti-mutated citrullinated vimentin (anti-MCV antibodies for the diagnosis of RA. We compared three groups: RA (n=142, chronic inflammatory disease (CIRD, n=86, and clinically healthy subjects (CHS, n=56 to evaluate sensitivity, specificity, predictive values, and likelihood ratios (LR of these two assays for the presence of RA. A lower frequency of positivity for anti-CCP2 was found in RA (66.2% as compared with anti-MCV (81.0%. When comparing RA versus other CIRD, sensitivity increased when both assays were performed. This strategy of testing both assays had high specificity and LR+. We conclude that adding the assay of anti-MCV antibodies to the determination of anti-CCP2 increases the sensitivity for detecting seropositive RA. Therefore, we propose the use of both assays in the initial screening of RA in longitudinal studies, including early onset of undifferentiated arthritis.

  13. Cyclic Vitalism

    DEFF Research Database (Denmark)

    Halse, Sven

    2014-01-01

    of taking such a unilateral view of what constituted a Vitalist concept of life. It could lead to a misunderstanding of Vitalist way of thinking, Rasch said, if the focus were only set upon the enthusiastic surplus, the worshipping of youth and health. To Vitalists, life is more than that. It is a totality...... that also encompasses notions of destruction, decay and death. “All life symbols in literature around 1900 are at the same time symbols of death”. (Rasch, W. 1967:24) Through the analyses of three poems, this article aims to show concrete examples of how cyclic Vitalist thinking is embedded in poetry...... of the era. The analyses include a further sub-categorisation to capture the different types of Life Force dealt with in the texts. By way of an introduction, Vitalism is discussed within the context of the scientific and social developments of the 19th Century....

  14. Cyclic modular beta-sheets.

    Science.gov (United States)

    Woods, R Jeremy; Brower, Justin O; Castellanos, Elena; Hashemzadeh, Mehrnoosh; Khakshoor, Omid; Russu, Wade A; Nowick, James S

    2007-03-07

    The development of peptide beta-hairpins is problematic, because folding depends on the amino acid sequence and changes to the sequence can significantly decrease folding. Robust beta-hairpins that can tolerate such changes are attractive tools for studying interactions involving protein beta-sheets and developing inhibitors of these interactions. This paper introduces a new class of peptide models of protein beta-sheets that addresses the problem of separating folding from the sequence. These model beta-sheets are macrocyclic peptides that fold in water to present a pentapeptide beta-strand along one edge; the other edge contains the tripeptide beta-strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. The pentapeptide and Hao-containing peptide strands are connected by two delta-linked ornithine (deltaOrn) turns [JACS 2003, 125, 876]. Each deltaOrn turn contains a free alpha-amino group that permits the linking of individual modules to form divalent beta-sheets. These "cyclic modular beta-sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular beta-sheets 1a-1h containing sequences based on beta-amyloid and macrophage inflammatory protein 2 were synthesized and characterized by 1H NMR. Linked cyclic modular beta-sheet 2, which contains two modules of 1b, was also synthesized and characterized. 1H NMR studies show downfield alpha-proton chemical shifts, deltaOrn delta-proton magnetic anisotropy, and NOE cross-peaks that establish all compounds but 1c and 1g to be moderately or well folded into a conformation that resembles a beta-sheet. Pulsed-field gradient NMR diffusion experiments show little or no self-association at low (

  15. The status of rheumatoid factor and anti-cyclic citrullinated peptide antibody are not associated with the effect of anti-TNFα agent treatment in patients with rheumatoid arthritis: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Qianwen Lv

    Full Text Available OBJECTIVES: This meta-analysis was conducted to investigate whether the status of rheumatoid factor (RF and anti-cyclic citrullinated peptide (anti-CCP antibody are associated with the clinical response to anti-tumor necrosis factor (TNF alpha treatment in rheumatoid arthritis (RA. METHODS: A systemic literature review was performed using the MEDLINE, SCOPUS, Cochrane Library, ISI Web of Knowledge, and Clinical Trials Register databases, and Hayden's criteria of quality assessment for prognostic studies were used to evaluate all of the studies. The correlation between the RF and anti-CCP antibody status with the treatment effect of anti-TNFα agents was analyzed separately using the Mantel Haenszel method. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was applied. Publication bias was assessed using Egger's linear regression and a funnel plot. RESULTS: A total of 14 studies involving 5561 RA patients meeting the inclusion criteria were included. The overall analysis showed that the pooled relative risk for the predictive effects of the RF and anti-CCP antibody status on patient response to anti-TNFα agents was 0.98 (95% CI: 0.91-1.05, p=0.54 and 0.88 (95% CI: 0.76-1.03, p=0.11, respectively, with I(2 values of 43% (p=0.05 and 67% (p<0.01, respectively. Subgroup analyses of different anti-TNFα treatments (infliximab vs. etanercept vs. adalimumab vs. golimumab, response criteria (DAS28 vs. ACR20 vs. EULAR response, follow-up period (≥ 6 vs. <6 months, and ethnic group did not reveal a significant association for the status of RF and anti-CCP. CONCLUSIONS: Neither the RF nor anti-CCP antibody status in RA patients is associated with a clinical response to anti-TNFα treatment.

  16. Dynamic Cyclic Thiodepsipeptide Libraries from Thiol-Thioester Exchange

    Science.gov (United States)

    2010-04-01

    the reaction dynamics are discussed. Cyclic peptides have been described as “privileged structures” for drug design because so many natural and...inhibitors, which hold promise for treatment of cancer.4 As drug scaffolds, cyclic peptides are advantageous because they mimic native protein structure...but instead an influence of chirality on the accessibility of the thioester or thiol. We also investigated the effect of positively charged amino

  17. Design and Activity Determination of Cyclic RGD Peptide and Preparation of 99Tcm Labeled Cyclic RGD Dimer%RGD多肽类药物设计、活性测定及99Tcm-cRGD二聚体的制备

    Institute of Scientific and Technical Information of China (English)

    张丽; 张春丽; 王荣福; 闫平; 康磊; 郭凤琴; 魏海亮; 崔永刚; 卢霞

    2011-01-01

    通过V-life计算机模拟软件建立cRGD(cyclic Arg-Gly-Asp,cRGD)多肽类分子库,利用V-life软件中的DOCK功能对分子库内cRGD肽结构进行筛选评分,挑选出能与整合素αvβ3受体高特异性结合的cRGD 结构.将该结构进行改造后制备成二聚体,用99Tcm对该结构进行标记,制备成肿瘤分子探针.并对其标记条件、稳定性、水溶性和亲和力进行评价.结果表明,DOCK功能计算出评分最佳的cRGD分子结构为Cys-Arg-Gly-Asp-(D)Ser-Cys.将该结构进行改造制备成二聚体后,室温下、ρ(SnCl2·2H2O)=1 g/L、反应时间为30 min时,标记率可达(87.42±3.21)%,经Sephadex G10层析柱纯化后,其放化纯大于95%;在室温和37℃条件下,99Tcm-cRGD于生理盐水和正常人新鲜血清中均保持良好的标记稳定性;其脂水分配系数对数值lg P(正辛醇/生理盐水)为-1.96±0.01;与U87人神经胶质瘤细胞进行受体的放射性配基结合分析(radioligand binding assay of receptors,RBA)实验,其平衡解离常数(equilibrium dissociation constant,Kd)为(0.089±0.052)×10-9 L/mol.这表明,通过计算机模拟系统筛选出的cRGD肽可与整合素αvβ3特异性结合,是一种有前景的整合素αvβ3受体阳性肿瘤显像剂.%This paper was to design a cyclic RGD peptide tumor inhibitor with high affinity to integrin αvβ3 receptor by molecular docking technique. cRGD molecular library was built and an optimal structure of cRGD peptide with the lowest score that was Cys-Arg-Gly-Asp-(D)Ser-Cy s was screened out using the function of DOCK procedure of the V-life software. Based on the moiety a dimer linked by Tyr-(D)Ser-Lys-(D)Ser-Ser and with a side chain Gly-Gly-(D)Ala-Gly on Lys was synthesisized and 99Tcm-cRGD dimer was prepared. Its radiolabeled efficiency,stability, water-soluble and affinity in vitro were evaluated. Under the reaction condition of room temperature, 1 g/L SnCl2 · 2H2O and the 30 min of reaction time, labeling efficiency reachs (87

  18. Superextensions of cyclic semigroups

    Directory of Open Access Journals (Sweden)

    V. M. Gavrylkiv

    2013-06-01

    Full Text Available Given a cyclic semigroup $S$ we study right and left zeros,singleton left ideals, the minimal ideal, left cancelable andright cancelable elements of superextensions $lambda(S$ andcharacterize cyclic semigroups whose superextensions arecommutative.

  19. Presence of antibodies to cyclic citrullinated peptides in juvenile-onset systemic lupus erythematosus%儿童系统性红斑狼疮抗环瓜氨酸肽抗体检测及其临床意义

    Institute of Scientific and Technical Information of China (English)

    刘海英; 刘云锋; 关启鸿; 钟艳玲; 皮蕾; 张白杜; 郭彩娇; 曾华松

    2010-01-01

    Objective To determine the prevalence of antibodies to cyclic citrullinated peptides (antiCCP) in patients with juvenile-onset systemic lupus erythematosus (JSLE) and its potential clinical significance. Methods Anti-CCP was measured in sera from patients with JSLE (n=47), juvenile idiopathic arthritis (JIA, n=54) and the sera from age-matched healthy children (n=40) using the third generation of anti-CCP ELISA commercial kit. The association of anti-CCP with other laboratory parameters and clinical features, especially arthritic symptoms in JSLE was also analyzed. T-test, Mann-Whitney U test, Chi-square and Fisher's exact test were used for statistical analysis. Results Out of the 47 JSLE patients, 6 (13%) were anti-CCP positive, which was significantly higher than that of the healthy controls( 13% vs 0, P<0.05 ), but not different from that of the JIA group (26%, P=0.098). RF was more prevalent in JSLE patients with anti-CCP than patients without (83% vs 15%, P<0.01 ), but there was no difference in other laboratory parameters and the clinical features ineluding the occurrence of arthritis (67% vs 51%, P>0.05). As one of the initial symptoms, arthritis was observed in 25 of 47 JSLE patients and no one had developed deforming arthropathy.There was no statistical difference in anti-CCP positivity between JSLE patients with and without articular involvement ( 16% vs 9%, P>0.05 ). Anti-CCP was not detected in any of the 3 patients with JSLE who had experienced joint pain and limited activity during 3 years follow-up. Conclusion Anti-CCP could be detected in patients with JSLE. It is noteworthy when differentiate from juvenile idiopathic arthritis, but the presence of anti-CCP does not relate with the occurrence of arthritis at presentation and persistence of arthritis in JSLE.%目的 检测儿童系统性红斑狼疮(JSLE)患者血清抗环瓜氨酸肽(CCP)抗体水平,了解抗CCP抗体在该病中的阳性检出率以及探讨其与

  20. The evaluation of rheumatoid factor, anti-cyclic citrullinated peptide antibody and antikeratin antibody in the diagnosis of rheumatoid arthritis%RF、抗CCP抗体和AKA对类风湿性关节炎诊断的评价

    Institute of Scientific and Technical Information of China (English)

    胥国强; 杨佳佳; 蒲泽宴; 康清秀

    2013-01-01

    目的 评价类风湿因子(RF)、抗环瓜氨酸肽(CCP)抗体以及抗角蛋白抗体(AKA)在类风湿性关节炎(RA)诊断中的意义.方法 对177例确诊为RA患者的上述3项指标进行回顾分析.RF、抗CCP抗体和AKA分别用速率散射比浊法、酶联免疫吸附法(ELISA)和间接免疫荧光法(ⅡF)检测.应用x2检验和Pearson相关分析,比较3种抗体在RA诊断中的价值及相关性,并讨论RF、抗CCP抗体与新诊断标准评分的关系.结果 RF、抗CCP抗体和AKA对RA诊断的灵敏度分别是77.40%、64.97%和21.47%;3种抗体中任一抗体阳性的联合检测对RA诊断的灵敏度为85.88%,任2种抗体阳性的灵敏度为58.76%,3种抗体平均阳性的灵敏度为19.21%.抗CCP抗体和AKA在6个不同RF水平组的阳性率均有显著性差异(P<0.05),其中抗CCP抗体阳性率在RF阳性各组与阴性组之间差异显著(P<0.01),并与RF呈正相关(r=0.339,P=0.000);而AKA阳性率在RF阳性各组与阴性组之间无显著性差异(P>0.01),仅在RF值500~1 000 U/mL组的阳性率显著高于RF<20 U/mL组(x2=16.485,P=0.000),AKA与RF呈正相关(r=0.184,P=0.014).抗CCP抗体与AKA呈正相关(r=0.326,P=0.000).2010年ACR/EULAR分类标准评分大于或等于6分在6个不同RF水平组的阳性率无显著性差异(x2 =8.547,P=o.129),且与RF相关(r=0.199,P=0.005);而抗CCP抗体与RA评分不相关(r=0.123,P=0.103).结论 RF、抗CCP抗体和AKA均可作为RA血清学诊断指标,三者两两相关,前两者灵敏度较高,联合检测有助于RA的早期诊断.%Objective To explore the significance of rheumatoid factor(RF),anti-cyclic citrullinated peptide(anti-CCP) antibody and anti keratin antibody(AKA) in the diagnosis of Rheumatoid Arthritis(RA).Methods 177 patients with RA,who had these three tests,were analyzed basing on retrospectively available data.RF,anti-CCP antibody and AKA were respectively detected by nephelometry,Enzyme linked immunosorbent assay(ELISA) and

  1. Affordable Cyclic Voltammetry

    Science.gov (United States)

    Stewart, Greg; Kuntzleman, Thomas S.; Amend, John R.; Collins, Michael J.

    2009-01-01

    Cyclic voltammetry is an important component of the undergraduate chemical curriculum. Unfortunately, undergraduate students rarely have the opportunity to conduct experiments in cyclic voltammetry owing to the high cost of potentiostats, which are required to control these experiments. By using MicroLab data acquisition interfaces in conjunction…

  2. Cyclic anamorphic cosmology

    CERN Document Server

    Ijjas, Anna

    2016-01-01

    Cyclic models of the universe have the advantage of avoiding initial conditions problems related to postulating any sort of beginning in time. To date, the only known viable examples of cyclic models have been ekpyrotic. In this paper, we show that the recently proposed anamorphic scenario can also be made cyclic. The key to the cyclic completion is a classically stable, non-singular bounce. Remarkably, even though the bounce construction was originally developed to connect a period of contraction with a period of expansion both described by Einstein gravity, we show here that it can naturally be modified to connect an ordinary contracting phase described by Einstein gravity with a phase of anamorphic smoothing. The paper will present the basic principles and steps in constructing cyclic anamorphic models.

  3. Fabrication of Odor Sensor Using Peptide

    Science.gov (United States)

    Hotokebuchi, Yuta; Hayashi, Kenshi; Toko, Kiyoshi; Chen, Ronggang; Ikezaki, Hidekazu

    We report fabrication of an odor sensor using peptides. Peptides were designed to acquire the specific reception for a target odor molecule. Au surface of the sensor electrode was coated by the designed peptide using the method of self assembled monolayers (SAMs). Functionalized Au surfaces by the peptides were confirmed by ellipsometry and cyclic voltammetry. The odorants of vanillin, phenethyl alcohol and hexanol were discriminated by QCM sensor with the peptide surface. Moreover, we verified specific interaction between amino acid (Trp) and vanillin by fluorescence assay.

  4. Selective inhibition by a synthetic hirudin peptide of fibrin-dependent thrombosis in baboons

    Energy Technology Data Exchange (ETDEWEB)

    Cadroy, Y.; Hanson, S.R.; Harker, L.A. (Emory Univ., Atlanta, GA (United States)); Maraganore, J.M. (Biogen Inc., Cambridge, MA (United States))

    1991-02-15

    To determine the importance of the thrombin substrate recognition exosite for fibrinogen binding in the formation of both arterial and venous thrombi the authors evaluated the antithrombotic effects of the tyrosine-sulfated dodecapeptide from residues 53-64 of hirudin (H peptide) in a nonhuman primate model. This peptide was studied because it inhibits thrombin cleavages of fibrinogen by simple competition without blocking enzyme catalytic-site function. When an exteriorized arteriovenous access shunt model was used in baboons (Papio anubis), thrombus formation was induced by placing a thrombogenic device made of (i) a segment of tubing coated covalently with type I collagen, which generated platelet-rich thrombi under arterial flow conditions, and (ii) two subsequent annular regions of flow expansion that produced fibrin-rich thrombi typically associated with venous valves and veins. Thrombus formation was quantified by measurements of {sup 111}In-labeled platelet and {sup 125}I-labeled fibrinogen deposition in both arterial-flow and venous-flow portions of the device. These finding suggest that, by competitive inhibition of fibrinogen binding to thrombin, fibrin-rich venous-type thrombus formation may be selectively prevented. This strategy may be therapeutically attractive for preserving normal platelet function when conventional anticoagulant therapy is contraindicated.

  5. Cyclic Vomiting Syndrome

    Science.gov (United States)

    ... Eating, Diet, & Nutrition Clinical Trials View All Content Gastritis Gastrointestinal (GI) Bleeding Definition & Facts Symptoms & Causes Diagnosis ... diet. References [1] Hejazi, RA, McCallum RW. Review article: cyclic vomiting syndrome in adults—rediscovering and redefining ...

  6. Cup products in Hopf cyclic cohomology via cyclic modules I

    CERN Document Server

    Rangipour, Bahram

    2007-01-01

    This is the first one in a series of two papers on the continuation of our study in cup products in Hopf cyclic cohomology. In this note we construct cyclic cocycles of algebras out of Hopf cyclic cocycles of algebras and coalgebras. In the next paper we consider producing Hopf cyclic cocycle from "equivariant" Hopf cyclic cocycles. Our approach in both situations is based on (co)cyclic modules and bi(co)cyclic modules together with Eilenberg-Zilber theorem which is different from the old definition of cup products defined via traces and cotraces on DG algebras and coalgebras.

  7. Cyclic polymers from alkynes

    Science.gov (United States)

    Roland, Christopher D.; Li, Hong; Abboud, Khalil A.; Wagener, Kenneth B.; Veige, Adam S.

    2016-08-01

    Cyclic polymers have dramatically different physical properties compared with those of their equivalent linear counterparts. However, the exploration of cyclic polymers is limited because of the inherent challenges associated with their synthesis. Conjugated linear polyacetylenes are important materials for electrical conductivity, paramagnetic susceptibility, optical nonlinearity, photoconductivity, gas permeability, liquid crystallinity and chain helicity. However, their cyclic analogues are unknown, and therefore the ability to examine how a cyclic topology influences their properties is currently not possible. We have solved this challenge and now report a tungsten catalyst supported by a tetraanionic pincer ligand that can rapidly polymerize alkynes to form conjugated macrocycles in high yield. The catalyst works by tethering the ends of the polymer to the metal centre to overcome the inherent entropic penalty of cyclization. Gel-permeation chromatography, dynamic and static light scattering, viscometry and chemical tests are all consistent with theoretical predictions and provide unambiguous confirmation of a cyclic topology. Access to a wide variety of new cyclic polymers is now possible by simply choosing the appropriate alkyne monomer.

  8. PET imaging of {alpha}{sub v}{beta}{sub 3} integrin expression in tumours with {sup 68}Ga-labelled mono-, di- and tetrameric RGD peptides

    Energy Technology Data Exchange (ETDEWEB)

    Dijkgraaf, Ingrid; Franssen, Gerben M.; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, P.O. Box 9101, Nijmegen (Netherlands); Yim, Cheng-Bin [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, P.O. Box 9101, Nijmegen (Netherlands); Utrecht University, Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht (Netherlands); Schuit, Robert C. [VU University Medical Centre, Department of Nuclear Medicine and PET Research, P.O. Box 7057, Amsterdam (Netherlands); Luurtsema, Gert [University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, P.O. Box 30.001, Groningen (Netherlands); Liu, Shuang [Purdue University, School of Health Sciences, West Lafayette, IN (United States)

    2011-01-15

    Due to the restricted expression of {alpha}{sub v}{beta}{sub 3} in tumours, {alpha}{sub v}{beta}{sub 3} is considered a suitable receptor for tumour targeting. In this study the {alpha}{sub v}{beta}{sub 3}-binding characteristics of {sup 68}Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their {sup 111}In-labelled counterparts. A monomeric (E-c(RGDfK)), a dimeric (E-[c(RGDfK)]{sub 2}) and a tetrameric (E{l_brace}E[c(RGDfK)]{sub 2}{r_brace}{sub 2}) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with {sup 68}Ga. In vitro {alpha}{sub v}{beta}{sub 3}-binding characteristics were determined in a competitive binding assay. In vivo {alpha}{sub v}{beta}{sub 3}-targeting characteristics of the compounds were assessed in mice with subcutaneously growing SK-RC-52 xenografts. In addition, microPET images were acquired using a microPET/CT scanner. The IC{sub 50} values for the Ga(III)-labelled DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)]{sub 2} and DOTA-E{l_brace}E[c(RGDfK)]{sub 2}{r_brace}{sub 2} were 23.9 {+-} 1.22, 8.99 {+-} 1.20 and 1.74 {+-} 1.18 nM, respectively, and were similar to those of the In(III)-labelled mono-, di- and tetrameric RGD peptides (26.6 {+-} 1.15, 3.34 {+-} 1.16 and 1.80 {+-} 1.37 nM, respectively). At 2 h post-injection, tumour uptake of the {sup 68}Ga-labelled mono-, di- and tetrameric RGD peptides (3.30 {+-} 0.30, 5.24 {+-} 0.27 and 7.11 {+-} 0.67%ID/g, respectively) was comparable to that of their {sup 111}In-labelled counterparts (2.70 {+-} 0.29, 5.61 {+-} 0.85 and 7.32 {+-} 2.45%ID/g, respectively). PET scans were in line with the biodistribution data. On all PET scans, the tumour could be clearly visualised. The integrin affinity and the tumour uptake followed the order of DOTA-tetramer > DOTA-dimer > DOTA-monomer. The {sup 68}Ga-labelled tetrameric RGD peptide has excellent characteristics for imaging of {alpha}{sub v} {beta}{sub 3} expression with PET. (orig.)

  9. EXPRESSED PROTEIN LIGATION. A NEW TOOL FOR THE BIOSYNTHESIS OF CYCLIC POLYPEPTIDES

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, R; Camarero, J A

    2004-11-11

    The present paper reviews the use of expressed protein ligation for the biosynthesis of backbone cyclic polypeptides. This general method allows the in vivo and in vitro biosynthesis of cyclic polypeptides using recombinant DNA expression techniques. Biosynthetic access to backbone cyclic peptides opens the possibility to generate cell-based combinatorial libraries that can be screened inside living cells for their ability to attenuate or inhibit cellular processes.

  10. [Effect of cyclic somatostatin on ethanol-induced hypoglycemia].

    Science.gov (United States)

    Piccardo, M G; Marchetti, A M; Breda, E

    1979-06-30

    The authors examined the activity of the cyclic Somatostatin on Ethanol hypoglycemia. While the peptide is capable of increasing the plasma glucose levels of hypoglicemia starved rats, it does not increase the levels of plasma glucose in normal rats under the action of ethanol perfusion.

  11. cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .

    Science.gov (United States)

    Marelli, Udaya Kiran; Ovadia, Oded; Frank, Andreas Oliver; Chatterjee, Jayanta; Gilon, Chaim; Hoffman, Amnon; Kessler, Horst

    2015-10-19

    Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template. These molecules generally showed moderate to low transport in intestinal epithelia with a few of them exhibiting a Caco-2 permeability equal to or slightly higher than that of mannitol, a marker for paracellular permeability. We identified that the majority of the permeable cyclic penta- and hexapeptides possess an N-methylated cis-peptide bond, a structural feature that is also present in the orally available peptides cyclosporine A and the tri-N-methylated analogue of the Veber-Hirschmann peptide. Based on these observations it appears that the presence of N-methylated cis-peptide bonds at certain locations may promote the intestinal permeability of peptides through a suitable conformational preorganization.

  12. The cyclic reduction algorithm

    Science.gov (United States)

    Bini, Dario; Meini, Beatrice

    2009-05-01

    Cyclic reduction is an algorithm invented by G.H. Golub and R. W. Hockney in the mid 1960s for solving linear systems related to the finite differences discretization of the Poisson equation over a rectangle. Among the algorithms of Gene Golub, it is one of the most versatile and powerful ever created. Recently, it has been applied to solve different problems from different applicative areas. In this paper we survey the main features of cyclic reduction, relate it to properties of analytic functions, recall its extension to solving more general finite and infinite linear systems, and different kinds of nonlinear matrix equations, including algebraic Riccati equations, with applications to Markov chains, queueing models and transport theory. Some new results concerning the convergence properties of cyclic reduction and its applicability are proved under very weak assumptions. New formulae for overcoming breakdown are provided.

  13. Generalized Wideband Cyclic MUSIC

    Directory of Open Access Journals (Sweden)

    Zhang-Meng Liu

    2009-01-01

    Full Text Available The method of Spectral Correlation-Signal Subspace Fitting (SC-SSF fails to separate wideband cyclostationary signals with coherent second-order cyclic statistics (SOCS. Averaged Cyclic MUSIC (ACM method made up for the drawback to some degree via temporally averaging the cyclic cross-correlation of the array output. This paper interprets ACM from another perspective and proposes a new DOA estimation method by generalizing ACM for wideband cyclostationary signals. The proposed method successfully makes up for the aforementioned drawback of SC-SSF and obtains a more satisfying performance than ACM. It is also demonstrated that ACM is a simplified form of the proposed method when only a single spectral frequency is exploited, and the integration of the frequencies within the signal bandwidth helps the new method to outperform ACM.

  14. Availability of /sup 111/In-labeled platelet scintigraphy in patients with postinfarction left ventricular aneurysm

    Energy Technology Data Exchange (ETDEWEB)

    Tsuda, Takatoshi; Kubota, Masahiro; Iwakubo, Akifumi and others

    1989-03-01

    Eighteen patients with postinfarction left ventricular aneurysm (LVA) were examined with indium-111-labeled autologous platelet scintigraphy to identify intracardiac thrombi and to investigate the effect of antithrombotic agents on thrombogenesitiy within the LVA. Indium-111-platelet scintigraphy had a sensitivity of 60% and a specificity of 100% in detecting LVA mural thrombi. Among 6 patients showing false-negative scintigraphic studies, 4 was managed on antiplatelet therapy. Of 9 patients showing active platelet deposition on initial study, including 8 not receiving antiplatelet therapy, 5 were treated with tichlopidine (300 mg/day) for 29.8+-5.0 days. For the 5 patients, 2 had resolution and the 3 others had interruption of intraaneurysmal deposition in the second platelet study. For one patient receiving the third platelet study after warfarin therapy, it took two weeks to completely interrupt platelet deposition within the LVA. ECG gated radionuclide ventriculography and thallium-201 myocardial SPECT were also performed to assess left ventricular wall motion of left ventricular ejection fraction (LVEF) and myocardial blood perfusion. Thallium-201 SPECT showed apical or anteroapical perfusion defects. Radionuclide ventriculography pinpointed all 18 apical and anteroseptal aneurysms. A comparison between the thrombus positive group and the thrombus negative group revealed no statistical differences in LVEF and the period from the last myocardial infarction to the initial platelet scanning. These results suggest that indium-111 labeled platelet scintigraphy may be useful for identifying active left ventricular mural thrombi and for judging antiplatelet and anticoagulant therapy. (Namekawa, K).

  15. Cyclic Voltammetry Experiment.

    Science.gov (United States)

    Van Benschoten, James J.; And Others

    1983-01-01

    Describes a three-part experiment designed to introduce cyclic voltammetry to graduate/undergraduate students. Part 1 demonstrates formal reduction potential, redox electron transfer, diffusion coefficient, and electrochemical reversibility. Part 2 investigates electrochemical behavior of acetaminophen. Part 3 examines such experimental variables…

  16. On Expanded Cyclic Codes

    CERN Document Server

    Wu, Yingquan

    2008-01-01

    The paper has a threefold purpose. The first purpose is to present an explicit description of expanded cyclic codes defined in $\\GF(q^m)$. The proposed explicit construction of expanded generator matrix and expanded parity check matrix maintains the symbol-wise algebraic structure and thus keeps many important original characteristics. The second purpose of this paper is to identify a class of constant-weight cyclic codes. Specifically, we show that a well-known class of $q$-ary BCH codes excluding the all-zero codeword are constant-weight cyclic codes. Moreover, we show this class of codes achieve the Plotkin bound. The last purpose of the paper is to characterize expanded cyclic codes utilizing the proposed expanded generator matrix and parity check matrix. We analyze the properties of component codewords of a codeword and particularly establish the precise conditions under which a codeword can be represented by a subbasis. With the new insights, we present an improved lower bound on the minimum distance of...

  17. Cyclic Vomiting Syndrome

    Science.gov (United States)

    ... digestive diseases specialist (gastroenterologist). If you or your child is in the middle of a severe vomiting episode, the doctor may ... system disorders There's no cure for cyclic vomiting syndrome, so treatment ... may be prescribed: Anti-nausea drugs Sedatives Medications ...

  18. 抗CCP抗体和RF联检在RA诊疗中的临床价值%Clinical Value of Combined Detection of Serum Anti-Cyclic Citrullinated Peptide Antibody(Anti-CCP Ab)and Rheumatoid Factor(RF)in Diagnosis of Rheumatoid Arthritis

    Institute of Scientific and Technical Information of China (English)

    葛文亮

    2010-01-01

    目的:研究抗环瓜氨酸肽(anti-cyclic citrullinated peptide,Anti-CCP)(抗CCP抗体)和RF的检测在类风湿关节炎(RA)诊疗中的临床价值.方法:分别用酶联免疫吸附试验(ELISA)、BeckMan全自动蛋白分析仪同时检测早期RA组(病程<1年)42例,RA组(病程>1年)40例,非RA对照组40例患者血清抗CCP抗体和RF.结果:早期RA组、RA组的抗CCP抗体、RF阳性率显著高于非RA对照组(P<0.05)RA组抗CCP水平显著高于早期RA组(P<0.01),两者RF无显著差别(P>0.05).RA组与早期RA组CCP抗体与RF二者无相关性.结论:联检抗CCP抗体、RF有助于类风湿的早期诊断和预测病情的进展.

  19. Anti-CCP和RF联合检测在诊断RA中的意义%Significance of detecting anti-cyclic citrullinated peptide and rheumatoid factor in the diagnosis of rheumatoid arthritis

    Institute of Scientific and Technical Information of China (English)

    郭玉娟

    2012-01-01

    目的 分析比较抗环瓜氨酸肽抗体(Anti-CCP)和类风湿因子(RF)在类风湿关节炎(RA)中的灵敏度和特异性,探讨将两种指标联合检测在RA诊断中的价值.方法 利用酶联免疫吸附试验和乳胶增强免疫透射比浊法分别测定76例RA 患者,56例非RA 患者血清中的Anti-CCP和RF.结果 Anti-CCP和RF在RA组的阳性率明显高于非RA组.特异度和灵敏度RF分别为76.8%、78.9%,Anti-CCP分别为96.4%、60.5%,将两者联合检测则分别为86.6%、73.1%.结论 Anti-CCP在诊断RA中具有较高的特异性和灵敏度,可作为诊断RA的新的血清学指标.将Anti-CCP和RF联合检测有助于RA的临床诊断.%Objective To analyse the specificily and sensilivily of anli-cyclic cilrullinaled peplide (Anli-CCP) and rheumatoid factor (RF) in the diagnosis of rheumatoid arlhrilis (RA) to invesligale the value when the Iwo anlibodies were used togelher. Methods ELISA and Lalex enhanced immune lurbidimelric were used to deled serum levels of Anli-CCP and RF in 76 palienls wilh RA and 56 non- RA palienls. Results The positive rale of Anli-CCP and RF of palienls wilh RA was significantly higher lhan lhal of non-RA palienls. The diagnostic specificily of RF for RA was 76. 8% and the sensilivily was 78. 9% , whereas the diagnostic specificily of Anti-CCP for RA was 96. 4% and the sensitivity was 60. 5%. The diagnostic specificily of the Anli-CCP and RF was 86. 6% and the sensitivity was 73. 1%. Conclusion The Anti-CCP might have high specificity and sensitivity, which might be used as the new serum sign for the diagnosis of RA. Combined wilh the detection of Anti-CCP and RF , the sensitivity will be higher.

  20. Cyclic Voltammograms from First Principles

    DEFF Research Database (Denmark)

    Karlberg, Gustav; Jaramillo, Thomas; Skulason, Egill

    2007-01-01

    Cyclic voltammetry is a fundamental experimental tool for characterizing electrochemical surfaces. Whereas cyclic voltammetry is widely used within the field of electrochemistry, a way to quantitatively and directly relate the cyclic voltammogram to ab initio calculations has been lacking, even f...

  1. The Cyclic Model Simplified

    CERN Document Server

    Steinhardt, P J; Steinhardt, Paul J.; Turok, Neil

    2004-01-01

    The Cyclic Model attempts to resolve the homogeneity, isotropy, and flatness problems and generate a nearly scale-invariant spectrum of fluctuations during a period of slow contraction that precedes a bounce to an expanding phase. Here we describe at a conceptual level the recent developments that have greatly simplified our understanding of the contraction phase and the Cyclic Model overall. The answers to many past questions and criticisms are now understood. In particular, we show that the contraction phase has equation of state w>1 and that contraction with w>1 has a surprisingly similar properties to inflation with w < -1/3. At one stroke, this shows how the model is different from inflation and why it may work just as well as inflation in resolving cosmological problems.

  2. Dynamics of cyclic machines

    CERN Document Server

    Vulfson, Iosif

    2015-01-01

    This book focuses on modern methods of oscillation analysis in machines, including cyclic action mechanisms (linkages, cams, steppers, etc.). It presents schematization techniques and mathematical descriptions of oscillating systems, taking into account the variability of the parameters and nonlinearities, engineering evaluations of dynamic errors, and oscillation suppression methods. The majority of the book is devoted to the development of new methods of dynamic analysis and synthesis for cyclic machines that form regular oscillatory systems with multiple duplicate modules.  There are also sections examining aspects of general engineering interest (nonlinear dissipative forces, systems with non-stationary constraints, impacts and pseudo-impacts in clearances, etc.)  The examples in the book are based on the widely used results of theoretical and experimental studies as well as engineering calculations carried out in relation to machines used in the textile, light, polygraphic and other industries. Particu...

  3. Geometry of Cyclic Pursuit

    Science.gov (United States)

    2009-12-18

    analysis of the equilibria based on linearization of the shape dynamics. In [10], the authors extend their analysis to incorporate feedback control...differentiable curves in R2, deriving our dynamics from the natural Frenet frame equations (see, e.g., [5] for details). (A three- dimensional analysis of...cyclic pursuit formulated in terms of the natural Frenet frame equations is a topic of ongoing work.) As is depicted in figure 1, we let ri denote the

  4. Diagnosis of Cyclic Vomiting

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-12-01

    Full Text Available In a study at Children’s Hospital, Ann Arbor, MI, and Children’s Memorial Hospital, Chicago, designed primarily to compare cost-effectiveness of three methods of management of cyclic vomiting cases, one group of patients received an extensive diagnostic evaluation, a second was treated with empiric antimigraine drugs for 2 months, and a third an upper GI series with small-bowel follow-through (UGI-SBFT plus empiric therapy.

  5. Synthesis of peptide .alpha.-thioesters

    Science.gov (United States)

    Camarero, Julio A.; Mitchell, Alexander R.; De Yoreo, James J.

    2008-08-19

    Disclosed herein is a new method for the solid phase peptide synthesis (SPPS) of C-terminal peptide .alpha. thioesters using Fmoc/t-Bu chemistry. This method is based on the use of an aryl hydrazine linker, which is totally stable to conditions required for Fmoc-SPPS. When the peptide synthesis has been completed, activation of the linker is achieved by mild oxidation. The oxidation step converts the acyl-hydrazine group into a highly reactive acyl-diazene intermediate which reacts with an .alpha.-amino acid alkylthioester (H-AA-SR) to yield the corresponding peptide .alpha.-thioester in good yield. A variety of peptide thioesters, cyclic peptides and a fully functional Src homology 3 (SH3) protein domain have been successfully prepared.

  6. 抗环瓜氨酸肽抗体和类风湿因子联合检测对类风湿关节炎的临床价值%Clinical value of combined detection of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rhenmatoid arthritis

    Institute of Scientific and Technical Information of China (English)

    阮艳秋; 殷明刚; 刘伟平

    2016-01-01

    目的:探讨抗环瓜氨酸肽(CCP)抗体和类风湿因子(RF)联合检测对类风湿关节炎(RA )诊治的临床价值。方法收集2013年11月至2014年12月该院182例风湿性疾病患者血清,采用 ELISA 方法检测 CCP 抗体,使用免疫透射比浊终点法检测 RF 。结果(1)182例患者中 RA 99例,CCP 中位数是4.20,RF 是392,非类风湿疾病患者83例,CCP 中位数是2.30,RF 是20.1,健康对照者106例,CCP 中位数是1.23,RF 是12.3。健康对照者与非风湿性疾病患者比较,差异无统计学意义(P>0.05);与 RA 患者比较,差异有统计学意义(P <0.01)。(2) CCP 抗体诊断 RA 的特异度是90.5%,RF 是79.2%,CCP 抗体高于 RF ,差异有统计学意义(P <0.05);CCP 抗体和 RF 联合检测诊断 RA 的灵敏度是71.4%,特异度是96.2%,高于单项检测(P<0.01)。 CCP 抗体和 RF 的灵敏度比较,差异无统计学意义(P>0.05)。 CCP 抗体特异度高于 RF 。结论 CCP 抗体和 RF 联合检测有助于 RA 的诊断和疗效监测,具有较高的临床意义。%Objective To estimate the clinical value of combined detection of anti‐cyclic citrullinated peptide (anti‐ccp)antibody and rheumatoid factor(RF) for the rhenmatoid arthritis .Methods Having collected the serum of 182 patients with rheumatic diseases in our hospital from November 2013 to December 2014 .With ELISA method measuring CCP and use immunity transmission turbidity to measurement RF ,the results were compared and ana‐lyzed .Results (1)Among the serum of 182 cases of patients ,99 cases were with rheumatoid arthritis ,with median of CCP 4 .20 and RF 392 .83 cases were with non‐rheumatoid diseases ,that with median of CCP 2 .30 and RF 20 .1 .106 cases of healthy control were ,with median of CCP 1 .23 and RF 12 .3 .Compared with non‐rheumatoid diseases ,P>0 .05 and the difference was of no statistical

  7. Application of Rheumatoid Factor and Anti Cyclic Citrullinated Peptide Combined Detection in the Early Diagnosis of Rheumatoid Arthritis%类风湿因子及抗环瓜氨酸肽联合检测在类风湿关节炎早期诊断中应用

    Institute of Scientific and Technical Information of China (English)

    曾频频

    2015-01-01

    目的:探讨类风湿关节炎早期诊断。方法采用整群抽样的方法,选取2013年1月~2015年1月到医院就诊的46例类风湿性关节炎疑似患者和52例确诊类风湿性关节炎1年以上, ELISA法检测血清类风湿因子(RF)、抗环瓜氨酸肽(CCP)水平。结果 RF联和抗CCP抗体诊断疑似类风湿性关节炎,1年以上的类风湿性关节炎的诊断阳性率分别为71.15%和82.61%,明显高于RF和抗CCP抗体单独测试(<0.05)。结论 RF联和抗CCP抗体对早期诊断类风湿性关节炎,效果优于RA和CCP的两中检测单用。%Objective To investigate the ef ect of RF and CCP in the early diagnosis of rheumatoid arthritis. Methods Using cluster sampling, selected in April 2009 to 2012 April to the hospital for treatment of rheumatoid arthritis suspected patients and 46 cases of diagnosed 1 year more than 52 cases that were, by ELISA detection of serum rheumatoid factor (RF) and anti cyclic citrul inated peptide (CCP) levels. Results RF and anti CCP for suspected rheumatoid arthritis and diagnosed for more than 1 year rheumatoid arthritis diagnosis positive rate was 71.15% and 82.61%, was significantly higher than that of RF and anti CCP testing alone ( <0.05). Conclusion In the early diagnosis of RF, the ef ect of RA and CCP was bet er than that of the two.

  8. To evaluate the clinical diagnosic value of anti-cyclic citrul inated peptide(anti-CCP) antibody and rheumatoid factor(RF) in patients with rheumatoid arthritis(RA)%联合检测抗CCP抗体与RF对类风湿关节炎诊断的临床意义

    Institute of Scientific and Technical Information of China (English)

    赵海燕

    2014-01-01

    目的:探讨联合检测抗环瓜氨酸肽抗体(抗CCP抗体)及类风湿因子(RF)对类风湿性关节炎(RA)的临床诊断价值。方法:分别检测130例RA患者,98例非RA的风湿病患者及40例正常人血清的抗CCP抗体和RF。结果:抗CCP抗体和RF联合检测的特异性,阳性预测值,阳性似然比,阴性似然比与任何单一项检测比较均有显著差异(P<0.05)。结论:联合检测抗CCP抗体和RF可明显提高类风湿性关节炎的诊断率。%Objective: To evaluate the clinical diagnosic value of anti-cyclic citrul inated peptide(anti-CCP) antibody and rheumatoid factor(RF) in patients with rheumatoid arthritis(RA). Methods: Anti-CCP antibody was defected by quantitative ELISA and rheumatoid factor by BNP nephelometer in 130 cases of RA, 98 cases of non-RA rheumatic diseases and 40 cases of healthy individuals. Results: The diagnosis specificity, positive predictive value, positive/negative likelihood ratios of combinate determination of anti-CCP antibody and RF were significantly higher than either one. Conclusion: The measurements of anti-CCP antibody and rheumatoid factor wil remarkably improve the accuracy of diagnosis of RA.

  9. The Diagnostic Value of Combinate Determination of Anti-cyclic Citrullinated Peptide Antibody and Rheumatoid Factor for the Rheumatoid Arthritis%抗CCP抗体与RF联合检测对类风湿性关节炎的诊断价值

    Institute of Scientific and Technical Information of China (English)

    游其勇; 易朝阳

    2011-01-01

    目的 探讨联合检测抗环瓜氨酸肽抗体(抗CCP抗体)及类风湿因子(RF)对类风湿关节炎(RA)的临床诊断价值.方法 分别用胶体金免疫层析法(GICA)、速率散射比浊法联合检测52例RA患者、37例非RA的自身免疫性疾病患者和15例正常人血清中抗CCP抗体和RF.结果 抗CCP抗体和RF联合检测的特异性、阳性预测值、阳性似然比、阴性似然比与任何单一项检测比较差异均有统计学意义(P<0.05).结论 联合检测抗CCP抗体和RF可明显提高类风湿关节炎的诊断率.%Objective To evaluate the clinical diagnosic value of anti - cyclic citrullinated peptide(anti- CCP) antibody and rheumatoid factor(RF) in patients with rhetrnatoid arthritis(PA).Methods Anti - CCP antibody was determined by quantitative GICA and rheumatoid factor by BNP nephelometer in 52 cases of PA ,37 cases of non - PA rhetrnatic diseases and 15 healths.Results The diagnosis specificity, positive predictive value, positive/negative likelihood ratios of combinate determination of anti - CCP antibodyand RF were significantly higher than either one.Conclusion The combinate determination of anti - CCP antibody and rheumatoid factor will remarkably improve the accuracy for diagnosis of RA.

  10. The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: A proof-of-concept study using the integrin-binding RGD motif.

    Science.gov (United States)

    Conibear, Anne C; Bochen, Alexander; Rosengren, K Johan; Stupar, Petar; Wang, Conan; Kessler, Horst; Craik, David J

    2014-02-10

    Peptides have the specificity and size required to target the protein-protein interactions involved in many diseases. Some cyclic peptides have been utilised as scaffolds for peptide drugs because of their stability; however, other cyclic peptide scaffolds remain to be explored. θ-Defensins are cyclic peptides from mammals; they are characterised by a cyclic cystine ladder motif and have low haemolytic and cytotoxic activity. Here we demonstrate the potential of the cyclic cystine ladder as a scaffold for peptide drug design by introducing the integrin-binding Arg-Gly-Asp (RGD) motif into the θ-defensin RTD-1. The most active analogue had an IC50 of 18 nM for the αv β3 integrin as well as high serum stability, thus demonstrating that a desired bioactivity can be imparted to the cyclic cystine ladder. This study highlights how θ-defensins can provide a stable and conformationally restrained scaffold for bioactive epitopes in a β-strand or turn conformation. Furthermore, the symmetry of the cyclic cystine ladder presents the opportunity to design peptides with dual bioactive epitopes to increase activity and specificity.

  11. Development of a renal collecting duct homing peptide using phage display

    DEFF Research Database (Denmark)

    Svenningsen, Per; Peti-Peterdi, Janos

    Homing peptides are useful for in vivo labeling and nonviral gene transfer to selective tissues and cell types. The aim of this project was to develop a renal collecting duct homing peptide. Using phage display, we identified a phage expressing a cyclic 7 amino acid peptide, which was internalize...

  12. [Asthma and cyclic neutropenia].

    Science.gov (United States)

    Salazar Cabrera, A N; Berrón Pérez, R; Ortega Martell, J A; Onuma Takane, E

    1996-01-01

    We report a male with history of recurrent infections (recurrent oral aphtous disease [ROAD], middle ear infections and pharyngo amigdalitis) every 3 weeks since he was 7 months old. At the age of 3 years cyclic neutropenia was diagnosed with cyclic fall in the total neutrophil count in blood smear every 21 days and prophylactic antimicrobial therapy was indicated. Episodic events every 3 weeks of acute asthma and allergic rhinitis were detected at the age of 6 years old and specific immunotherapy to Bermuda grass was given during 3 years with markedly improvement in his allergic condition but not in the ROAD. He came back until the age of 16 with episodic acute asthma and ROAD. The total neutrophil count failed to 0 every 21 days and surprisingly the total eosinophil count increased up to 2,000 at the same time, with elevation of serum IgE (412 Ul/mL). Specific immunotherapy to D.pt. and Aller.a. and therapy with timomodulin was indicated. After 3 months we observed clinical improvement in the asthmatic condition and the ROAD disappeared, but the total neutrophil count did not improve. We present this case as a rare association between 2 diseases with probably no etiological relationship but may be physiopatological that could help to understand more the pathogenesis of asthma.

  13. Ekpyrotic and Cyclic Cosmology

    CERN Document Server

    Lehners, Jean-Luc

    2008-01-01

    Ekpyrotic and cyclic cosmologies provide theories of the very early and of the very late universe. In these models, the big bang is described as a collision of branes - and thus the big bang is not the beginning of time. Before the big bang, there is an ekpyrotic phase with equation of state w=P/rho >> 1 (where P is the average pressure and rho the average energy density) during which the universe slowly contracts. This phase resolves the standard cosmological puzzles and generates a nearly scale-invariant spectrum of cosmological perturbations containing a significant non-gaussian component. At the same time it produces small-amplitude gravitational waves with a blue spectrum. The dark energy dominating the present-day cosmological evolution is reinterpreted as a small attractive force between our brane and a parallel one. This force eventually induces a new ekpyrotic phase and a new brane collision, leading to the idea of a cyclic universe. This review discusses the detailed properties of these models, thei...

  14. Bioprospecting open reading frames for peptide effectors.

    Science.gov (United States)

    Xiong, Ling; Scott, Charles

    2014-01-01

    Recent successes in the development of small-molecule antagonists of protein-protein interactions designed based on co-crystal structures of peptides bound to their biological targets confirm that short peptides derived from interacting proteins can be high-value ligands for pharmacologic validation of targets and for identification of druggable sites. Evolved sequence space is likely to be enriched for interacting peptides, but identifying minimal peptide effectors within genomic sequence can be labor intensive. Here we describe the use of incremental truncation to diversify genetic material on the scale of open reading frames into comprehensive libraries of constituent peptides. The approach is capable of generating peptides derived from both continuous and discontinuous sequence elements, and is compatible with the expression of free linear or backbone cyclic peptides, with peptides tethered to amino- or carboxyl-terminal fusion partners or with the expression of peptides displayed within protein scaffolds (peptide aptamers). Incremental truncation affords a valuable source of molecular diversity to interrogate the druggable genome or evaluate the therapeutic potential of candidate genes.

  15. Exploiting Protected Maleimides to Modify Oligonucleotides, Peptides and Peptide Nucleic Acids

    Directory of Open Access Journals (Sweden)

    Clément Paris

    2015-04-01

    Full Text Available This manuscript reviews the possibilities offered by 2,5-dimethylfuran-protected maleimides. Suitably derivatized building blocks incorporating the exo Diels-Alder cycloadduct can be introduced at any position of oligonucleotides, peptide nucleic acids, peptides and peptoids, making use of standard solid-phase procedures. Maleimide deprotection takes place upon heating, which can be followed by either Michael-type or Diels-Alder click conjugation reactions. However, the one-pot procedure in which maleimide deprotection and conjugation are simultaneously carried out provides the target conjugate more quickly and, more importantly, in better yield. This procedure is compatible with conjugates involving oligonucleotides, peptides and peptide nucleic acids. A variety of cyclic peptides and oligonucleotides can be obtained from peptide and oligonucleotide precursors incorporating protected maleimides and thiols.

  16. Targeting the Eph System with Peptides and Peptide Conjugates.

    Science.gov (United States)

    Riedl, Stefan J; Pasquale, Elena B

    2015-01-01

    Eph receptor tyrosine kinases and ephrin ligands constitute an important cell communication system that controls development, tissue homeostasis and many pathological processes. Various Eph receptors/ephrins are present in essentially all cell types and their expression is often dysregulated by injury and disease. Thus, the 14 Eph receptors are attracting increasing attention as a major class of potential drug targets. In particular, agents that bind to the extracellular ephrin-binding pocket of these receptors show promise for medical applications. This pocket comprises a broad and shallow groove surrounded by several flexible loops, which makes peptides particularly suitable to target it with high affinity and selectivity. Accordingly, a number of peptides that bind to Eph receptors with micromolar affinity have been identified using phage display and other approaches. These peptides are generally antagonists that inhibit ephrin binding and Eph receptor/ ephrin signaling, but some are agonists mimicking ephrin-induced Eph receptor activation. Importantly, some of the peptides are exquisitely selective for single Eph receptors. Most identified peptides are linear, but recently the considerable advantages of cyclic scaffolds have been recognized, particularly in light of potential optimization towards drug leads. To date, peptide improvements have yielded derivatives with low nanomolar Eph receptor binding affinity, high resistance to plasma proteases and/or long in vivo half-life, exemplifying the merits of peptides for Eph receptor targeting. Besides their modulation of Eph receptor/ephrin function, peptides can also serve to deliver conjugated imaging and therapeutic agents or various types of nanoparticles to tumors and other diseased tissues presenting target Eph receptors.

  17. Review stapling peptides using cysteine crosslinking.

    Science.gov (United States)

    Fairlie, David P; Dantas de Araujo, Aline

    2016-11-01

    Stapled peptides are an emerging class of cyclic peptide molecules with enhanced biophysical properties such as conformational and proteolytic stability, cellular uptake and elevated binding affinity and specificity for their biological targets. Among the limited number of chemistries available for their synthesis, the cysteine-based stapling strategy has received considerable development in the last few years driven by facile access from cysteine-functionalized peptide precursors. Here we present some recent advances in peptide and protein stapling where the side-chains of cysteine residues are covalently connected with a range of different crosslinkers affording bisthioether macrocyclic peptides of varying topology and biophysical properties. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 843-852, 2016.

  18. Structural characterization of the cyclic cystine ladder motif of θ-defensins.

    Science.gov (United States)

    Conibear, Anne C; Rosengren, K Johan; Harvey, Peta J; Craik, David J

    2012-12-04

    The θ-defensins are, to date, the only known ribosomally synthesized cyclic peptides in mammals, and they have promising antimicrobial bioactivities. The characteristic structural motif of the θ-defensins is the cyclic cystine ladder, comprising a cyclic peptide backbone and three parallel disulfide bonds. In contrast to the cyclic cystine knot, which characterizes the plant cyclotides, the cyclic cystine ladder has not been as well described as a structural motif. Here we report the solution structures and nuclear magnetic resonance relaxation properties in aqueous solution of three representative θ-defensins from different species. Our data suggest that the θ-defensins are more rigid and structurally defined than previously thought. In addition, all three θ-defensins were found to self-associate in aqueous solution in a concentration-dependent and reversible manner, a property that might have a role in their mechanism of action. The structural definition of the θ-defensins and the cyclic cystine ladder will help to guide exploitation of these molecules as structural frameworks for the design of peptide drugs.

  19. Cyclic cohomology of Hopf algebras

    NARCIS (Netherlands)

    Crainic, M.

    2001-01-01

    We give a construction of ConnesMoscovicis cyclic cohomology for any Hopf algebra equipped with a character Furthermore we introduce a noncommutative Weil complex which connects the work of Gelfand and Smirnov with cyclic cohomology We show how the Weil complex arises naturally when looking at Hopf

  20. The arabidopsis cyclic nucleotide interactome

    KAUST Repository

    Donaldson, Lara

    2016-05-11

    Background Cyclic nucleotides have been shown to play important signaling roles in many physiological processes in plants including photosynthesis and defence. Despite this, little is known about cyclic nucleotide-dependent signaling mechanisms in plants since the downstream target proteins remain unknown. This is largely due to the fact that bioinformatics searches fail to identify plant homologs of protein kinases and phosphodiesterases that are the main targets of cyclic nucleotides in animals. Methods An affinity purification technique was used to identify cyclic nucleotide binding proteins in Arabidopsis thaliana. The identified proteins were subjected to a computational analysis that included a sequence, transcriptional co-expression and functional annotation analysis in order to assess their potential role in plant cyclic nucleotide signaling. Results A total of twelve cyclic nucleotide binding proteins were identified experimentally including key enzymes in the Calvin cycle and photorespiration pathway. Importantly, eight of the twelve proteins were shown to contain putative cyclic nucleotide binding domains. Moreover, the identified proteins are post-translationally modified by nitric oxide, transcriptionally co-expressed and annotated to function in hydrogen peroxide signaling and the defence response. The activity of one of these proteins, GLYGOLATE OXIDASE 1, a photorespiratory enzyme that produces hydrogen peroxide in response to Pseudomonas, was shown to be repressed by a combination of cGMP and nitric oxide treatment. Conclusions We propose that the identified proteins function together as points of cross-talk between cyclic nucleotide, nitric oxide and reactive oxygen species signaling during the defence response.

  1. The cyclic cystine ladder in θ-defensins is important for structure and stability, but not antibacterial activity.

    Science.gov (United States)

    Conibear, Anne C; Rosengren, K Johan; Daly, Norelle L; Henriques, Sónia Troeira; Craik, David J

    2013-04-12

    θ-Defensins are ribosomally synthesized cyclic peptides found in the leukocytes of some primate species and have promising applications as antimicrobial agents and scaffolds for peptide drugs. The cyclic cystine ladder motif, comprising a cyclic peptide backbone and three parallel disulfide bonds, is characteristic of θ-defensins. In this study, we explore the role of the cyclic peptide backbone and cystine ladder in the structure, stability, and activity of θ-defensins. θ-Defensin analogues with different numbers and combinations of disulfide bonds were synthesized and characterized in terms of their NMR solution structures, serum and thermal stabilities, and their antibacterial and membrane-binding activities. Whereas the structures and stabilities of the peptides were primarily dependent on the number and position of the disulfide bonds, their antibacterial and membrane-binding properties were dependent on the cyclic backbone. The results provide insights into the mechanism of action of θ-defensins and illustrate the potential of θ-defensin analogues as scaffolds for peptide drug design.

  2. Protein mimics by attachment of cyclic peptides to molecular scaffolds

    NARCIS (Netherlands)

    van de Langemheen, W.

    2014-01-01

    The interaction between proteins is important in all biological functions. In practically every cellular process protein complexes have been identified as essential components. Defects or disturbance in the regulation of protein-protein interactions are responsible for many diseases. Therefore, the

  3. New Synthetic routes towards constrained cyclic peptides inspired by vancomycin

    NARCIS (Netherlands)

    Brink, H.T. ten

    2007-01-01

    Vancomycin is the last resort antibiotic against MRSA. Vancomycin causes the bacteria to die by physically blocking a recognition site within the cell wall. This recognition site binds to the inner cavity of vancomycin, which consists of a rigid bicyclic structure. The objective of my research was t

  4. Peptide identification

    Science.gov (United States)

    Jarman, Kristin H [Richland, WA; Cannon, William R [Richland, WA; Jarman, Kenneth D [Richland, WA; Heredia-Langner, Alejandro [Richland, WA

    2011-07-12

    Peptides are identified from a list of candidates using collision-induced dissociation tandem mass spectrometry data. A probabilistic model for the occurrence of spectral peaks corresponding to frequently observed partial peptide fragment ions is applied. As part of the identification procedure, a probability score is produced that indicates the likelihood of any given candidate being the correct match. The statistical significance of the score is known without necessarily having reference to the actual identity of the peptide. In one form of the invention, a genetic algorithm is applied to candidate peptides using an objective function that takes into account the number of shifted peaks appearing in the candidate spectrum relative to the test spectrum.

  5. Stable Peptides Instead of Stapled Peptides: Highly Potent αvβ6-Selective Integrin Ligands.

    Science.gov (United States)

    Maltsev, Oleg V; Marelli, Udaya Kiran; Kapp, Tobias G; Di Leva, Francesco Saverio; Di Maro, Salvatore; Nieberler, Markus; Reuning, Ute; Schwaiger, Markus; Novellino, Ettore; Marinelli, Luciana; Kessler, Horst

    2016-01-22

    The αvβ6 integrin binds the RGD-containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub-nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies were performed to disclose the molecular bases underlying the high binding affinity and receptor subtype selectivity of this peptide. Finally, the utility of the ligand for use in biomedical studies was also demonstrated here.

  6. Pseudoprolines as removable turn inducers: tools for the cyclization of small peptides.

    Science.gov (United States)

    Skropeta, Danielle; Jolliffe, Katrina A; Turner, Peter

    2004-12-10

    The cyclization of small peptides which do not incorporate turn inducers is often difficult. We have developed a method involving the use of removable turn inducers, in the form of pseudoprolines, for the cyclization of difficult peptide sequences. The pseudoprolines induce a cisoid amide bond in the peptide backbone which facilitates cyclization. They are then readily removed to yield a cyclic peptide that does not contain any turn inducers.

  7. Rheumatoid factor and anti-cyclic citrullinated peptides antibody in diagnosing significance in patients with rheumatoid arthritis and their correlation with disease activity%类风湿因子和抗环瓜酸抗体联合检测对类风湿关节炎的诊断价值及与疾病活动的相关性

    Institute of Scientific and Technical Information of China (English)

    李雪飞; 武加标; 任敏

    2011-01-01

    目的:比较类风湿因子(RF)和抗环瓜酸抗体(抗CCP抗体)在类风湿关节炎(RA)诊断及预测疾病活动性中的价值.方法:采用酶联免疫吸附法(ELISA)、速率散射比浊法检测RF和抗CCP抗体,比较它们单独或联合诊断RA的价值,分析RF和抗CCP抗体与疾病活动性的相关性.结果:RF和抗CCP抗体诊断RA的敏感性分别为81.5%和95.4%,特异性分别为58.8%和95.6%,联合诊断RA特异性增高;RF和抗CCP抗体均与C反应蛋白、红细胞沉降率显著相关.结论:RF联合抗CCP抗体应用可进一步提高RA的诊断准确性,RF和抗CCP抗体与RA疾病活动性密切相关.%Objective: To evaluate the diagnostic significance through detecting rheumatoid factor(RF-IgM) and anti-cyclic citrullinated peptide (CCP) antibody and their correlation with disease activity.Methods: We used enzyme-linked immunosorbent assay and rate nephelometry to detect CCP and RF in patients with 65 RA, 68 nonRA.Results: The sensitivity for RF and anti-CCP were 81.5% and 95.4%, respectively, and the specificity were 58.8%, 95.6%, respectively.The specificity was increased by combining the tests.A significant correlation was found between RF, anti-CCP and CRP, ESR, respectively.Conclusion: The higher specificity was achieved by combining the tests.There was an association between RF, anti-CCP and disease activity.

  8. Cyclic $n$-gonal Surfaces

    CERN Document Server

    Broughton, S Allen

    2010-01-01

    A cyclic $n$-gonal surface is a compact Riemann surface $X$ of genus $g\\geq 2$ admitting a cyclic group of conformal automorphisms $C$ of order $n$ such that the quotient space $X/C$ has genus 0. In this paper, we provide an overview of ongoing research into automorphism groups of cyclic $n$-gonal surfaces. Much of the paper is expository or will appear in forthcoming papers, so proofs are usually omitted. Numerous explicit examples are presented illustrating the computational methods currently being used to study these surfaces.

  9. Accurate de novo design of hyperstable constrained peptides

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-09-14

    Covalently-crosslinked peptides present attractive opportunities for developing new therapeutics. Lying between small molecule and protein therapeutics in size, natural crosslinked peptides play critical roles in signaling, virulence and immunity. Engineering novel peptides with precise control over their three-dimensional structures is a significant challenge. Here we describe the development of computational methods for de novo design of conformationally-restricted peptides, and the use of these methods to design hyperstable disulfide-stabilized miniproteins, heterochiral peptides, and N-C cyclic peptides. Experimentally-determined X-ray and NMR structures for 12 of the designs are nearly identical to the computational models. The computational design methods and stable scaffolds provide the basis for a new generation of peptide-based drugs.

  10. The effect of glycine replacement with flexible ω-amino acids on the antimicrobial and haemolytic activity of an amphipathic cyclic heptapeptide

    DEFF Research Database (Denmark)

    Oddo, Alberto; Nyberg, Nils; Frimodt-Møller, Niels

    2015-01-01

    Although cyclic peptide structures are usually investigated as highly constrained scaffolds, cyclic antimicrobial peptides of natural origin often feature flexible residues. Hereby we report our findings concerning a structure-activity study conducted on a model sequence by replacing a glycine re...... to study changes in conformation. Increments as high as 16-fold in antimicrobial activity (as effective as lipidation) and >2-fold in haemolytic EC50 values were observed. Interestingly, secondary structures can be stabilized by increasing, rather than decreasing, ring flexibility....

  11. Prognosis of Cyclic Vomiting Syndrome

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2016-03-01

    Full Text Available Investigators from Teikyo University School of Medicine, Tokyo, Japan, evaluated the clinical features, prognosis, and prophylaxis of cyclic vomiting syndrome and the relationship between the syndrome and levels of adrenocorticotropic/antidiuretic hormones (ACTH/ADH.

  12. Algebraic curves of maximal cyclicity

    Science.gov (United States)

    Caubergh, Magdalena; Dumortier, Freddy

    2006-01-01

    The paper deals with analytic families of planar vector fields, studying methods to detect the cyclicity of a non-isolated closed orbit, i.e. the maximum number of limit cycles that can locally bifurcate from it. It is known that this multi-parameter problem can be reduced to a single-parameter one, in the sense that there exist analytic curves in parameter space along which the maximal cyclicity can be attained. In that case one speaks about a maximal cyclicity curve (mcc) in case only the number is considered and of a maximal multiplicity curve (mmc) in case the multiplicity is also taken into account. In view of obtaining efficient algorithms for detecting the cyclicity, we investigate whether such mcc or mmc can be algebraic or even linear depending on certain general properties of the families or of their associated Bautin ideal. In any case by well chosen examples we show that prudence is appropriate.

  13. Cyclic Cushing's syndrome: an overview.

    Science.gov (United States)

    Albiger, Nora Maria Elvira; Scaroni, Carla M; Mantero, Franco

    2007-11-01

    Cyclic Cushing's syndrome (CS) is a disorder in which glucocorticoid levels are alternately normal and high, the latter occurring in episodes that can last from a few days to several months. It is more common in children than in adults. Cyclic CS may be either of the two different forms of CS (ACTH-dependent or -independent CS). Clinically, it may present with one or many symptoms, depending on the duration of disease activity and the timing of the fluctuations. A serotoninergic influence, cyclic changes in central dopaminergic tone, spontaneous episodic hemorrhage in the tumor, and the action of inflammatory cytokines with antitumor properties are some of the mechanisms suggested to explain the physiopathology of this phenomenon but the exact mechanism remains to be clarified. The cyclic pattern of hypercortisolism can delay the final diagnosis of CS and make it difficult to interpret the results of dynamic tests. Patients may have paradoxical responses to dexamethasone that can reflect increasing or decreasing levels of endogenous activity. Hormone assessments have to be repeated periodically when a diagnosis of CS is suspected. The cyclic pattern can also interfere with medical treatment because patients may show unexpected clinical and biochemical signs of hypocortisolism when cortisol secretion cyclically returns to normal, so an accurate follow-up is mandatory in these patients.

  14. Converting a Staphylococcus aureus toxin into effective cyclic pseudopeptide antibiotics.

    Science.gov (United States)

    Solecki, Olivia; Mosbah, Amor; Baudy Floc'h, Michèle; Felden, Brice

    2015-03-19

    Staphylococcus aureus produces peptide toxins that it uses to respond to environmental cues. We previously characterized PepA1, a peptide toxin from S. aureus, that induces lytic cell death of both bacterial and host cells. That led us to suggest that PepA1 has an antibacterial activity. Here, we demonstrate that exogenously provided PepA1 has activity against both Gram-positive and Gram-negative bacteria. We also see that PepA1 is significantly hemolytic, thus limiting its use as an antibacterial agent. To overcome these limitations, we converted PepA1 into nonhemolytic derivatives. Our most promising derivative is a cyclic heptapseudopeptide with inconsequential toxicity to human cells, enhanced stability in human sera, and sharp antibacterial activity. Mechanistically, linear and helical PepA1 derivatives form pores at the bacterial and erythrocyte surfaces, while the cyclic peptide induces bacterial envelope reorganization, with insignificant action on the erythrocytes. Our work demonstrates that bacterial toxins might be an attractive starting point for antibacterial drug development.

  15. Genome-based discovery, structure prediction and functional analysis of cyclic lipopeptide antibiotics in Pseudomonas species

    NARCIS (Netherlands)

    Bruijn, de I.; Kock, de M.J.D.; Meng, Y.; Waard, de P.; Beek, van T.A.; Raaijmakers, J.M.

    2007-01-01

    Analysis of microbial genome sequences have revealed numerous genes involved in antibiotic biosynthesis. In Pseudomonads, several gene clusters encoding non-ribosomal peptide synthetases (NRPSs) were predicted to be involved in the synthesis of cyclic lipopeptide (CLP) antibiotics. Most of these pre

  16. Transitive oriented 3-Hypergraphs of cyclic orders

    OpenAIRE

    2012-01-01

    In this paper we introduce the definition of transitivity for oriented 3-hypergraphs in order to study partial and complete cyclic orders. This definition allow us to give sufficient conditions on a partial cyclic order to be totally extendable. Furthermore, we introduce the 3-hypergraph associated to a cyclic permutation and characterize it in terms of cyclic comparability 3-hypergraphs.

  17. Dissecting and Exploiting Nonribosomal Peptide Synthetases

    Institute of Scientific and Technical Information of China (English)

    Qing-Tao SHEN; Xiu-Lan CHEN; Cai-Yun SUN; Yu-Zhong ZHANG

    2004-01-01

    A large number of therapeutically useful cyclic and linear peptides of bacteria or fungal origin are synthesized via a template-directed, nucleic-acid-independent nonribosomal mechanism. This process is carried out by mega-enzymes called nonribosomal peptide synthetases (NRPSs). NRPSs contain repeated coordinated groups of active sites called modules, and each module is composed of several domains with different catalytic activities. The familiarity to these domains lays base for the future genetic engineering of NRPSs to generate entirely "unnature" Products. The details about NRPSs domain structures and the exploitation of NRPSs are described in this review.

  18. Macrocyclic beta-sheet peptides that mimic protein quaternary structure through intermolecular beta-sheet interactions.

    Science.gov (United States)

    Khakshoor, Omid; Demeler, Borries; Nowick, James S

    2007-05-02

    This paper reports the design, synthesis, and characterization of a family of cyclic peptides that mimic protein quaternary structure through beta-sheet interactions. These peptides are 54-membered-ring macrocycles comprising an extended heptapeptide beta-strand, two Hao beta-strand mimics [JACS 2000, 122, 7654] joined by one additional alpha-amino acid, and two delta-linked ornithine beta-turn mimics [JACS 2003, 125, 876]. Peptide 3a, as the representative of these cyclic peptides, contains a heptapeptide sequence (TSFTYTS) adapted from the dimerization interface of protein NuG2 [PDB ID: 1mio]. 1H NMR studies of aqueous solutions of peptide 3a show a partially folded monomer in slow exchange with a strongly folded oligomer. NOE studies clearly show that the peptide self-associates through edge-to-edge beta-sheet dimerization. Pulsed-field gradient (PFG) NMR diffusion coefficient measurements and analytical ultracentrifugation (AUC) studies establish that the oligomer is a tetramer. Collectively, these experiments suggest a model in which cyclic peptide 3a oligomerizes to form a dimer of beta-sheet dimers. In this tetrameric beta-sheet sandwich, the macrocyclic peptide 3a is folded to form a beta-sheet, the beta-sheet is dimerized through edge-to-edge interactions, and this dimer is further dimerized through hydrophobic face-to-face interactions involving the Phe and Tyr groups. Further studies of peptides 3b-3n, which are homologues of peptide 3a with 1-6 variations in the heptapeptide sequence, elucidate the importance of the heptapeptide sequence in the folding and oligomerization of this family of cyclic peptides. Studies of peptides 3b-3g show that aromatic residues across from Hao improve folding of the peptide, while studies of peptides 3h-3n indicate that hydrophobic residues at positions R3 and R5 of the heptapeptide sequence are important in oligomerization.

  19. Significance of serum anti-cyclic citrullinated peptide antibodies in diagnosis of juvenile idiopathic arthritis%血清抗环瓜氨酸肽抗体水平对幼年特发性关节炎的诊断价值

    Institute of Scientific and Technical Information of China (English)

    郭桂梅; 何威逊; 朱光华; 王娟

    2013-01-01

    Objective To investigate the clinical significance of serum anti-cyclic citrullinated peptide ( anti-CCP) antibodies in diagnosis of juvenile idiopathic arthritis (JIA). Methods Serum anti-CCP antibodies of 68 children suspected of JIA with fever and arthritis of unknown causes were determined by ELISA, and comprehensive analysis was carried out with clinical data and related laboratory findings. Results Among the 68 children suspected of JIA, there were 10 cases of polyarticular JIA, 13 cases of systemic onset JIA, 8 cases of oligoarticular JIA and 13 cases of enthesitis related JIA. There were 11 cases of other rheumatoid diseases, 8 cases of neoplastic diseases of blood and 5 cases of infectious diseases. The serum anti-CCP level in children suspected of polyarticular JIA was significantly higher than those, in children suspected of systemic onset JIA, oligoarticular JIA and enthesitis related JIA (P <0.05). With serum anti-CCP ≥15.8 RU/mL as the positive threshold value, the area under receiver operating characteristic curve was 0.80, and the sensitivity and specificity in diagnosis of polyarticular JIA were 80% and 67. 6% respectively. The serum anti-CCP level was positively related to serum C-reaction protein level in children suspected of polyarticular JIA (r = 0. 764, P = 0. 017). Conclusion Serum anti-CCP can be used for the diagnosis of polyarticular JIA, and 15.8 RU/mL may be a suitable cut-off level.%目的 探讨血清抗环瓜氨酸肽(anti-CCP)抗体对幼年特发性关节炎(JIA)的诊断价值.方法 采用ELISA法对68例因不明原因发热和关节痛疑诊为JIA患儿进行血清anti-CCP抗体水平检测,并结合临床资料及相关实验室检查指标进行综合分析.结果 68例疑诊JIA患儿中,多关节型JIA 10例,全身型JIA 13例,少关节型JIA 8例,与附着点炎症相关的JIA 13例;其他风湿性疾病11例,血液与肿瘤疾病8例,感染性疾病5例.多关节型JIA患儿的血清anti-CCP水平显著高于全身

  20. Clinical value of anti-cyclic citrullinated peptide antibody combined with rheumatoid factor IgA and IgM for diagnosing rheumatoid arthritis%抗环瓜氨酸肽抗体联合类风湿因子IgA和IgM诊断类风湿关节炎的临床价值

    Institute of Scientific and Technical Information of China (English)

    邢雪梅; 李艳琴; 沈钢; 张军

    2014-01-01

    Objective To evaluate the value of the single or combined detection of anti-keratin antibody (AKA) ,anti-cyclic citrullinated peptide(CCP) antibody and rheumatoid factor (RF) for the diagnosis of rheumatoid arthritis(RA) .Methods Serum AKA ,anti-CCP antibody ,IgA-RF and IgM-RF were detected in 195 cases of RA and 195 controls .AKA was detected by using the indirect immunofluorescence method ,RF and anti-CCP antibody were detected by using ELISA .The specificity and sensitivity of those antibodies in RA were analyzed in the diagnosis of RA .The sensitivity ,specificity ,positive predictive value(PPV) and negative predictive value(NPV) of anti-CCP anti-body combined IgA-RF and/or IgM-RF for diagnosing RA were compared .Results The combination detection of an-ti-CCP antibody ,IgA-RF and IGM-RF had the highest specificity .The positive predictive value of anti-CCP antibody+ IgA-RF was 87 .59% ,which was significantly higher than 78 .49% of anti-CCP antibody + IGM-RF .Conclusion The combined detection of anti-CCP antibody and IgA /IgM-RF can significantly improve the diagnostic efficiency and reduce the misdiagnosis rate .%目的:评估单独或联合检测抗角蛋白抗体(AKA)、抗环瓜氨酸肽(CCP)抗体、类风湿因子(RF)IgA和 IgM 对类风湿关节炎(RA)的诊断价值。方法分别检测195例 RA 患者和195例对照者血清中的 AKA 、抗-CCP 抗体、IgA-RF 和 IgM-RF ,AKA 采用间接免疫荧光的方法检测,抗-CCP 抗体、IgA-RF 和 IgM-RF 采用酶联免疫吸附试验检测,分析上述抗体在 RA 中的敏感性和特异性,比较抗-CCP 抗体联合 IgA-RF 或(和)IgM-RF 诊断RA 的敏感性、特异性、阳性预测值和阴性预测值。结果抗-CCP 抗体、IgA-RF 和 IgM-RF 3项联合检测特异性最高。抗-CCP 抗体+ IgA-RF 的阳性预测值(87.59%)要明显高于抗-CCP 抗体+ IgM-RF(78.49%)。结论抗-CCP抗体与 IgA/IgM-RF 联合检测可以显著提高 RA 的诊断效能,降低误诊率。

  1. Diagnostic value evaluation of serum anti-cyclic citrullinated peptide antibody by contrast detection for rheumatoid arthritis%对比检测血清中抗环瓜氨酸肽抗体对类风湿关节炎的诊断价值评估

    Institute of Scientific and Technical Information of China (English)

    邓毅; 吴雪峰; 雷鸣; 吴建华

    2015-01-01

    Objective To investigate the diagnostic value of serum anti-cyclic citrullinated peptide (anti-CCP) antibody detection for rheumatoid arthritis (RA). Methods There were 86 RA patients (RA group), 44 non-RA patients (non-RA group), and 32 health physical examination people (control group). The level of anti-CCP antibody was detected by enzyme linked immunosorbent assay, and rheumatoid factor (RF) was detected by immunity transmission turbidity. The detection results of every group were compared. Results The Anti-CCP antibody and RF levels of the RA group were significantly higher than those in the non-RA group and the control group (P<0.05). The sensitivity of anti-CCP of the RA group was 69.77%, which was obviously lower than 81.40%of RF (P<0.05). Anti-CCP had higher diagnostic specificity and positive predicted value for RA than RF (P<0.05). The sensitivity, specificity, and negative predicted value of anti-CCP combined with RF were all significantly increased. It had a statistically significant difference from single detection (P<0.05). Conclusion Serum anti-CCP antibody detection has high specificity for the diagnosis of RA, and its combination with RF in detection can improve the accuracy and sensitivity of diagnosis.%目的:探讨检测血清中抗环瓜氨酸肽(抗-CCP)抗体对类风湿关节炎(RA)的诊断价值。方法收集RA患者86例(RA组)、非RA患者44例(非RA组)和健康体检者32例(对照组),分别采用酶联免疫吸附法检测抗-CCP抗体水平,并以免疫透射比浊法检测类风湿因子(RF),比较各组的检测结果。结果 RA组的抗-CCP抗体及RF水平均显著高于非RA组与对照组(P<0.05);RA组的抗-CCP灵敏度为69.77%,显著低于RF的灵敏度81.40%(P<0.05);抗-CCP对RA的诊断特异度与阳性预测值显著高于RF(P<0.05);抗-CCP联合RF的灵敏度、特异度及阴性预测值均获得显著提高,与单项检测相比,差异具有统计学意义(P<0.05)。结论血清抗-CCP抗体

  2. Combined detection rheumatoid factor、anti-cyclic citrullinated peptide antibody and Anti-keratin Antibody in the diagnosis of rheumatoid arthritis%类风湿因子、抗环瓜氨酸肽抗体与抗角蛋白抗体联合测定对类风湿性关节炎诊断价值

    Institute of Scientific and Technical Information of China (English)

    陈建平; 杨曙梅; 杨春兰; 祝文彩

    2014-01-01

    Objective:In the study, we clarity the combined detection of rheumatoid factor(RF)、anti-cyclic citrullinated peptide antibody(Anti-CCP) and anti-keratin antibody(AKA) in the diagnosis of rheumatoid arthritis(RA).Methods:132 patients with RA, 51 patients with other arthritis. RF was measured by immune rate nephelometry. Anti-CCP was measured by chemiluminescence immunoassay. Indirect Immunofluorescence assay was used to detect AKA.Results:The diagnostic sensitivity of RF for RA was 78.0% and the specificity was 64.7%. Whereas the diagnostic sensitivity of Anti-CCP for RA was 75.0% and the specificity was 88.2%. The diagnostic sensitivity of AKA for RA was 75.8% and the specificity was 86.3%. The combined detection of RF、Anti-CCP and AKA had a sensitivity of 63.6%% and the specificity of 96.1%.Conclusions:The results suggest that for diagnosis RA, the sensitivity of RF is better than Anti-CCP and AKA, whereas the specificity of Anti-CCP and AKA is better than RF. Combination of RF、Anti-CCP and AKA may be more helpful in early cliagnosis of RA patients.%目的:本文旨在探讨联合测定类风湿因子(RF)、抗环瓜氨酸肽抗体(Anti-CCP)及抗角蛋白抗体(AKA)在诊断类风湿性关节炎(RA)中的应用价值。方法:分别运用免疫速率散射比浊法、化学发光法及间接免疫荧光法检测132例类RA患者及51例非RA患者血清中的RF、Anti-CCP及AKA。结果:RF对RA敏感性为78.0%,特异性为64.7%,阳性预测值85.1%;Anti-CCP对RA敏感性为75.0%,特异性为88.2%,阳性预测值94.2%;AKA对RA敏感性为75.8%,特异性为86.3%,阳性预测值93.5%;RF、Anti-CCP及AKA联合检测诊断RA的敏感性为63.6%,特异性为96.1%,阳性预测值97.7%。结论: RF在RA诊断中敏感性较Anti-CCP及AKA高,但特异性较Anti-CCP及AKA低;RF、Anti-CCP及AKA联合检测的应用,更有助于类风湿关节炎的早期诊断。

  3. Manual for Cyclic Triaxial Test

    DEFF Research Database (Denmark)

    Shajarati, Amir; Sørensen, Kris Wessel; Nielsen, Søren Kjær

    /dynamic triaxial cell is overall constructed in the same way as the static triaxial cell at Aalborg University, but with the ability to apply any kind of load sequence to the test sample. When conducting cyclic triaxial tests, it is recommended that the manual is followed very tediously since there are many steps...... and if they are done improperly or in the wrong order there is a risk of destroying the test sample or obtaining invalid results.......This manual describes the different steps that is included in the procedure for conducting a cyclic triaxial test at the geotechnical Laboratory at Aalborg University. Furthermore it contains a chapter concerning some of the background theory for the static triaxial tests. The cyclic...

  4. Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics.

    Science.gov (United States)

    Oueis, Emilia; Jaspars, Marcel; Westwood, Nicholas J; Naismith, James H

    2016-05-04

    The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme-mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4-substituted 1,2,3-triazole moieties. The introduction of non-peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non-natural triazole-containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.

  5. Microwave-assisted click polymerization for the synthesis of A beta(16-22) cyclic oligomers and their self-assembly into polymorphous aggregates

    NARCIS (Netherlands)

    Elgersma, R.C.; van Dijk, M.; Dechesne, A.C.; van Nostrum, C.F.; Hennink, W.E.; Rijkers, D.T.S.; Liskamp, R.M.J.

    2009-01-01

    We report on the design, synthesis, and structural analysis of cyclic oligomers with an amyloidogenic peptide sequence as the repeating unit to obtain novel self-assembling bionanomaterials. The peptide was derived from the Alzheimer A beta(16-22) sequence since its strong tendency to form antiparal

  6. Recursive processing of cyclic graphs.

    Science.gov (United States)

    Bianchini, Monica; Gori, Marco; Sarti, Lorenzo; Scarselli, Franco

    2006-01-01

    Recursive neural networks are a powerful tool for processing structured data. According to the recursive learning paradigm, the input information consists of directed positional acyclic graphs (DPAGs). In fact, recursive networks are fed following the partial order defined by the links of the graph. Unfortunately, the hypothesis of processing DPAGs is sometimes too restrictive, being the nature of some real-world problems intrinsically cyclic. In this paper, a methodology is proposed, which allows us to process any cyclic directed graph. Therefore, the computational power of recursive networks is definitely established, also clarifying the underlying limitations of the model.

  7. Design of a cyclic multiverse

    Energy Technology Data Exchange (ETDEWEB)

    Piao Yunsong, E-mail: yspiao@gucas.ac.c [College of Physical Sciences, Graduate School of Chinese Academy of Sciences, Beijing 100049 (China)

    2010-08-09

    Recently, it has been noticed that the amplification of the amplitude of curvature perturbation cycle by cycle can lead to a cyclic multiverse scenario, in which the number of universes increases cycle by cycle. However, this amplification will also inevitably induce either the ultimate end of corresponding cycle, or the resulting spectrum of perturbations inside corresponding universe is not scale invariant, which baffles the existence of observable universes. In this Letter, we propose a design of a cyclic multiverse, in which the observable universe can emerges naturally. The significance of a long period of dark energy before the turnaround of each cycle for this implementing is shown.

  8. Hopf cyclic cohomology and transverse characteristic classes

    CERN Document Server

    Moscovici, Henri

    2010-01-01

    By refining the cyclic cohomological apparatus for computing the Hopf cyclic cohomology of the Hopf algebras associated to infinite primitive Cartan-Lie pseudogroup, we explicitly identify, as a Hopf cyclic complex, the image of the canonical homomorphism from the Gelfand-Fuks complex to the Bott complex for equivariant cohomology. Distinct from the original realization due to A. Connes and the first named author of the cyclic cohomology of such Hopf algebras as differentiable cyclic cohomology, this construction provides a convenient front-end model for their Hopf cyclic cohomology. Relying on it, we produce characteristic homomorphisms from newly developed models for Hopf cyclic characteristic classes to the cyclic cohomology of the convolution algebras of \\'etale holonomy groupoids, which in particular work in the relative case with no compactness restriction. As an illustration, we apply the latter feature to transfer the universal Hopf cyclic Chern classes found by us in a previous paper, and produce in ...

  9. 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.

  10. Interactions of disulfide-constrained cyclic tetrapeptides with Cu(2+).

    Science.gov (United States)

    Zhang, Liyun; Luo, Zhaofeng; Zhang, Lidong; Jia, Liangyuan; Wu, Lifang

    2013-02-01

    The purpose of this work is to characterize the interactions of two disulfide-constrained cyclic tetrapeptides [c(Ac-Cys-Pro-Phe-Cys-NH(2)), SS1; c(Ac-Cys-Pro-Gly-Cys-NH(2)), SS2] with Cu(2+) ions in order to facilitate the design of cyclic peptides as sensors for metal ions. The Cu(2+)-peptide complex cations at m/z 569.1315 for Cu(2+)-SS1 and m/z 479.0815 for Cu(2+)-SS2 were detected by mass spectrometry. The gas-phase fragmentation of the Cu(2+)-peptide complexes was studied by collision-induced dissociation and suggests the atoms involved in the coordination. Cu(2+) ion binds to a single SS1 or SS2 with K (d(app)) of 0.57 ± 0.02 and 0.55 ± 0.01 μM, respectively. Isothermal titration calorimetry data indicate both enthalpic and entropic contributions for the binding of Cu(2+) ion to SS1 and SS2. The characteristic wavenumber of 947 cm(-1) and the changes at 1,664 and 1,530 cm(-1) in the infrared spectrum suggest that the sulfydryl of cysteine, the carbonyl group, and amide II are involved in the coordination of Cu(2+). The X-ray absorption near-edge structure signal from the Cu(2+)-peptide complex corresponds to the four-coordination structure. The extended X-ray absorption fine structure and electron paramagnetic resonance results demonstrate the Cu(2+) ion is in an S/N/2O coordination environment, and is a distinct type II copper center. Theoretical calculations further demonstrate that Cu(2+) ion binds to SS1 or SS2 in a slightly distorted tetragonal geometry with an S/N/2O environment and the minimum potential energy.

  11. Peptide arrays for screening cancer specific peptides.

    Science.gov (United States)

    Ahmed, Sahar; Mathews, Anu Stella; Byeon, Nara; Lavasanifar, Afsaneh; Kaur, Kamaljit

    2010-09-15

    In this paper, we describe a novel method to screen peptides for specific recognition by cancer cells. Seventy peptides were synthesized on a cellulose membrane in an array format, and a direct method to study the peptide-whole cell interaction was developed. The relative binding affinity of the cells for different peptides with respect to a lead 12-mer p160 peptide, identified by phage display, was evaluated using the CyQUANT fluorescence of the bound cells. Screening allowed identification of at least five new peptides that displayed higher affinity (up to 3-fold) for MDA-MB-435 and MCF-7 human cancer cells compared to the p160 peptide. These peptides showed very little binding to the control (noncancerous) human umbilical vein endothelial cells (HUVECs). Three of these peptides were synthesized separately and labeled with fluorescein isothiocyanate (FITC) to study their uptake and interaction with the cancer and control cells using confocal laser scanning microscopy and flow cytometry. The results confirmed the high and specific affinity of an 11-mer peptide 11 (RGDPAYQGRFL) and a 10-mer peptide 18 (WXEAAYQRFL) for the cancer cells versus HUVECs. Peptide 11 binds different receptors on target cancer cells as its sequence contains multiple recognition motifs, whereas peptide 18 binds mainly to the putative p160 receptor. The peptide array-whole cell binding assay reported here is a complementary method to phage display for further screening and optimization of cancer targeting peptides for cancer therapy and diagnosis.

  12. Color visualization of cyclic magnitudes

    Science.gov (United States)

    Restrepo, Alfredo; Estupiñán, Viviana

    2014-02-01

    We exploit the perceptual, circular ordering of the hues in a technique for the visualization of cyclic variables. The hue is thus meaningfully used for the indication of variables such as the azimuth and the units of the measurement of time. The cyclic (or circular) variables may be both of the continuous type or the discrete type; among the first there is azimuth and among the last you find the musical notes and the days of the week. A correspondence between the values of a cyclic variable and the chromatic hues, where the natural circular ordering of the variable is respected, is called a color code for the variable. We base such a choice of hues on an assignment of of the unique hues red, yellow, green and blue, or one of the 8 even permutations of this ordered list, to 4 cardinal values of the cyclic variable, suitably ordered; color codes based on only 3 cardinal points are also possible. Color codes, being intuitive, are easy to remember. A possible low accuracy when reading instruments that use this technique is compensated by fast, ludic and intuitive readings; also, the use of a referential frame makes readings precise. An achromatic version of the technique, that can be used by dichromatic people, is proposed.

  13. Cyclic Codes of Length 2

    Indian Academy of Sciences (India)

    Manju Pruthi

    2001-11-01

    In this paper explicit expressions of + 1 idempotents in the ring $R = F_q[X]/\\langle X^{2^m}-1\\rangle$ are given. Cyclic codes of length 2 over the finite field , of odd characteristic, are defined in terms of their generator polynomials. The exact minimum distance and the dimension of the codes are obtained.

  14. Design of Self-Assembling Peptide Nanotubes with Delocalized Electronic States[**

    Science.gov (United States)

    Ashkenasy, Nurit; Horne, W. Seth; Reza Ghadiri, M.

    2007-01-01

    Electronically active biomaterials via directed peptide self-assembly Redox-promoted self-assembly of an eight-residue cyclic D,L-α-peptide bearing four 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) side chains results in the formation of electronically delocalized peptide nanotubes hundreds of nm in length. The supramolecular approach described provides a rational basis for the design and fabrication of 1-D materials with potential utility in optical and electronic devices. PMID:17193563

  15. Synthetic Channel-forming Peptides and Ion Selectivity

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Introduction Peptides made up of alternating L- and D- amino acids can form β-helices as in gramicidin A or cyclic peptides that aggregate to form tubes[1]. In both cases the structures are hollow with all the side chains projecting outwards. Kennedy et al. [2] postulated that peptides having the (LLLD)n configuration could form helices with every fourth side chain projecting inward.It is a fact that synthetic N-formyl-( LeuSerLeuGly)6-OH, when added to a lipid bilayer, dimerizes, to form ion channels having conductances greater than that of gramicidin.

  16. CYCLIC CODES OVER FORMAL POWER SERIES RINGS

    Institute of Scientific and Technical Information of China (English)

    Dougherty Steven T.; Liu Hongwei

    2011-01-01

    In this article, cyclic codes and negacyclic codes over formal power series rings are studied. The structure of cyclic codes over this class of rings is given, and the relationship between these codes and cyclic codes over finite chain rings is obtained. Using an isomorphism between cyclic and negacyclic codes over formal power series rings, the structure of negacyclic codes over the formal power series rings is obtained.

  17. Powers of Convex-Cyclic Operators

    Directory of Open Access Journals (Sweden)

    Fernando León-Saavedra

    2014-01-01

    Full Text Available A bounded operator T on a Banach space X is convex cyclic if there exists a vector x such that the convex hull generated by the orbit Tnxn≥0 is dense in X. In this note we study some questions concerned with convex-cyclic operators. We provide an example of a convex-cyclic operator T such that the power Tn fails to be convex cyclic. Using this result we solve three questions posed by Rezaei (2013.

  18. Peptide pheromone signaling in Streptococcus and Enterococcus.

    Science.gov (United States)

    Cook, Laura C; Federle, Michael J

    2014-05-01

    Intercellular chemical signaling in bacteria, commonly referred to as quorum sensing (QS), relies on the production and detection of compounds known as pheromones to elicit coordinated responses among members of a community. Pheromones produced by Gram-positive bacteria are comprised of small peptides. Based on both peptide structure and sensory system architectures, Gram-positive bacterial signaling pathways may be classified into one of four groups with a defining hallmark: cyclical peptides of the Agr type, peptides that contain Gly-Gly processing motifs, sensory systems of the RNPP family, or the recently characterized Rgg-like regulatory family. The recent discovery that Rgg family members respond to peptide pheromones increases substantially the number of species in which QS is likely a key regulatory component. These pathways control a variety of fundamental behaviors including conjugation, natural competence for transformation, biofilm development, and virulence factor regulation. Overlapping QS pathways found in multiple species and pathways that utilize conserved peptide pheromones provide opportunities for interspecies communication. Here we review pheromone signaling identified in the genera Enterococcus and Streptococcus, providing examples of all four types of pathways.

  19. Correlation of phenylpropanolamine bioavailability with gastrointestinal transit by scintigraphic monitoring of /sup 111/In-labeled hydroxypropylmethylcellulose matrices

    Energy Technology Data Exchange (ETDEWEB)

    Feely, L.C.; Davis, S.S.

    1989-04-01

    Two controlled-release hydroxypropylmethylcellulose (HPMC) matrix formulations, a single-unit and a multiple-unit system, have been evaluated in human volunteers. Both formulations contained the sympathomimetic drug phenylpropanolamine hydrochloride and each was radiolabeled with /sup 111/Inbound Amberlite IR 120 ion-exchange resin. The formulations were administered to each of six healthy male volunteers and gastrointestinal (GI) transit was monitored using a gamma camera. Serum samples were taken at set time intervals and assayed for phenylpropanolamine content, thus allowing blood drug levels to be correlated with the position of the dosage form in the GI tract. The multiple-unit system emptied from the stomach gradually over a period of about 180 min, when administered after a light breakfast, whereas the single-unit dosage forms had extremely variable gastric emptying times (range, 60 to greater than 570 min). However, both formulations provided prolonged phenylpropanolamine blood levels. The differences in the blood profiles obtained with the two formulations were attributed to variations in their in vitro release rates and not to any differences in their GI transit times.

  20. Characterization and in vivo distribution of sup 99m Tc- and sup 111 In-labelled magnetite

    Energy Technology Data Exchange (ETDEWEB)

    Bligh, S.W.A.; Sadler, P.J. (Birkbeck Coll., London (UK)); Marriott, J.A.; Latham, I.A.; Kelly, J.D. (Amersham International Ltd. (UK))

    1989-01-01

    Magnetite (Fe{sub 3}O{sub 4}) particles 0.1-0.5 {mu}m in diameter doped with either {sup 99m}Tc or {sup 111}In have been prepared and characterized by electron microscopy and Moessbauer spectroscopy. The time courses of their distributions after injection into rats were determined, including studies by {gamma}-camera imaging; the main targets were the liver and lung. The radiolabelled magnetic agents may be of value in research studies combining radio- and magnetic resonance imaging procedures. (author).

  1. The cyclic theory of Hopf algebroids

    NARCIS (Netherlands)

    Kowalzig, N.; Posthuma, H.

    2011-01-01

    We give a systematic description of the cyclic cohomology theory of Hopf alge\\-broids in terms of its associated category of modules. Then we introduce a dual cyclic homology theory by applying cyclic duality to the underlying cocyclic object. We derive general structure theorems for these theories

  2. The Cyclic Graph of a Finite Group

    Directory of Open Access Journals (Sweden)

    Xuan Long Ma

    2013-01-01

    and characterize certain finite groups whose cyclic graphs have some properties. Then, we present some properties of the cyclic graphs of the dihedral groups D2n and the generalized quaternion groups Q4n for some n. Finally, we present some parameters about the cyclic graphs of finite noncyclic groups of order up to 14.

  3. 40 CFR 721.2120 - Cyclic amide.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Cyclic amide. 721.2120 Section 721... Cyclic amide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a cyclic amide (PMN P-92-131) is subject to reporting under this section for...

  4. Exploring the chemical space of quorum sensing peptides.

    Science.gov (United States)

    Wynendaele, Evelien; Gevaert, Bert; Stalmans, Sofie; Verbeke, Frederick; De Spiegeleer, Bart

    2015-09-01

    Quorum sensing peptides are signalling molecules that are produced by mainly gram-positive bacteria. These peptides can exert different effects, ranging from intra- and interspecies bacterial virulence to bacterial-host interactions. To better comprehend these functional differences, we explored their chemical space, bacterial species distribution and receptor-binding properties using multivariate data analyses, with information obtained from the Quorumpeps database. The quorum sensing peptides can be categorized into three main clusters, which, in turn, can be divided into several subclusters: the classification is based on characteristic chemical properties, including peptide size/compactness, hydrophilicity/lipophilicity, cyclization and the presence of (unnatural) S-containing and aromatic amino acids. Most of the bacterial species synthesize peptides located into one cluster. However, some Streptococcus, Stapylococcus, Clostridium, Bacillus and Lactobacillus species produce peptides that are distributed over more than one cluster, with the quorum sensing peptides of Bacillus subtilis even occupying the total peptide space. The AgrC, FsrC and LamC receptors are only activated by cyclic (thio)lacton or lactam quorum sensing peptides, while the lipophilic isoprenyl-modified peptides solely bind the ComP receptor in Bacillus species.

  5. Early diagnostic and predictive value of antikeratin antibody, anti-cyclic citrullinated peptide antibody, and rheumatoid factors in juvenile idiopathic arthritis%4种自身抗体在幼年特发性关节炎早期诊断和预后评估中的意义

    Institute of Scientific and Technical Information of China (English)

    曾萍; 李丰; 唐盈; 刘海英; 关启鸿; 刘云锋; 曾华松

    2011-01-01

    目的 探讨免疫学指标抗角蛋白抗体(AKA)、抗环瓜氨酸肽(抗CCP)、类风湿因子(RF)-IgG、RF-IgM与各分型幼年特发性关节炎(JIA)患儿早期诊断和预后之间的关系.方法 收集76名经系统治疗并坚持随访治疗至少6个月的JIA患儿,在诊断初期进行AKA、抗CCP、RF.IgG、RF-IgM等免疫指标的检测,对不同亚型和预后作阳性检出率的比较,进行敏感性、特异性、相关危险度的统计学分析,并与49例健康儿童作对照比较.结果 多关节炎型组的AKA、抗CCP、RF-IgG、RF-IgM的阳性检出率与正常对照组比较差异有统计学意义,全身型、少关节型、附着点炎相关型的自身抗体阳性检出率与正常对照组差异无统计学意义.4种抗体的检测对多关节炎型组的分型敏感件依次为AKA>抗CCP,RF-IgG>RF-1gM;特异性依次为RF-IgM>AKA>RF-IgG>抗CCP.难治型JIA患儿的AKA阳性检出率与普通JIA患儿差异有统计学意义;相对危险度OR为3.514.结论 AKA、抗CCP、RF-IgG、RF-IgM在JIA不同亚型早期诊断中的作用有区别;AKA、抗CCP抗体的检测对JIA多关节炎型有较好的敏感性和特异性;AKA抗体的出现与难治型JIA相关,是否能作为成为多关节炎型早期诊断和预后评估的血清学指标,有待大样本的研究证实.%Objective To investigate the value of antikeratin antibody ( AKA ), anti-cyclic citrullinated peptide antibody ( anti-CCP ) and rheumatoid factor ( RF-IgG, RF-IgM ) in early diagnosis and prediction of juvenile idiopathic arthritis (JlA). Methods Seventy-six palients with JlA were enrolled and follow-up at least 6 months. The blood samples were collected to measure AKA, anti-CCP, RF-IgG, RF-IgM upon admission. The fiequency of positive AKA, anti-CCP, RF-IgG and RF-IgM in different subtype and refiractoriness were compared. Forty-nine healthy children were enrolled as control group. Results Compared with control group, the positive rates of AKA, anti-CCP,RF-IgG and RF

  6. Detection of anti-cyclic citrullinated peptide antibody in patients with psoriatic arthritis disease and its significance%抗环瓜氨酸肽抗体在银屑病关节炎患者中的检测及意义

    Institute of Scientific and Technical Information of China (English)

    潘虹; 李明

    2013-01-01

    目的 研究抗环瓜氨酸肽(CCP)抗体在银屑病关节炎(PsA)患者中的临床意义,探讨抗CCP抗体与PsA患者伴发关节炎、骨侵蚀破坏的关系及判断预后的意义.方法 采用酶联免疫吸附法,分别检测56例PsA患者血清的抗CCP 抗体水平,分析比较抗CCP 抗体与患者临床特征的关系.结果 抗CCP抗体在PsA患者中的阳性率为12.5%(7/56).抗CCP抗体在PsA五种临床分型中的阳性率分别为7.1%、21.4%、0%、0%、0%,抗CCP抗体阳性率在对称性多关节炎型PsA中明显高于其他四种PsA(P<0.05).抗CCP抗体阳性与阴性PsA患者临床及其他实验室指标比较结果显示:抗CCP抗体阳性组外周关节肿胀数、腕关节受累比例及红细胞沉降率(ESR)均高于抗CCP阴性组(P<0.05);在发病年龄、关节炎病程、阳性家族史、肘关节受累、腊肠指(趾)、腰骶痛和C反应蛋白(CRP)之间比较,差异无统计学意义.结论 12.5%的PsA患者体内存在抗CCP抗体;抗CCP抗体的出现与PsA患者多发性关节炎和骨侵蚀密切相关,对判断PsA关节炎的预后具有重要的临床价值.%Objective To study the clinical significance of anti-cyclic citrullinated peptide antibody( anti-CCP )in patients with psoriatic arthritis( PsA ), and to explore the correlation between anti-CCP and the complicated arthritis and bone erosion and also the significance of anti-CCP in the judgment of prognosis. Methods Enzyme linked immunosorbent assay was used to detect the anti-CCP level in the serum of 56 patients with PsA. The correlation between anti-CCP and the clinical features of those patients was analyzed. Results The positive rate of anti-CCP in patients with PsA was 12. 5 %( 7/56 ). The positive rate of anti-CCP in the five clinical classification of PsA was 7. 1% ,21.4% ,0% ,0% ,0% , respectively. The positive rate of anti-CCP in symmetry polyarthritis PsA was significantly higher that those in the other four kinds of PsA( P <0. 05 ). The

  7. 血清抗环瓜氨酸肽抗体对幼年特发性关节炎和成人类风湿关节炎诊断意义的比较%Diagnostic Value of Anti-Cyclic Citrullinated Peptide Antibodies in Juvenile Idiopahtic Arthritis and Adult Rheumatoid Arthritis

    Institute of Scientific and Technical Information of China (English)

    许峥; 黄小兰; 吴凤岐; 崔小岱; 黄峰; 张江林

    2011-01-01

    目的 比较分析幼年特发性关节炎(JIA)和成人类风湿关节炎(RA)患儿血清抗环瓜氨酸肽(CCP)抗体水平,探讨抗CCP抗体在JIA诊断中的价值和意义.方法 2009年2- 12月首都儿科研究所风湿免疫科确诊的JIA患儿72例.男33例,女39例;年龄(7.58 ±3.93)岁,全身型29例,少关节型27例,多关节型16例.同期在中国人民解放军总医院风湿科确诊的RA患者共65例.男14例,女51例;年龄(47.38±14.28)岁.健康对照组22例,为同期健康查体儿童.男10例,女12例;年龄(14.10±0.38)岁.选用英国Axis- shield Diagnostics Limit公司、德国欧蒙公司和上海富莼科芯公司生产的CCP抗体ELISA检测试剂盒,分别检测JIA患儿、RA患者和健康儿童血清CCP抗体水平.结果 英国Axis- shield Diagnostics Limit公司检测JIA患儿血清抗CCP抗体的阳性率为12.5%(9/72例),RA患者血清阳性率高达73.85%(48/65例),健康对照组无阳性(0/22例).RA患者血清抗CCP抗体阳性率显著高于JIA患儿(P<0.01),其中JIA组中多关节型阳性率31.25%(5/16例),少关节型阳性率14.8% (4/23例),全身型阳性率为0(0/29例),差异有统计学意义(P<0.001).另2家公司试剂盒检测结果.HA患儿血清抗CCP抗体的阳性率为15.3%(11/72例),RA患者血清阳性率为73.85% (48/65例),健康儿童无阳性.RA患者血清和健康儿童血清结果3家公司检测试剂盒完全一致.JIA患儿3种抗CCP抗体试剂盒检测结果之间差异无统计学意义(P>0.05).结论 ELISA方法检测血清抗CCP抗体水平较为稳定可靠,抗CCP抗体在JIA患儿中血清阳性率低于成人RA,抗CCP抗体在JIA各亚型分布差异显著,抗CCP抗体与多关节型相关.%Objective To evaluate the value of anti - cyclic citrullinated peptide antibodies (CCP) in the diagnosis of juvenile idiopathic arthritis (JIA) by analyzing results of detection from both JIA and adult rheumatoid arthritis ( RA) patients. Methods Seventy - two samples with

  8. The role of imidazole in peptide cyclization by transesterification: parallels to the catalytic triads of serine proteases

    OpenAIRE

    Byler, Kendall G.; Li, Yangmei; Houghten, Richard A.; Martinez-Mayorga, Karina

    2013-01-01

    The improved bioavailability, stability and selectivity of cyclic peptides over their linear counterparts make them attractive structures in the design and discovery of novel therapeutics. In our previous work, we developed an imidazole-promoted preparation of cyclic depsipeptides in which we observed that increasing the concentration of imidazole resulted in the concomitant increase in the yield of cyclic product and reduction in dimerization, but also resulted in the generation of an acyl-s...

  9. Chemical posttranslational modification of phage-displayed peptides.

    Science.gov (United States)

    Ng, Simon; Tjhung, Katrina F; Paschal, Beth M; Noren, Christopher J; Derda, Ratmir

    2015-01-01

    Phage-displayed peptide library has fueled the discovery of novel ligands for diverse targets. A new type of phage libraries that displays not only linear and disulfide-constrained cyclic peptides but moieties that cannot be encoded genetically or incorporated easily by bacterial genetic machinery has emerged recently. Chemical posttranslational modification of phage library is one of the simplest approaches to encode nonnatural moieties. It confers the library with new functionality and makes it possible to select and evolve molecules with properties not found in the peptides, for instance, glycopeptides recognized by carbohydrate-binding protein and peptides with photoswitching capability. To this end, we describe the newly emerging techniques to chemically modify the phage library and quantify the efficiency of the reaction with a biotin-capture assay. Finally, we provide the methods to construct N-terminal Ser peptide library that allows site-selective modification of phage.

  10. Sectoral Shifts and Cyclical Fluctuations Sectoral Shifts and Cyclical Fluctuations

    Directory of Open Access Journals (Sweden)

    Richard Rogerson

    1991-03-01

    Full Text Available Sectoral Shifts and Cyclical Fluctuations This paper studies a two sector real business cycle model in which the sectors experience different trend rates of growth and labor mobility is costly. Predictions are derived concerning the correlation between sectoral reallocation of workers and the cycle. This correlation may be positive or negative depending upon whether the growing sector displays larger or smaller fluctuations than the shrinking sector. The post- World War II period has witnessed two major patterns of sectoral change in industrialized countries: movement out of agriculture and movement out of the industrial sector. The model's basic prediction is shown to be consistent with the observed pattern of reallocation.

  11. Tandem mass spectrometry of kahalalides: Identification of two new cyclic depsipeptides, kahalalide R and S from Elysia grandifolia

    Digital Repository Service at National Institute of Oceanography (India)

    Tilvi, S.; Naik, C.G.

    and by comparison with the amino acid sequence of kahalalide F. The pathway is presented for the loss of amino acid residues in kahalalide F. It is observed that there is sequential loss of amino acids in the linear peptide chain but in the cyclic part, the ring...

  12. Clinical endocrinology and metabolism. Receptors for gut peptides.

    Science.gov (United States)

    Harmar, Anthony J

    2004-12-01

    Most gut peptides exert their effects through G protein-coupled receptors, a family of about 700 membrane proteins, 87 of which are presently known to have peptide ligands. Three additional gut peptide receptors are not G protein-coupled receptors but regulate intracellular cyclic GMP accumulation. The aim of this review is to illustrate how the sequencing of the human genome and other recent advances in genomics has contributed to our understanding of the role of peptides and their receptors in gastrointestinal function. Recent discoveries include the identification of receptors for the peptides motilin and neuromedin U, and new physiological ligands for the PTH2 receptor, the CRF(2) receptor and the growth hormone secretagogue receptor. Knockout mice lacking specific peptide receptors or their ligands provide informative animal models in which to determine the functions of the numerous peptide-receptor systems in the gut and to predict which of them may be the most fruitful for drug development. Some peptide-receptor signalling systems may be more important in disease states than they are in normal physiology. For example, substance P, galanin, bradykinin and opioids play important roles in visceral pain and inflammation. Other peptides may have developmental roles: for example, disruption of endothelin-3 signalling prevents the normal development of the enteric nervous system and contributes to the pathogenesis of Hirschsprung disease.

  13. Peptide Formation Mechanism on Montmorillonite Under Thermal Conditions

    Science.gov (United States)

    Fuchida, Shigeshi; Masuda, Harue; Shinoda, Keiji

    2014-02-01

    The oligomerization of amino acids is an essential process in the chemical evolution of proteins, which are precursors to life on Earth. Although some researchers have observed peptide formation on clay mineral surfaces, the mechanism of peptide bond formation on the clay mineral surface has not been clarified. In this study, the thermal behavior of glycine (Gly) adsorbed on montmorillonite was observed during heating experiments conducted at 150 °C for 336 h under dry, wet, and dry-wet conditions to clarify the mechanism. Approximately 13.9 % of the Gly monomers became peptides on montmorillonite under dry conditions, with diketopiperazine (cyclic dimer) being the main product. On the other hand, peptides were not synthesized in the absence of montmorillonite. Results of IR analysis showed that the Gly monomer was mainly adsorbed via hydrogen bonding between the positively charged amino groups and negatively charged surface sites (i.e., Lewis base sites) on the montmorillonite surface, indicating that the Lewis base site acts as a catalyst for peptide formation. In contrast, peptides were not detected on montmorillonite heated under wet conditions, since excess water shifted the equilibrium towards hydrolysis of the peptides. The presence of water is likely to control thermodynamic peptide production, and clay minerals, especially those with electrophilic defect sites, seem to act as a kinetic catalyst for the peptide formation reaction.

  14. 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...

  15. Cyclic voltammetry of supported BLMs

    Science.gov (United States)

    Murgasova, Renata; Sabo, Jan; Ottova, Angelica L.; Tien, H. T.

    1996-06-01

    The transfer of an electron across a bilayer lipid membrane (BLM) is one of the BLMs most exciting processes. A number of well known electron mediators have been investigated using the method of cyclic voltammetry on a Teflon coated platinum wire, the tip of which has been modified by a self-assembled bilayer lipid membrane (s-BLM). The electrical capacitance of the s-BLM system was measured as a function of frequency. The results are discussed in terms of electron transfer and redox reactions.

  16. Cu(II) coordination chemistry of patellamide derivatives: possible biological functions of cyclic pseudopeptides.

    Science.gov (United States)

    Comba, Peter; Dovalil, Nina; Gahan, Lawrence R; Haberhauer, Gebhard; Hanson, Graeme R; Noble, Christopher J; Seibold, Björn; Vadivelu, Prabha

    2012-02-27

    Two synthetic derivatives of the naturally occurring cyclic pseudooctapeptides patellamide  A-F and ascidiacyclamide, that is, H(4)pat(2), H(4)pat(3), as well as their Cu(II) complexes are described. These cyclic peptide derivatives differ from the naturally occurring macrocycles by the variation of the incorporated heterocyclic donor groups and the configuration of the amino acids connecting the heterocycles. The exchange of the oxazoline and thiazole groups by dimethylimidazoles or methyloxazoles leads to more rigid macrocycles, and the changes in the configuration of the side chains leads to significant differences in the folding of the cyclic peptides. These variations allow a detailed study of the various possible structural changes on the chemistry of the Cu(II) complexes formed. The coordination of Cu(II) with these macrocyclic species was monitored by high-resolution electrospray mass spectrometry (ESI-MS), spectrophotometric (UV/Vis) and circular dichroic (CD) titrations, and electron paramagnetic resonance (EPR) spectroscopy. Density functional theory (DFT) calculations and molecular mechanics (MM) simulations have been used to model the structures of the Cu(II) complexes and provide a detailed understanding of their geometric preferences and conformational flexibility. This is related to the Cu(II) coordination chemistry and the reactivity of the dinuclear Cu(II) complexes towards CO(2) fixation. The variation observed between the natural and various synthetic peptide systems enables conclusions about structure-reactivity correlations, and our results also provide information on why nature might have chosen oxazolines and thiazoles as incorporated heterocycles.

  17. The biosynthesis of cyclic carotenes.

    Science.gov (United States)

    Williams, R J; Britton, G; Goodwin, T W

    1967-10-01

    1. The incorporation of (3RS)-[2-(14)C,(4R)-4-(3)H(1)]mevalonic acid into various cyclic carotenes in the fruit of the tomato mutant delta has been studied. The results confirm our previous view that the alpha-ionone ring of alpha-carotene does not arise by isomerization of a beta-ionone residue, and show that the same is also true for the alpha-ionone ring of delta- and in-carotene and alpha-zeacarotene. 2. The incorporation of (3RS)-[2-(14)C,2-(3)H(2)]mevalonic acid into alpha- and beta-carotene in carrot roots has been studied. The results show that the beta-ionone ring of beta-carotene does not arise by isomerization of the alpha-ionone residue of alpha-carotene. 3. These experiments show that alpha- and beta-ionone rings in cyclic carotenes are formed independently, probably by elimination of different protons from the same carbonium ion intermediates.

  18. Cyclic Cohomology of the Weyl Algebra

    CERN Document Server

    Willwacher, Thomas

    2008-01-01

    We give an explicit formula for symplectically basic representatives of the cyclic cohomology of the Weyl algebra. This paper can be seen as cyclic addendum to the paper by Feigin, Felder and Shoikhet, where the analogous Hochschild case was treated. As an application, we prove a generalization of a Theorem of Nest and Tsygan concerning the relation of the Todd class and the cyclic cohomology of the differential operators on a complex manifold.

  19. [Cyclic Cushing's Syndrome - rare or rarely recognized].

    Science.gov (United States)

    Kiałka, Marta; Doroszewska, Katarzyna; Mrozińska, Sandra; Milewicz, Tomasz; Stochmal, Ewa

    2015-01-01

    Cyclic Cushing's syndrome is a type of Cushing's disease which is characterized by alternating periods of increasing and decreasing levels of cortisol in the blood. The diagnostic criteria for cyclic Cushing's syndrome are at least three periods of hypercortisolism alternating with at least two episodes of normal levels of serum cortisol concentration. The epidemiology, signs, symptoms, pathogenesis and treatment of cyclic Cushing's syndrome have been discussed.

  20. Cyclic and Inductive Calculi are equivalent

    CERN Document Server

    Voicu, Razvan

    2011-01-01

    Brotherston and Simpson [citation] have formalized and investigated cyclic reasoning, reaching the important conclusion that it is at least as powerful as inductive reasoning (specifically, they showed that each inductive proof can be translated into a cyclic proof). We add to their investigation by proving the converse of this result, namely that each inductive proof can be translated into an inductive one. This, in effect, establishes the equivalence between first order cyclic and inductive calculi.

  1. Cyclic and Inductive Calculi are equivalent

    OpenAIRE

    Razvan VOICU; Li, Mengran

    2011-01-01

    Brotherston and Simpson [citation] have formalized and investigated cyclic reasoning, reaching the important conclusion that it is at least as powerful as inductive reasoning (specifically, they showed that each inductive proof can be translated into a cyclic proof). We add to their investigation by proving the converse of this result, namely that each inductive proof can be translated into an inductive one. This, in effect, establishes the equivalence between first order cyclic and inductive...

  2. Improved labelling of DTPA- and DOTA-conjugated peptides and antibodies with 111In in HEPES and MES buffer.

    NARCIS (Netherlands)

    Brom, M.; Joosten, L.; Oyen, W.J.G.; Gotthardt, M.; Boerman, O.C.

    2012-01-01

    ABSTRACT: BACKGROUND: In single photon emission computed tomography [SPECT], high specific activity of 111In-labelled tracers will allow administration of low amounts of tracer to prevent receptor saturation and/or side effects. To increase the specific activity, we studied the effect of the buffer

  3. The Use of Aryl Hydrazide Linkers for the Solid Phase Synthesis of Chemically Modified Peptides

    Energy Technology Data Exchange (ETDEWEB)

    Woo, Y; Mitchell, A R; Camarero, J A

    2006-11-03

    Since Merrifield introduced the concept of solid phase synthesis in 1963 for the rapid preparation of peptides, a large variety of different supports and resin-linkers have been developed that improve the efficiency of peptide assembly and expand the myriad of synthetically feasible peptides. The aryl hydrazide is one of the most useful resin-linkers for the synthesis of chemically modified peptides. This linker is completely stable during Boc- and Fmoc-based solid phase synthesis and yet it can be cleaved under very mild oxidative conditions. The present article reviews the use of this valuable linker for the rapid and efficient synthesis of C-terminal modified peptides, head-to-tail cyclic peptides and lipidated peptides.

  4. Backbone cyclization of a recombinant cystine-knot peptide by engineered Sortase A.

    Science.gov (United States)

    Stanger, Karen; Maurer, Till; Kaluarachchi, Harini; Coons, Mary; Franke, Yvonne; Hannoush, Rami N

    2014-11-28

    Cyclotides belong to the family of cyclic cystine-knot peptides and have shown promise as scaffolds for protein engineering and pharmacological modulation of cellular protein activity. Cyclotides are characterized by a cystine-knotted topology and a head-to-tail cyclic polypeptide backbone. While they are primarily produced in plants, cyclotides have also been obtained by chemical synthesis. However, there is still a need for methods to generate cyclotides in high yields to near homogeneity. Here, we report a biomimetic approach which utilizes an engineered version of the enzyme Sortase A to catalyze amide backbone cyclization of the recombinant cyclotide MCoTI-II, thereby allowing the efficient production of active homogenous species in high yields. Our results provide proof of concept for using engineered Sortase A to produce cyclic MCoTI-II and should be generally applicable to generating other cyclic cystine-knot peptides.

  5. Changes in cyclic nucleotides, locomotory behavior, and body length produced by novel endogenous neuropeptides in the parasitic nematode Ascaris suum.

    Science.gov (United States)

    Reinitz, Catharine A; Pleva, Anthony E; Stretton, Antony O W

    2011-11-01

    Recent technical advances have rapidly advanced the discovery of novel peptides, as well as the transcripts that encode them, in the parasitic nematode Ascaris suum. Here we report that many of these novel peptides produce profound and varied effects on locomotory behavior and levels of cyclic nucleotides in A. suum. We investigated the effects of 31 endogenous neuropeptides encoded by transcripts afp-1, afp-2, afp-4, afp-6, afp-7, and afp-9-14 (afp: Ascaris FMRFamide-like Precursor protein) on cyclic nucleotide levels, body length and locomotory behavior. Worms were induced to generate anteriorly propagating waveforms, peptides were injected into the pseudocoelomic cavity, and changes in the specific activity (nmol/mg protein) of second messengers cAMP (3'5' cyclic adenosine monophosphate) and cGMP (3'5' cyclic guanosine monophosphate) were determined. Many of these neuropeptides changed the levels of cAMP (both increases and decreases were found), whereas few neuropeptides changed the level of cGMP. A subset of the peptides that lowered cAMP was investigated for effects on the locomotory waveform and on body length. Injection of AF19, or AF34 (afp-13), AF9 (afp-14), AF26 or AF41 (afp-11) caused immediate paralysis and cessation of propagating body waveforms. These neuropeptides also significantly increased body length. In contrast, injection of AF15 (afp-9) reduced the body length, and decreased the amplitude of waves in the body waveform. AF30 (afp-10) produced worms with tight ventral coils. Although injection of neuropeptides encoded by afp-1 (AF3, AF4, AF10 or AF13) produced an increased number of exaggerated body waves, there were no effects on either cAMP or cGMP. By injecting peptides into behaving A. suum, we have provided an initial screen of the effects of novel peptides on several behavioral and biochemical parameters.

  6. Human Antimicrobial Peptides and Proteins

    Directory of Open Access Journals (Sweden)

    Guangshun Wang

    2014-05-01

    medicine to combat drug-resistant superbugs, fungi, viruses, parasites, or cancer. Alternatively, multiple factors (e.g., albumin, arginine, butyrate, calcium, cyclic AMP, isoleucine, short-chain fatty acids, UV B light, vitamin D, and zinc are able to induce the expression of antimicrobial peptides, opening new avenues to the development of anti-infectious drugs.

  7. Small cationic antimicrobial peptides delocalize peripheral membrane proteins.

    Science.gov (United States)

    Wenzel, Michaela; Chiriac, Alina Iulia; Otto, Andreas; Zweytick, Dagmar; May, Caroline; Schumacher, Catherine; Gust, Ronald; Albada, H Bauke; Penkova, Maya; Krämer, Ute; Erdmann, Ralf; Metzler-Nolte, Nils; Straus, Suzana K; Bremer, Erhard; Becher, Dörte; Brötz-Oesterhelt, Heike; Sahl, Hans-Georg; Bandow, Julia Elisabeth

    2014-04-08

    Short antimicrobial peptides rich in arginine (R) and tryptophan (W) interact with membranes. To learn how this interaction leads to bacterial death, we characterized the effects of the minimal pharmacophore RWRWRW-NH2. A ruthenium-substituted derivative of this peptide localized to the membrane in vivo, and the peptide also integrated readily into mixed phospholipid bilayers that resemble Gram-positive membranes. Proteome and Western blot analyses showed that integration of the peptide caused delocalization of peripheral membrane proteins essential for respiration and cell-wall biosynthesis, limiting cellular energy and undermining cell-wall integrity. This delocalization phenomenon also was observed with the cyclic peptide gramicidin S, indicating the generality of the mechanism. Exogenous glutamate increases tolerance to the peptide, indicating that osmotic destabilization also contributes to antibacterial efficacy. Bacillus subtilis responds to peptide stress by releasing osmoprotective amino acids, in part via mechanosensitive channels. This response is triggered by membrane-targeting bacteriolytic peptides of different structural classes as well as by hypoosmotic conditions.

  8. Cell reorientation under cyclic stretching

    CERN Document Server

    Livne, Ariel; Geiger, Benjamin

    2014-01-01

    Mechanical cues from the extracellular microenvironment play a central role in regulating the structure, function and fate of living cells. Nevertheless, the precise nature of the mechanisms and processes underlying this crucial cellular mechanosensitivity remains a fundamental open problem. Here we provide a novel framework for addressing cellular sensitivity and response to external forces by experimentally and theoretically studying one of its most striking manifestations -- cell reorientation to a uniform angle in response to cyclic stretching of the underlying substrate. We first show that existing approaches are incompatible with our extensive measurements of cell reorientation. We then propose a fundamentally new theory that shows that dissipative relaxation of the cell's passively-stored, two-dimensional, elastic energy to its minimum actively drives the reorientation process. Our theory is in excellent quantitative agreement with the complete temporal reorientation dynamics of individual cells, measu...

  9. Cyclic malyl anthocyanins in Dianthus caryophyllus.

    Science.gov (United States)

    Nakayama, M; Koshioka, M; Yoshida, H; Kan, Y; Fukui, Y; Koike, A; Yamaguchi, M

    2000-12-01

    3,5-Di-O-(beta-glucopyranosyl) pelargonidin 6''-O-4,6'''-O-1-cyclic malate and a previously reported cyanidin equivalent, 3,5-di-O-(beta-glucopyranosyl) cyanidin 6''-O-4,6'''-O-1-cyclic malate were identified from petals of deep pink and red-purple flower cultivars of Dianthus caryophyllus, respectively.

  10. Cyclicality in Losses on Bank Loans

    NARCIS (Netherlands)

    B. Keijsers (Bart); B.F. Diris (Bart); H.J.W.G. Kole (Erik)

    2015-01-01

    markdownabstract__Abstract__ Cyclicality in the losses of bank loans is important for bank risk management. Because loans have a different risk profile than bonds, evidence of cyclicality in bond losses need not apply to loans. Based on unique data we show that the default rate and loss given defau

  11. Cyclic electrophoretic and chromatographic separation methods

    NARCIS (Netherlands)

    Eijkel, Jan C.T.; Berg, van den Albert; Manz, Andreas

    2004-01-01

    A review is given of the application of cyclic analytical methods in capillary electroseparation (CE) and liquid chromatography (LC) systems. Cyclic methods have been used since the early sixties in chromatographic systems to overcome pressure limitations to resolution. From the early nineties on th

  12. Products in Hopf-Cyclic Cohomology

    CERN Document Server

    Kaygun, Atabey

    2007-01-01

    We construct several pairings in Hopf-cyclic cohomology of (co)module (co)algebras with arbitrary coefficients. The key ideas instrumental in constructing these pairings are the derived functor interpretation of Hopf-cyclic and equivariant cyclic (co)homology, and the Yoneda interpretation of Ext-groups. As a special case of one of these pairings, we recover the Connes-Moscovici characteristic map in Hopf-cyclic cohomology. We also prove that this particular pairing, along with few others, would stay the same if we replace the derived category of (co)cyclic modules with the homotopy category of (special) towers of $X$-complexes, or the derived category of mixed complexes.

  13. High-throughput screening of one-bead-one-compound libraries: identification of cyclic peptidyl inhibitors against calcineurin/NFAT interaction.

    Science.gov (United States)

    Liu, Tao; Qian, Ziqing; Xiao, Qing; Pei, Dehua

    2011-09-12

    One-bead-one-compound (OBOC) libraries provide a powerful tool for drug discovery as well as biomedical research. However, screening a large number of beads/compounds (>1 million) and rank ordering the initial hits (which are covalently attached to a solid support) according to their potencies still post significant technical challenges. In this work, we have integrated some of the latest technical advances from our own as well as other laboratories to develop a general methodology for rapidly screening large OBOC libraries. The methodology has been applied to synthesize and screen a cyclic peptide library that features: (1) spatially segregated beads containing cyclic peptides on the surface layer and linear encoding peptides in their interior; (2) rapid on-bead screening of the library (>1 million) by a multistage procedure (magnetic bead sorting, enzyme-linked assay, and fluorescence based screening); (3) selective release of cyclic peptides from single positive beads for solution-phase determination of their binding affinities; and (4) hit identification by partial Edman degradation/mass spectrometry (PED/MS). Screening of the library against protein phosphatase calcineurin (Cn) identified a series of cyclic peptides that bind to the substrate-docking site for nuclear factor of activated T cells (NFAT) with K(D) values of ∼1 μM. Further improvement of the affinity and specificity of these compounds may lead to a new class of immunosuppressive agents that are more selective and therefore less toxic than cyclosporine A and FK506.

  14. The efficacy of trivalent cyclic hexapeptides to induce lipid clustering in PG/PE membranes correlates with their antimicrobial activity.

    Science.gov (United States)

    Finger, Sebastian; Kerth, Andreas; Dathe, Margitta; Blume, Alfred

    2015-11-01

    Various models have been proposed for the sequence of events occurring after binding of specific antimicrobial peptides to lipid membranes. The lipid clustering model arose by the finding that antimicrobial peptides can induce a segregation of certain negatively charged lipids in lipid model membranes. Anionic lipid segregation by cationic peptides is initially an effect of charge interaction where the ratio of peptide and lipid charges is thought to be the decisive parameter in the peptide induced lipid demixing. However, the sequence of events following this initial lipid clustering is more complex and can lead to deactivation of membrane proteins involved in cell division or perturbation of lipid reorganization essential for cell division. In this study we used DSC and ITC techniques to investigate the effect of binding different cyclic hexapeptides with varying antimicrobial efficacy, to phosphatidylglycerol (PG)/phosphatidylethanolamine (PE) lipid membranes and their ability to induce lipid segregation in these mixtures. We found that these cyclic hexapeptides consisting of three charged and three aromatic amino acids showed indeed different abilities to induce lipid demixing depending on their amino acid composition and their sequence. The results clearly showed that the cationic amino acids are essential for electrostatic binding but that the three hydrophobic amino acids in the peptides and their position in the sequence also contribute to binding affinity and to the extent of induction of lipid clustering. The efficacy of these different hexapeptides to induce PG clusters in PG/PE membranes was found to be correlated with their antimicrobial activity.

  15. 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...

  16. Cyclic pentapeptide analogs based on endomorphin-2 structure: cyclization studies using liquid chromatography combined with on-line mass spectrometry and tandem mass spectrometry.

    Science.gov (United States)

    Piekielna, Justyna; Kluczyk, Alicja; Perlikowska, Renata; Janecka, Anna

    2014-05-01

    The cyclization of linear analogs based on endomorphin-2 structure, Tyr/Dmt-d-Lys-Phe-Phe-Asp-NH2 and Tyr/Dmt-d-Cys-Phe-Phe-Cys-NH2 (where Dmt=2',6'-dimethyltyrosine), resulting in obtaining lactam or disulfide derivatives, was studied using liquid chromatography combined with on-line mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS/MS). In case of cyclization via an amide bond, the formation of the cyclic monomers, cyclic but not linear dimers and even traces of cyclic trimers was observed. Disulfide bridge containing peptides was obtained by the solid-phase synthesis of the linear sequences, followed by either in-solution or on-resin cyclization. In case of the in-solution cyclization, the expected cyclic monomers were the only products. When oxidation of the cysteine residues was performed when the peptides were still on the resin, cyclic monomer and two cyclodimers, parallel and antiparallel, were found. Digestion of the isolated cyclodimers with α-chymotrypsin allowed for their unambiguous identification. The comparison of the cyclic monomer/dimer ratios for analogs with Tyr versus Dmt in position 1 revealed that the presence of the exocyclic Dmt favored formation of the cyclic monomer, most likely due to the increased steric bulk of this amino acid side-chain as compared with Tyr.

  17. De Novo Design of Skin-Penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs.

    Science.gov (United States)

    Menegatti, Stefano; Zakrewsky, Michael; Kumar, Sunny; De Oliveira, Joshua Sanchez; Muraski, John A; Mitragotri, Samir

    2016-03-09

    Skin-penetrating peptides (SPPs) are attracting increasing attention as a non-invasive strategy for transdermal delivery of therapeutics. The identification of SPP sequences, however, currently performed by experimental screening of peptide libraries, is very laborious. Recent studies have shown that, to be effective enhancers, SPPs must possess affinity for both skin keratin and the drug of interest. We therefore developed a computational process for generating and screening virtual libraries of disulfide-cyclic peptides against keratin and cyclosporine A (CsA) to identify SPPs capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin, as determined by mass spectrometry and affinity chromatography, and enhance transdermal permeation of CsA. Four heptameric sequences that emerged as leading candidates (ACSATLQHSCG, ACSLTVNWNCG, ACTSTGRNACG, and ACSASTNHNCG) were tested and yielded CsA permeation on par with previously identified SPP SPACE (TM) . An octameric peptide (ACNAHQARSTCG) yielded significantly higher delivery of CsA compared to heptameric SPPs. The safety profile of the selected sequences was also validated by incubation with skin keratinocytes. This method thus represents an effective procedure for the de novo design of skin-penetrating peptides for the delivery of desired therapeutic or cosmetic agents.

  18. 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.

  19. 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....

  20. 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....

  1. 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....

  2. 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....

  3. 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....

  4. 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.

  5. Specificity of the Cyclic GMP-Binding Activity and of a Cyclic GMP-Dependent Cyclic GMP Phosphodiesterase in Dictyostelium discoideum

    NARCIS (Netherlands)

    Haastert, Peter J.M. van; Walsum, Hans van; Meer, Rob C. van der; Bulgakov, Roman; Konijn, Theo M.

    1982-01-01

    The nucleotide specificity of the cyclic GMP-binding activity in a homogenate of Dictyostelium discoideum was determined by competition of cyclic GMP derivatives with [8-3H] cyclic GMP for the binding sites. The results indicate that cyclic GMP is bound to the binding proteins by hydrogen bonds at N

  6. Cyclic Shearing Deformation Behavior of Saturated Clays

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The apparatus for static and dynamic universal triaxial and torsional shear soil testing is employed to perform stress-controlled cyclic single-direction torsional shear tests and two-direction coupled shear tests under unconsolidated-undrained conditions. Through a series of tests on saturated clay, the effects of initial shear stress and stress reversal on the clay's strain-stress behavior are examined, and the behavior of pore water pressure is studied. The experimental results indicate that the patterns of stress-strain relations are distinctly influenced by the initial shear stress in the cyclic single-direction shear tests. When the initial shear stress is large and no stress reversal occurs, the predominant deformation behavior is characterized by an accumulative effect. When the initial shear stress is zero and symmetrical cyclic stress occurs, the predominant deformation behavior is characterized by a cyclic effect. The pore water pressure fluctuates around the confining pressure with the increase of cycle number. It seems that the fluctuating amplitude increases with the increase of the cyclic stress. But a buildup of pore water pressure does not occur. The deformations of clay samples under the complex initial and the cyclic coupled stress conditions include the normal deviatoric deformation and horizontal shear deformation, the average deformation and cyclic deformation. A general strain failure criterion taking into account these deformations is recommended and is proved more stable and suitable compared to the strain failure criteria currently used.

  7. Improved targeting of the {alpha}{sub v}{beta}{sub 3} integrin by multimerisation of RGD peptides

    Energy Technology Data Exchange (ETDEWEB)

    Dijkgraaf, Ingrid [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, P.O. Box 9101, Nijmegen (Netherlands); Utrecht University, Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, Utrecht (Netherlands); Kruijtzer, John A.W.; Liskamp, Rob M.J. [Utrecht University, Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, Utrecht (Netherlands); Liu, Shuang [Purdue University, School of Health Sciences, West Lafayette, IN (United States); Soede, Annemieke C.; Oyen, Wim J.G.; Corstens, Frans H.M.; Boerman, Otto C. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, P.O. Box 9101, Nijmegen (Netherlands)

    2007-02-15

    The integrin {alpha}{sub v}{beta}{sub 3} is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of {alpha}{sub v}{beta}{sub 3} in tumours, {alpha}{sub v}{beta}{sub 3} is considered a suitable receptor for tumour targeting. In this study the {alpha}{sub v}{beta}{sub 3} binding characteristics of an {sup 111}In-labelled monomeric, dimeric and tetrameric RGD analogue were compared. A monomeric (E-c(RGDfK)), dimeric (E-[c(RGDfK)]{sub 2}), and tetrameric (E{l_brace}E[c(RGDfK)]{sub 2}{r_brace}{sub 2}) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with {sup 111}In. In vitro {alpha}{sub v}{beta}{sub 3} binding characteristics were determined in a competitive binding assay. In vivo {alpha}{sub v}{beta}{sub 3} targeting characteristics of the compounds were assessed in mice with SK-RC-52 xenografts. The IC{sub 50} values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)]{sub 2}, and DOTA-E{l_brace}E[c(RGDfK)]{sub 2}{r_brace}{sub 2}were 120 nM, 69.9 nM and 19.6 nM, respectively. At all time points, the tumour uptake of the dimer was significantly higher as compared to that of the monomer. At 8 h p.i., tumour uptake of the tetramer (7.40 {+-}1.12%ID/g) was significantly higher than that of the monomer (2.30 {+-}0.34%ID/g), p <0.001, and the dimer (5.17 {+-}1.22%ID/g), p <0.05. At 24 h p.i., the tumour uptake was significantly higher for the tetramer (6.82 {+-}1.41%ID/g) than for the dimer (4.22 {+-}0.96%ID/g), p <0.01, and the monomer (1.90 {+-}0.29%ID/g), p <0.001. Multimerisation of c(RGDfK) resulted in enhanced affinity for {alpha}{sub v}{beta}{sub 3} as determined in vitro. Tumour uptake of a tetrameric RGD peptide was significantly higher than that of the monomeric and dimeric analogues, presumably owing to the enhanced statistical likelihood for rebinding to {alpha}{sub v}{beta}{sub 3}. (orig.)

  8. Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide

    Science.gov (United States)

    Dijkgraaf, Ingrid; Terry, Samantha; McBride, William J.; Goldenberg, David M.; Laverman, Peter; Franssen, Gerben M.; Oyen, Wim J. G.; Boerman, Otto C.

    2014-01-01

    Integrin αvβ3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αvβ3, but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of 18F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with 18F in a simple one-pot process with a radiolabeling yield of 20%; the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with 18F at a specific activity of 1.8 MBq/nmol and a radiochemical purity of 100% could be achieved. Log P value of 18F-labeled NODAGA-E-[c(RGDfK)]2 was −4.26 ± 0.02. In biodistribution studies, 18F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 %ID/g in the blood at 2 h p.i., mainly via the kidneys and showed good in vivo stability. Tumor uptake of 18F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID/g, 2 h p.i.) was significantly lower than that of reference compounds 68Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID/g; P <0.001) and 111In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID/g; P < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with 18F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID/g). The αvβ3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with 18F-labeled NODAGA-E-[c(RGDfK)]2. In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with 18F using a direct aqueous, one-pot method and it accumulated specifically in αvβ3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET. PMID:23606427

  9. Design of Self-Assembling Peptide Nanotubes with Delocalized Electronic States[**

    OpenAIRE

    Ashkenasy, Nurit; Horne, W. Seth; Reza Ghadiri, M.

    2006-01-01

    Redox-promoted self-assembly of an eight-residue cyclic D,L-α-peptide bearing four 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) side chains results in the formation of electronically delocalized peptide nanotubes hundreds of nm in length. The supramolecular approach described provides a rational basis for the design and fabrication of 1-D materials with potential utility in optical and electronic devices.

  10. Undrained Cyclic Behaviour of Dense Frederikshavn Sand

    DEFF Research Database (Denmark)

    Nielsen, Søren Kjær; Ibsen, Lars Bo; Sørensen, Kris Wessel;

    2013-01-01

    of undrained cyclic triaxial tests, which have been performed at the Geotechnical Laboratory at Aalborg University. In order to ensure offshore conditions, the tests were fully saturated and performed with a relative density of 80 %. During cyclic loading, special attention was given to the development of pore......A modified contour diagram is created for the Frederikshavn Sand in the undrained case for a relative density of ID = 80 %. It can be used to estimate the number of cycles to failure for a given combination of pore pressure, average and cyclic load ratio. The diagram is based on a series...

  11. Monopod bucket foundations under cyclic lateral loading

    OpenAIRE

    Foglia, Aligi; Ibsen, Lars Bo

    2014-01-01

    The monopod bucket foundation can be a cost-reducing sub-structure for offshore wind turbines. To avoid problems during the turbine operation, the long-term effect of cyclic loading must be considered in the design of the foundation. In this paper a 1g testing rig is adopted to extend the knowledge on bucket foundations under lateral cyclic loading. The test setup is described in detail and a comprehensive experimental campaign is presented. The foundation is subjected to cyclic overturning m...

  12. General solution of cyclic Leibniz rule

    CERN Document Server

    Kadoh, Daisuke

    2015-01-01

    We study the general solution of the cyclic Leibniz rule (CLR) which was recently proposed as a new approach to the lattice supersymmetry. Introducing some mathematical preliminaries associated with the cyclic symmetry, we find the general solution of the 2-body CLR for the naive symmetric difference operator. The main theorems of this paper state that the general solution can be uniquely expressed as (A) a linear combination of the two fundamental solutions with cyclic invariant coefficients, and (B) a linear combination of the minimal solutions with complex coefficients. Moreover, an extension to the general difference operators is also discussed.

  13. Cyclic distillation technology - A mini-review

    DEFF Research Database (Denmark)

    Bîldea, Costin Sorin; Pătruţ, Cătălin; Jørgensen, Sten Bay;

    2016-01-01

    and reactive distillation were studied and reported in literature. All these techniques employ the conventional continuous counter-current contact of vapor and liquid phases. Cyclic distillation technology is based on an alternative operating mode using separate phase movement which leads to key practical...... advantages in both chemical and biochemical processes. This article provides a mini-review of cyclic distillation technology. The topics covered include the working principle, design and control methods, main benefits and limitations as well as current industrial applications. Cyclic distillation can...

  14. Cyclic Control Optimization for a Smart Rotor

    DEFF Research Database (Denmark)

    Bergami, Leonardo; Henriksen, Lars Christian

    2012-01-01

    The paper presents a method to determine cyclic control trajectories for a smart rotor undergoing periodic-deterministic load variations. The control trajectories result from a constrained optimization problem, where the cost function to minimize is given by the variation of the blade root flapwise...... bending moment within a rotor revolution. The method is applied to a rotor equipped with trailing edge flaps, and capable of individual blade pitching. Results show that the optimized cyclic control significantly alleviates the load variations from periodic disturbances; the combination of both cyclic...

  15. Peptide immobilization onto radiation grafted PVDF-g-poly(acrylic acid) films

    Science.gov (United States)

    Clochard, M.-C.; Betz, N.; Goncalves, M.; Bittencourt, C.; Pireaux, J.-J.; Gionnet, K.; Déléris, G.; Moël, A. Le

    2005-07-01

    Introducing hydrophilic functions on poly(vinylidene fluoride) (PVDF) films surface allows the covalent immobilization of peptides. Therefore radiation grafting of acrylic acid (AA) in pre-irradiated PVDF films was achieved to allow surface functionalization with linear and cyclic peptides. Peptides were bound via spacer molecules using EDC as a coupling agent. The reactions were followed by Fourier Transform Infrared (FTIR) spectroscopy in attenuated total reflection (ATR) mode. The amount of immobilized peptides was determined by UV spectroscopy. As well, an uncommon method for PVDF characterization and reactions quantification was used: high-resolution-magic angle spinning nuclear mass spectroscopy (HR-MAS NMR). Spacer saturation of the film surface corresponded to 25 mol% yield meaning that one spacer on 4 carboxylic acids was covalently bound. XPS experiments were also performed to deepen analysis of the surface composition. Peptide density is governed by steric hindrance. ELISA tests showed that the peptides' activity is maintained.

  16. Mortar constituent of concrete under cyclic compression

    Science.gov (United States)

    Maher, A.; Darwin, D.

    1980-10-01

    The behavior of the mortar constituent of concrete under cyclic compression was studied and a simple analytic model was developed to represent its cyclic behavior. Experimental work consisted of monotonic and cyclic compressive loading of mortar. Two mixes were used, with proportions corresponding to concretes having water cement ratios of 0.5 and 0.6. Forty-four groups of specimens were tested at ages ranging from 5 to 70 days. complete monotonic and cyclic stress strain envelopes were obtained. A number of loading regimes were investigated, including cycles to a constant maximum strain. Major emphasis was placed on tests using relatively high stress cycles. Degradation was shown to be a continuous process and a function of both total strain and load history. No stability or fatigue limit was apparent.

  17. Cyclic Period in the CBE Model

    CERN Document Server

    Frampton, Paul H

    2016-01-01

    In a cyclic entropy model in which the extroverse is jettisoned at turnaround with a Come Back Empty (CBE) assumption, we address matching of the contaction scale factor $\\hat{a}(t)=f(t_T){a}(t)$ to the expansion scale factor $a(t)$, where $f(t_T)$ is the ratio at turnaround of the introverse to extroverse radii. Such matching is necessary for infinite cyclicity and fixes the CBE period at $\\sim 2.6Ty$.

  18. Synthesis of Chiral Amino Cyclic Phosphoric Acids

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Chirai amino cyclic phosphoric acids, 5-amino-2-hydroxy-4- (4-nitrophenyl)-l, 3,2-dioxaphospho- rinane 2-oxide and 2-hydroxy-4- (4-methylsulfonylphenyl)-5-phthalimido-1,3,2-dioxaphos phorinane 2-oxide are synthesized in good over yields (64. 2% and 72. 8% respectively) from 2-amino-l-aryl-l,3-propanediols. The different reaction conditions are necessary in hydrolysis reactions of amino cyclic phosphonyl chlorides.

  19. The Permutation Groups and the Equivalence of Cyclic and Quasi-Cyclic Codes

    CERN Document Server

    Guenda, Kenza

    2010-01-01

    We give the class of finite groups which arise as the permutation groups of cyclic codes over finite fields. Furthermore, we extend the results of Brand and Huffman et al. and we find the properties of the set of permutations by which two cyclic codes of length p^r can be equivalent. We also find the set of permutations by which two quasi-cyclic codes can be equivalent.

  20. Cyclic Voltammetry And Linear Sweep Voltammetry Study Of Cyclic Tertiary Amines

    Institute of Scientific and Technical Information of China (English)

    ZHAO Ping; TIAN JinPing; YIN YingWu

    2001-01-01

    @@ Cyclic six membered a-aminonitrile have proved to be very versatile synthetic intermediates and have been widely used in the construction of a large number of indole alkaloids. In order to obtain some information about the mechanisn of electrochemical synthesis of aaminonitrile. Electrochemistry behaviors that include cyclic voltammetry and linear sweep voltammetry of cyclic tertiary amines which including N-benzylpiperidine (NBP), 1-(l-Methoxycarbonyl ethyl) piperidine (MCEP), N-methylcarbonylppiperidine (NMCP), Nethylpiperidine(NEP) was studied.

  1. Cyclic Voltammetry And Linear Sweep Voltammetry Study Of Cyclic Tertiary Amines

    Institute of Scientific and Technical Information of China (English)

    ZHAO; Ping

    2001-01-01

    Cyclic six membered a-aminonitrile have proved to be very versatile synthetic intermediates and have been widely used in the construction of a large number of indole alkaloids. In order to obtain some information about the mechanisn of electrochemical synthesis of aaminonitrile. Electrochemistry behaviors that include cyclic voltammetry and linear sweep voltammetry of cyclic tertiary amines which including N-benzylpiperidine (NBP), 1-(l-Methoxycarbonyl ethyl) piperidine (MCEP), N-methylcarbonylppiperidine (NMCP), Nethylpiperidine(NEP) was studied.……

  2. Cyclic behaviors of amorphous shape memory polymers.

    Science.gov (United States)

    Yu, Kai; Li, Hao; McClung, Amber J W; Tandon, Gyaneshwar P; Baur, Jeffery W; Qi, H Jerry

    2016-04-01

    Cyclic loading conditions are commonly encountered in the applications of shape memory polymers (SMPs), where the cyclic characteristics of the materials determine their performance during the service life, such as deformation resistance, shape recovery speed and shape recovery ratio. Recent studies indicate that in addition to the physical damage or some other irreversible softening effects, the viscoelastic nature could also be another possible reason for the degraded cyclic behavior of SMPs. In this paper, we explore in detail the influence of the viscoelastic properties on the cyclic tension and shape memory (SM) behavior of an epoxy based amorphous thermosetting polymer. Cyclic experiments were conducted first, which show that although the epoxy material does not have any visible damage or irreversible softening effect during deformation, it still exhibits obvious degradation in the cyclic tension and SM behaviors. A linear multi-branched model is utilized to assist in the prediction and understanding of the mechanical responses of amorphous SMPs. Parametric studies based on the applied model suggest that the shape memory performance can be improved by adjusting programming and recovery conditions, such as lowering the loading rate, increasing the programming temperature, and reducing the holding time.

  3. Design and activity of a cyclic mini-β-defensin analog: a novel antimicrobial tool.

    Science.gov (United States)

    Scudiero, Olga; Nigro, Ersilia; Cantisani, Marco; Colavita, Irene; Leone, Marilisa; Mercurio, Flavia Anna; Galdiero, Massimiliano; Pessi, Antonello; Daniele, Aurora; Salvatore, Francesco; Galdiero, Stefania

    2015-01-01

    We have designed a cyclic 17-amino acid β-defensin analog featuring a single disulfide bond. This analog, designated "AMC" (ie, antimicrobial cyclic peptide), combines the internal hydrophobic domain of hBD1 and the C-terminal charged region of hBD3. The novel peptide was synthesized and characterized by nuclear magnetic resonance spectroscopy. The antimicrobial activities against gram-positive and gram-negative bacteria as well as against herpes simplex virus type 1 were analyzed. The cytotoxicity and serum stability were assessed. Nuclear magnetic resonance of AMC in aqueous solution suggests that the structure of the hBD1 region, although not identical, is preserved. Like the parent defensins, AMC is not cytotoxic for CaCo-2 cells. Interestingly, AMC retains the antibacterial activity of the parent hBD1 and hBD3 against Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli, and exerts dose-dependent activity against herpes simplex virus type 1. Moreover, while the antibacterial and antiviral activities of the oxidized and reduced forms of the parent defensins are similar, those of AMC are significantly different, and oxidized AMC is also considerably more stable in human serum. Taken together, our data also suggest that this novel peptide may be added to the arsenal of tools available to combat antibiotic-resistant infectious diseases, particularly because of its potential for encapsulation in a nanomedicine vector.

  4. A non-canonical NRPS is involved in the synthesis of fungisporin and related hydrophobic cyclic tetrapeptides in Penicillium chrysogenum.

    Directory of Open Access Journals (Sweden)

    Hazrat Ali

    Full Text Available The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a 'trans-acting' adenylation domain.

  5. A non-canonical NRPS is involved in the synthesis of fungisporin and related hydrophobic cyclic tetrapeptides in Penicillium chrysogenum.

    Science.gov (United States)

    Ali, Hazrat; Ries, Marco I; Lankhorst, Peter P; van der Hoeven, Rob A M; Schouten, Olaf L; Noga, Marek; Hankemeier, Thomas; van Peij, Noël N M E; Bovenberg, Roel A L; Vreeken, Rob J; Driessen, Arnold J M

    2014-01-01

    The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a 'trans-acting' adenylation domain.

  6. Some Structure Properties of the Cyclic Fuzzy Group Family

    Institute of Scientific and Technical Information of China (English)

    Hacl Akta(s); Naim (C)a(g)man

    2005-01-01

    In crisp environment, the notion of cyclic group on a set is well known. We study an extension of this classical notion to the fuzzy sets to define the concept of cyclic fuzzy subgroups. By using these cyclic fuzzy subgroups, we then define a cyclic fuzzy group family and investigate its structure properties.

  7. 21 CFR 862.1230 - Cyclic AMP test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cyclic AMP test system. 862.1230 Section 862.1230....1230 Cyclic AMP test system. (a) Identification. A cyclic AMP test system is a device intended to measure the level of adenosine 3′, 5′-monophosphate (cyclic AMP) in plasma, urine, and other body...

  8. Vibrational analysis of amino acids and short peptides in aqueous media. V. The effect of the disulfide bridge on the structural features of the peptide hormone somatostatin-14.

    Science.gov (United States)

    Hernández, Belén; Carelli, Claude; Coïc, Yves-Marie; De Coninck, Joël; Ghomi, Mahmoud

    2009-09-24

    To emphasize the role played by the S-S bridge in the structural features of somatostatin-14 (SST-14), newly recorded CD and Raman spectra of this cyclic peptide and its open analogue obtained by Cys-->Ser substitution are presented. CD spectra of both peptides recorded in aqueous solutions in the 100-500 microM concentration range are strikingly similar. They reveal principally that random conformers constitute the major population in both peptides. Consequently, the S-S bridge has no structuring effect at submillimolar concentrations. In methanol, the CD spectrum of somatostatin-14 keeps globally the same spectral shape as that observed in water, whereas its open analogue presents a major population of helical conformers. Raman spectra recorded as a function of peptide concentration (5-20 mM) and also in the presence of 150 mM NaCl provide valuable conformational information. All Raman spectra present a mixture of random and beta-hairpin structures for both cyclic and open peptides. More importantly, the presence or the absence of the disulfide bridge does not seem to influence considerably different populations of secondary structures within this range of concentrations. CD and Raman data obtained in the submillimolar and millimolar ranges of concentrations, respectively, lead us to accept the idea that SST-14 monomers aggregate upon increasing concentration, thus stabilizing beta-hairpin conformations in solution. However, even at high concentrations, random conformers do not disappear. Raman spectra of SST-14 also reveal a concentration effect on the flexibility of the S-S linkage and consequently on that of its cyclic part. In conclusion, although the disulfide linkage does not seem to markedly influence the SST-14 conformational features in aqueous solutions, its presence seems to be necessary to ensure the flexibility of the cyclic part of this peptide and to maintain its closed structure in lower dielectric constant environments.

  9. A combined molecular dynamic and quantum mechanic study of the solvent and guest molecule effect on the stability and length of heterocyclic peptide nanotubes.

    Science.gov (United States)

    Izadyar, Mohammad; Khavani, Mohammad; Housaindokht, Mohammad Reza

    2015-05-07

    Molecular dynamic simulations were performed to investigate the stability of heterocyclic peptide nanotubes composed of 1,4-disubstituted-1,2,3-triazol ε-amino acid. 45 ns MD simulations were conducted on the cyclic peptide nanotube (CPNT) and cyclic peptide dimer in methanol, chloroform, and water and revealed that these structures are more stable in nonpolar solvents. MM-PBSA and MM-GBSA calculations were employed to analyze the solvent effect on the stability and length of the CPNT. These calculations showed that CPNT in chloroform was more stable and longer as compared to other solvents. In addition, the effect of the guest molecule (ethanol) inside the dimer and CPNT was investigated. The obtained results confirmed that guest molecule(s) stabilized the dimer and CPNT in all solvents. Quantum chemistry calculations on the cyclic peptide dimer were performed at the M06-2X/6-31G(d) level in the gas phase and three solvents. The obtained results from the quantum chemistry study were in good agreement with the MD simulation results. DFT calculations showed that the guest molecule stabilized the dimer structure and electrostatically interacted with the cyclic peptide dimer. Finally, for investigation of the solvent effects on the hydrogen bonds of the cyclic peptide dimer, NBO and AIM analysis were performed.

  10. Topical peptides as cosmeceuticals

    Directory of Open Access Journals (Sweden)

    Varadraj Vasant Pai

    2017-01-01

    Full Text Available Peptides are known to have diverse biological roles, most prominently as signaling/regulatory molecules in a broad variety of physiological processes including defense, immunity, stress, growth, homeostasis and reproduction. These aspects have been used in the field of dermatology and cosmetology to produce short, stable and synthetic peptides for extracellular matrix synthesis, pigmentation, innate immunity and inflammation. The evolution of peptides over the century, which started with the discovery of penicillin, has now extended to their usage as cosmeceuticals in recent years. Cosmeceutical peptides may act as signal modulators of the extracellular matrix component, as structural peptides, carrier peptides and neurotransmitter function modulators. Transdermal delivery of peptides can be made more effective by penetration enhancers, chemical modification or encapsulation of peptides. The advantages of using peptides as cosmeceuticals include their involvement in many physiological functions of the skin, their selectivity, their lack of immunogenicity and absence of premarket regulatory requirements for their use. However, there are disadvantages: clinical evidence for efficacy is often weak, absorption may be poor due to low lipophilicity, high molecular weight and binding to other ingredients, and prices can be quite high.

  11. Peptide immobilisation on porous silicon surface for metal ions detection

    Directory of Open Access Journals (Sweden)

    Chazalviel Jean-Noël

    2011-01-01

    Full Text Available Abstract In this work, a Glycyl-Histidyl-Glycyl-Histidine (GlyHisGlyHis peptide is covalently anchored to the porous silicon PSi surface using a multi-step reaction scheme compatible with the mild conditions required for preserving the probe activity. In a first step, alkene precursors are grafted onto the hydrogenated PSi surface using the hydrosilylation route, allowing for the formation of a carboxyl-terminated monolayer which is activated by reaction with N-hydroxysuccinimide in the presence of a peptide-coupling carbodiimide N-ethyl-N'-(3-dimethylaminopropyl-carbodiimide and subsequently reacted with the amino linker of the peptide to form a covalent amide bond. Infrared spectroscopy (FT-IR and X-ray photoelectron spectroscopy are used to investigate the different steps of functionalization. The property of peptides to form stable complexes with metal ions is exploited to achieve metal-ion recognition by the peptide-modified PSi-based biosensor. An electrochemical study of the GlyHisGlyHis-modified PSi electrode is achieved in the presence of copper ions. The recorded cyclic voltammograms show a quasi-irreversible process corresponding to the Cu(II/Cu(I couple. The kinetic factors (the heterogeneous rate constant and the transfer coefficient and the stability constant of the complex formed on the porous silicon surface are determined. These results demonstrate the potential role of peptides grafted on porous silicon in developing strategies for simple and fast detection of metal ions in solution.

  12. Peptide immobilisation on porous silicon surface for metal ions detection

    Science.gov (United States)

    Sam, Sabrina S.; Chazalviel, Jean-Noël Jn; Gouget-Laemmel, Anne Chantal Ac; Ozanam, François F.; Etcheberry, Arnaud A.; Gabouze, Nour-Eddine N.

    2011-06-01

    In this work, a Glycyl-Histidyl-Glycyl-Histidine (GlyHisGlyHis) peptide is covalently anchored to the porous silicon PSi surface using a multi-step reaction scheme compatible with the mild conditions required for preserving the probe activity. In a first step, alkene precursors are grafted onto the hydrogenated PSi surface using the hydrosilylation route, allowing for the formation of a carboxyl-terminated monolayer which is activated by reaction with N-hydroxysuccinimide in the presence of a peptide-coupling carbodiimide N-ethyl- N'-(3-dimethylaminopropyl)-carbodiimide and subsequently reacted with the amino linker of the peptide to form a covalent amide bond. Infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy are used to investigate the different steps of functionalization. The property of peptides to form stable complexes with metal ions is exploited to achieve metal-ion recognition by the peptide-modified PSi-based biosensor. An electrochemical study of the GlyHisGlyHis-modified PSi electrode is achieved in the presence of copper ions. The recorded cyclic voltammograms show a quasi-irreversible process corresponding to the Cu(II)/Cu(I) couple. The kinetic factors (the heterogeneous rate constant and the transfer coefficient) and the stability constant of the complex formed on the porous silicon surface are determined. These results demonstrate the potential role of peptides grafted on porous silicon in developing strategies for simple and fast detection of metal ions in solution.

  13. Peptide immobilisation on porous silicon surface for metal ions detection.

    Science.gov (United States)

    Sam, Sabrina S; Chazalviel, Jean-Noël Jn; Gouget-Laemmel, Anne Chantal Ac; Ozanam, François F; Etcheberry, Arnaud A; Gabouze, Nour-Eddine N

    2011-01-01

    In this work, a Glycyl-Histidyl-Glycyl-Histidine (GlyHisGlyHis) peptide is covalently anchored to the porous silicon PSi surface using a multi-step reaction scheme compatible with the mild conditions required for preserving the probe activity. In a first step, alkene precursors are grafted onto the hydrogenated PSi surface using the hydrosilylation route, allowing for the formation of a carboxyl-terminated monolayer which is activated by reaction with N-hydroxysuccinimide in the presence of a peptide-coupling carbodiimide N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide and subsequently reacted with the amino linker of the peptide to form a covalent amide bond. Infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy are used to investigate the different steps of functionalization.The property of peptides to form stable complexes with metal ions is exploited to achieve metal-ion recognition by the peptide-modified PSi-based biosensor. An electrochemical study of the GlyHisGlyHis-modified PSi electrode is achieved in the presence of copper ions. The recorded cyclic voltammograms show a quasi-irreversible process corresponding to the Cu(II)/Cu(I) couple. The kinetic factors (the heterogeneous rate constant and the transfer coefficient) and the stability constant of the complex formed on the porous silicon surface are determined. These results demonstrate the potential role of peptides grafted on porous silicon in developing strategies for simple and fast detection of metal ions in solution.

  14. Effect of ester to amide or N-methylamide substitution on bacterial membrane depolarization and antibacterial activity of novel cyclic lipopeptides.

    Science.gov (United States)

    Bionda, Nina; Fleeman, Renee M; Shaw, Lindsey N; Cudic, Predrag

    2013-08-01

    Cyclic lipopeptides derived from the fusaricidin/LI-F family of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents. In comparison with natural products, these derivatives may offer better stability under physiologically relevant conditions and lower nonspecific toxicity, while preserving their antibacterial activity. In this study we assessed the ability of cyclic lipodepsipeptide 1 and its analogues--amide 2, N-methylamide 3, and linear peptide 4--to interact with the cytoplasmic membranes of selected Gram-positive bacteria. We also investigated their bacteriostatic/bactericidal modes of action and in vivo potency by using a Galleria mellonella model of MRSA infection. Cyclic lipopeptides 1 and 2 depolarize the cytoplasmic membranes of Gram-positive bacteria in a concentration-dependent manner. The degree of membrane depolarization was influenced by the structural and physical properties of 1 and 2, with the more flexible and hydrophobic peptide 1 being most efficient. However, membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane-targeting activity is not the main mode of action for this class of antibacterial peptides. Conversely, substitution of the depsipeptide bond in 1 with an N-methylamide bond in 3, or its hydrolysis to peptide 4, lead to a complete loss of antibacterial activity and indicate that the conformation of cyclic lipopeptides plays a role in their antibacterial activities. Cyclic lipopeptides 1 and 2 are also capable of improving the survival of G. mellonella larvae infected with MRSA at varying efficiencies, reflecting their in vitro activities. Gaining more insight into the structure-activity relationship and mode of action of these cyclic lipopeptides may enable the development of new antibiotics of this class with improved antibacterial activity.

  15. Peptide Based Radiopharmaceuticals: Specific Construct Approach

    Energy Technology Data Exchange (ETDEWEB)

    Som, P; Rhodes, B A; Sharma, S S

    1997-10-21

    The objective of this project was to develop receptor based peptides for diagnostic imaging and therapy. A series of peptides related to cell adhesion molecules (CAM) and immune regulation were designed for radiolabeling with 99mTc and evaluated in animal models as potential diagnostic imaging agents for various disease conditions such as thrombus (clot), acute kidney failure, and inflection/inflammation imaging. The peptides for this project were designed by the industrial partner, Palatin Technologies, (formerly Rhomed, Inc.) using various peptide design approaches including a newly developed rational computer assisted drug design (CADD) approach termed MIDAS (Metal ion Induced Distinctive Array of Structures). In this approach, the biological function domain and the 99mTc complexing domain are fused together so that structurally these domains are indistinguishable. This approach allows construction of conformationally rigid metallo-peptide molecules (similar to cyclic peptides) that are metabolically stable in-vivo. All the newly designed peptides were screened in various in vitro receptor binding and functional assays to identify a lead compound. The lead compounds were formulated in a one-step 99mTc labeling kit form which were studied by BNL for detailed in-vivo imaging using various animals models of human disease. Two main peptides usingMIDAS approach evolved and were investigated: RGD peptide for acute renal failure and an immunomodulatory peptide derived from tuftsin (RMT-1) for infection/inflammation imaging. Various RGD based metallopeptides were designed, synthesized and assayed for their efficacy in inhibiting ADP-induced human platelet aggregation. Most of these peptides displayed biological activity in the 1-100 µM range. Based on previous work by others, RGD-I and RGD-II were evaluated in animal models of acute renal failure. These earlier studies showed that after acute ischemic injury the renal cortex displays

  16. Phage Display Screening for Tumor Necrosis Factor-α-Binding Peptides: Detection of Inflammation in a Mouse Model of Hepatitis

    Directory of Open Access Journals (Sweden)

    Coralie Sclavons

    2013-01-01

    Full Text Available TNF-α is one of the most abundant cytokines produced in many inflammatory and autoimmune conditions such as multiple sclerosis, chronic hepatitis C, or neurodegenerative diseases. These pathologies remain difficult to diagnose and consequently difficult to treat. The aim of this work is to offer a new diagnostic tool by seeking new molecular probes for medical imaging. The target-specific part of the probe consists here of heptameric peptides selected by the phage display technology for their affinity for TNF-α. Several affinity tests allowed isolating 2 peptides that showed the best binding capacity to TNF-α. Finally, the best peptide was synthesized in both linear and cyclic forms and tested on the histological sections of concanavalin-A-(ConA-treated mice liver. In this well-known hepatitis mouse model, the best results were obtained with the cyclic form of peptide 2, which allowed for the staining of inflamed areas in the liver. The cyclic form of peptide 2 (2C was, thus, covalently linked to iron oxide nanoparticles (magnetic resonance imaging (MRI contrast agent and tested in the ConA-induced hepatitis mouse model. The vectorized nanoparticles allowed for the detection of inflammation as well as of the free peptide. These ex vivo results suggest that phage display-selected peptides can direct imaging contrast agents to inflammatory areas.

  17. The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

    Directory of Open Access Journals (Sweden)

    Tom Willemse

    2017-02-01

    Full Text Available The (site-selective derivatization of amino acids and peptides represents an attractive field with potential applications in the establishment of structure–activity relationships and labeling of bioactive compounds. In this respect, bioorthogonal cross-coupling reactions provide valuable means for ready access to peptide analogues with diversified structure and function. Due to the complex and chiral nature of peptides, mild reaction conditions are preferred; hence, a suitable cross-coupling reaction is required for the chemical modification of these challenging substrates. The Suzuki reaction, involving organoboron species, is appropriate given the stability and environmentally benign nature of these reactants and their amenability to be applied in (partial aqueous reaction conditions, an expected requirement upon the derivatization of peptides. Concerning the halogenated reaction partner, residues bearing halogen moieties can either be introduced directly as halogenated amino acids during solid-phase peptide synthesis (SPPS or genetically encoded into larger proteins. A reversed approach building in boron in the peptidic backbone is also possible. Furthermore, based on this complementarity, cyclic peptides can be prepared by halogenation, and borylation of two amino acid side chains present within the same peptidic substrate. Here, the Suzuki–Miyaura reaction is a tool to induce the desired cyclization. In this review, we discuss diverse amino acid and peptide-based applications explored by means of this extremely versatile cross-coupling reaction. With the advent of peptide-based drugs, versatile bioorthogonal conversions on these substrates have become highly valuable.

  18. Regulation of cyclic GMP, cyclic amp and lactate dehydrogenase by putative neutrotransmitters in the C6 rat glioma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Bottenstein, J.E.; de Vellis, J.

    1977-01-01

    In C6 cells norepinephrine and dopamine caused transient increases in cyclic GMP and cyclic AMP, as well as an induction of lactate dehydrogenase. All of these responses were blocked by 1-propranolol, suggesting mediation by a ..beta..-receptor. Phentolamine potentiated the NE-increased cAMP levels by 5-fold when NE was used at suboptimal doses, suggesting the presence of ..cap alpha..-adrenergic receptors in C6 cells. Carbamylcholine decreased the levels of both cyclic nucleotides, with hexamethonium partially reversing the effect on cyclic GMP. Dibutyryl-cyclic GMP or carbamylcholine reduced catecholamine-induced cyclic AMP levels. Serotonin increased cyclic GMP levels 60% and decreased cyclic AMP levels 36%. Calcium- and magnesium-free media inhibited the norepinephrine-induced levels of cyclic GMP and cyclic AMP respectively.

  19. Regulation of cyclic GMP, cyclic AMP and lactate dehydrogenase by putative neurotransmitters in the C6 rat glioma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Bottenstein, J.E.; de Vellis, J.

    1978-01-01

    In C6 cells norepinephrine and dopamine caused transient increases in cyclic GMP and cyclic AMP, as well as an induction of lactate dehydrogenase. All of these responses were blocked by l-propranolol, suggesting mediation by a ..beta..-receptor. Phentolamine potentiated the NE-increased cAMP levels by 5-fold when NE was used at suboptimal doses, suggesting the presence of ..cap alpha..-adrenergic receptors in C6 cells. Carbamylcholine decreased the levels of both cyclic nucleotides, with hexamethonium partially reversing the effect on cyclic GMP. Dibutyryl-cyclic GMP or carbamylcholine reduced catecholamine-induced cyclic AMP levels. Serotonin increased cyclic GMP levels 60% and decreased cyclic AMP levels 36%. Calcium- and magnesium-free media inhibited the norepinephrine-induced levels of cyclic GMP and cyclic AMP respectively.

  20. Cyclic transformation of orbital angular momentum modes

    Science.gov (United States)

    Schlederer, Florian; Krenn, Mario; Fickler, Robert; Malik, Mehul; Zeilinger, Anton

    2016-04-01

    The spatial modes of photons are one realization of a QuDit, a quantum system that is described in a D-dimensional Hilbert space. In order to perform quantum information tasks with QuDits, a general class of D-dimensional unitary transformations is needed. Among these, cyclic transformations are an important special case required in many high-dimensional quantum communication protocols. In this paper, we experimentally demonstrate a cyclic transformation in the high-dimensional space of photonic orbital angular momentum (OAM). Using simple linear optical components, we show a successful four-fold cyclic transformation of OAM modes. Interestingly, our experimental setup was found by a computer algorithm. In addition to the four-cyclic transformation, the algorithm also found extensions to higher-dimensional cycles in a hybrid space of OAM and polarization. Besides being useful for quantum cryptography with QuDits, cyclic transformations are key for the experimental production of high-dimensional maximally entangled Bell-states.

  1. Cyclic transformation of orbital angular momentum modes

    CERN Document Server

    Schlederer, Florian; Fickler, Robert; Malik, Mehul; Zeilinger, Anton

    2015-01-01

    The spatial modes of photons are one realization of a QuDit, a quantum system that is described in a D-dimensional Hilbert space. In order to perform quantum information tasks with QuDits, a general class of D-dimensional unitary transformations is needed. Among these, cyclic transformations are an important special case required in many high-dimensional quantum communication protocols. In this paper, we experimentally demonstrate a cyclic transformation in the high-dimensional space of photonic orbital angular momentum (OAM). Using simple linear optical components, we show a successful four-fold cyclic transformation of OAM modes. Interestingly, our experimental setup was found by a computer algorithm. In addition to the four-cyclic transformation, the algorithm also found extensions to higher-dimensional cycles in a hybrid space of OAM and polarization. Besides being useful for quantum cryptography with QuDits, cyclic transformations are key for the experimental production of high-dimensional maximally enta...

  2. 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 ...

  3. Cyclic endomorphin analogs in targeting opioid receptors to achieve pain relief.

    Science.gov (United States)

    Janecka, Anna; Gentilucci, Luca

    2014-01-01

    Endomorphins, the endogenous ligands of the µ-opioid receptor, are attractive candidates for opioid-based pain-relieving agents. These tetrapeptides, with their remarkable affinity for the µ-opioid receptor, display favorable antinociceptive activity when injected directly into the brain of experimental animals. However, the application of endomorphins as clinical analgesics has been impeded by their instability in body fluids and inability to reach the brain after systemic administration. Among numerous modifications of the endomorphin structure aimed at improving their pharmacological properties, cyclization can be viewed as an interesting option. Here, we have summarized recent advances in obtaining endomorphin-based cyclic peptide analogs.

  4. Vascular effects and cyclic AMP production produced by VIP, PHM, PHV, PACAP-27, PACAP-38, and NPY on rabbit ovarian artery

    DEFF Research Database (Denmark)

    Yao, W; Sheikh, S P; Ottesen, B;

    1996-01-01

    The relationship between vessel tone and cAMP production induced by vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), peptide histidine valine (PHV), pituitary adenylate cyclase activating polypeptide (PACAP-27 and PACAP-38), and neuropeptide Y (NPY) was investigated......-38 all increased cyclic adenosine monophosphate (cAMP) accumulation. The cAMP accumulation induced by PACAP-27 and PACAP-38 was five times higher than the cAMP content induced by the other three peptides. The peptide-induced smooth muscle relaxation did not correlate to the cAMP accumulation. NPY (10......(-7) M) markedly reversed the relaxations induced by VIP, PHM, PHV, PACAP-27, and PACAP-38, but did not influence the cAMP production induced by these peptides. In conclusion, the relaxation induced by VIP, PHM, PHV, PACAP-27, and PACAP-38 and the contraction induced by NPY are not solely related...

  5. Descriptors for antimicrobial peptides

    DEFF Research Database (Denmark)

    Jenssen, Håvard

    2011-01-01

    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...

  6. PNA Peptide chimerae

    DEFF Research Database (Denmark)

    Koch, T.; Næsby, M.; Wittung, P.;

    1995-01-01

    Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields.......Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields....

  7. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds known as peptide nucleic acids, bind complementary DNA and RNA strands, and generally do so more strongly than the corresponding DNA or RNA strands while exhibiting increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from...

  8. Bacteriocin Inducer Peptides

    Science.gov (United States)

    Novel peptides produced by bacteriocin-producing bacteria stimulate the production of bacteriocins in vitro. The producer bacteria are cultured in the presence of a novel inducer bacteria and a peptide having a carboxy terminal sequence of VKGLT in order to achieve an increase in bacteriocin produc...

  9. Avian host defense peptides

    NARCIS (Netherlands)

    Cuperus, Tryntsje; Coorens, M.; van Dijk, A.; Haagsman, H.P.

    2013-01-01

    Host defense peptides (HDPs) are important effector molecules of the innate immune system of vertebrates. These antimicrobial peptides are also present in invertebrates, plants and fungi. HDPs display broad-spectrum antimicrobial activities and fulfill an important role in the first line of defense

  10. APD: the Antimicrobial Peptide Database

    OpenAIRE

    Wang, Zhe; Wang, Guangshun

    2004-01-01

    An antimicrobial peptide database (APD) has been established based on an extensive literature search. It contains detailed information for 525 peptides (498 antibacterial, 155 antifungal, 28 antiviral and 18 antitumor). APD provides interactive interfaces for peptide query, prediction and design. It also provides statistical data for a select group of or all the peptides in the database. Peptide information can be searched using keywords such as peptide name, ID, length, net charge, hydrophob...

  11. Evaluation of homogeneous electrocatalysts by cyclic voltammetry.

    Science.gov (United States)

    Rountree, Eric S; McCarthy, Brian D; Eisenhart, Thomas T; Dempsey, Jillian L

    2014-10-06

    The pursuit of solar fuels has motivated extensive research on molecular electrocatalysts capable of evolving hydrogen from protic solutions, reducing CO2, and oxidizing water. Determining accurate figures of merit for these catalysts requires the careful and appropriate application of electroanalytical techniques. This Viewpoint first briefly presents the fundamentals of cyclic voltammetry and highlights practical experimental considerations before focusing on the application of cyclic voltammetry for the characterization of electrocatalysts. Key metrics for comparing catalysts, including the overpotential (η), potential for catalysis (E(cat)), observed rate constant (k(obs)), and potential-dependent turnover frequency, are discussed. The cyclic voltammetric responses for a general electrocatalytic one-electron reduction of a substrate are presented along with methods to extract figures of merit from these data. The extension of this analysis to more complex electrocatalytic schemes, such as those responsible for H2 evolution and CO2 reduction, is then discussed.

  12. Cyclic distillation technology - A mini-review

    DEFF Research Database (Denmark)

    Bîldea, Costin Sorin; Pătruţ, Cătălin; Jørgensen, Sten Bay;

    2016-01-01

    Process intensification in distillation systems has received much attention during the past decades, with the aim of increasing both energy and separation efficiency. Various techniques, such as internal heat-integrated distillation, membrane distillation, rotating packed bed, dividing-wall columns...... and reactive distillation were studied and reported in literature. All these techniques employ the conventional continuous counter-current contact of vapor and liquid phases. Cyclic distillation technology is based on an alternative operating mode using separate phase movement which leads to key practical...... advantages in both chemical and biochemical processes. This article provides a mini-review of cyclic distillation technology. The topics covered include the working principle, design and control methods, main benefits and limitations as well as current industrial applications. Cyclic distillation can...

  13. Genome mining expands the chemical diversity of the cyanobactin family to include highly modified linear peptides.

    Science.gov (United States)

    Leikoski, Niina; Liu, Liwei; Jokela, Jouni; Wahlsten, Matti; Gugger, Muriel; Calteau, Alexandra; Permi, Perttu; Kerfeld, Cheryl A; Sivonen, Kaarina; Fewer, David P

    2013-08-22

    Ribosomal peptides are produced through the posttranslational modification of short precursor peptides. Cyanobactins are a growing family of cyclic ribosomal peptides produced by cyanobacteria. However, a broad systematic survey of the genetic capacity to produce cyanobactins is lacking. Here we report the identification of 31 cyanobactin gene clusters from 126 genomes of cyanobacteria. Genome mining suggested a complex evolutionary history defined by horizontal gene transfer and rapid diversification of precursor genes. Extensive chemical analyses demonstrated that some cyanobacteria produce short linear cyanobactins with a chain length ranging from three to five amino acids. The linear peptides were N-prenylated and O-methylated on the N and C termini, respectively, and named aeruginosamide and viridisamide. These findings broaden the structural diversity of the cyanobactin family to include highly modified linear peptides with rare posttranslational modifications.

  14. Cyclic Polymer with Alternating Monomer Sequence.

    Science.gov (United States)

    Zhu, Wen; Li, Zi; Zhao, Youliang; Zhang, Ke

    2015-11-01

    Cyclic polymers with alternating monomer sequence are synthesized for the first time based on the ring-closure strategy. Well-defined telechelic alternating polymers are synthesized by reversible addition-fragmentation chain transfer polymerization by copolymerizing the electron acceptor monomer of N-benzylmaleimide and donor monomer of styrene with a feed ratio of 1 between them. The corresponding cyclic alternating polymers are then produced by the UV-induced Diels-Alder click reaction to ring-close the linear alternating polymer precursors under highly diluted reaction solution.

  15. Ultrafast cyclic voltammetry with asymmetrical potential scan

    Institute of Scientific and Technical Information of China (English)

    Zhi Yong Guo; Xiang Qin Lin

    2008-01-01

    Based on the perfect ohmic drop compensation by online electronic positive feedback, ultrafast cyclic voltammetry withasymmetrical potential scan is achieved for the first time, with the reduction of anthracene acting as the test system. Compared withthe traditional cyclic voltammetry utilizing symmetrical triangular waveform as the excitation one, the new method allows a simplerapproach to mechanistic analysis of ultrafast chemical reactions coupled with a charge transfer. And perhaps more important, it alsoprovides a way to eliminate the interference of the adsorbed product in dynamic monitoring.

  16. Severe congenital cyclic neutropenia: A case report

    Science.gov (United States)

    Patil, Vidyavathi H; Hugar, Shivayogi M; Balikai, Girish; Patil, Sudha

    2016-01-01

    Congenital cyclic neutropenia syndrome is a constitutional genetic disorder which is characterized by very low number of neutrophils (neutropenia). Patients suffering from this disorder clinically present with neutropenia at early age, history of recurrent fever, ulcerations in the oral cavity, gingivitis, and other recurrent infections. This paper describes a case report of a child with recurrent mouth ulcers, fever, and later diagnosed with severe congenital cyclic neutropenia. This also emphasizes the importance of identification of rare causes of immunosuppressive conditions in children presenting with recurrent oral ulcers and poor dental hygiene, to prevent long-term complications of oral cavity and also morbidity and mortality secondary to neutropenic sepsis. PMID:27857902

  17. On cyclic associative Abel-Grassman groupoids

    OpenAIRE

    Iqbal, Muhammad; Ahmad, Imtiaz; Shah, Muhammad; Ali, Muhammad Irfan

    2015-01-01

    A new subclass of AG-groupoids, so called, cyclic associative Abel-Grassman groupoids or CA-AG-groupoid is studied. These have been enumerated up to order $6$. A test for the verification of cyclic associativity for an arbitrary AG-groupoid has been introduced. Various properties of CA-AG-groupoids have been studied. Relationship among CA-AG-groupoids and other subclasses of AG-groupoids is investigated. It is shown that the subclass of CA-AG-groupoid is different from that of the AG{*}-group...

  18. Cyclic Entropy: An Alternative to Inflationary Cosmology

    CERN Document Server

    Frampton, Paul Howard

    2015-01-01

    We address how to construct an infinitely cyclic universe model. A major consideration is to make the entropy cyclic which requires the entropy to be reset to zero in each cycle expansion to turnaround, to contraction, to bounce, etc. Here we reset entropy at the turnaround by selecting the visible universe from the multiverse which is generated by the accelerated expansion. In the model, the observed homogeneity is explained by the low entropy at the bounce, The observed flatness arises from the contraction together with the reduction in size between the expanding and contracting universe. The present flatness is predicted to be very precise.

  19. Development of a design methodology for high temperature cyclic applications of materials which experience cyclic softening

    Energy Technology Data Exchange (ETDEWEB)

    Marriott, D.L.; Stubbins, J.F. (Illinois Univ., Urbana, IL (USA). Dept. of Mechanical and Industrial Engineering)

    1988-12-01

    The project has as its original focus the high temperature behavior of 2.25 Cr-1 Mo steel, heat treated to produce a predominantly bainitic microstructure and the load carrying response of components made of this material. Experiments were carried out on uniform and notched specimens under both steady and cyclic loading using specially acquired electromechanical test machines. It emerged that a very important feature of mechanical behavior under the conditions of interest was the strong tendency of this material to cyclically soften, particularly at high temperature in the creep range, giving the illusion of a severe creep-fatigue interaction under certain conditions. This finding led to a significant component of the project being devoted to investigation of the effects of local, as opposed to generalized, cyclic softening, and the implications this phenomenon might have on the setting of allowable design stress limits. The format of this report is as follows: The second chapter is a review of the work carried out in approximately chronological order under the headings of work was carried out under the following: (1) 2.25 Cr 1 Mo Steel -- Elevated Temperature Fatigue and Environmental Effects; (2) Preliminary Studies of Advanced Austenitics; (3) A Uniaxial Constitutive Model for Cyclic Softening; (4) The Iso-Cyclic Stress-Strain Approach to Evaluation of Components in Cyclic Softening Materials; (5) Testing of High Temperature Austenitic Alloys; and (6) Design Methodology for Aging Materials -- Application to Cyclic Softening. 65 refs., 39 figs., 7 tabs.

  20. Cyclic RGD-peptide-modified nanoliposome significantly reduced the effective dosage and administration frequency of oxymatrine on CCl4-induced hepatic fibrosis in rats%RGD环肽修饰纳米脂质体显著降低氧化苦参碱抗大鼠四氯化碳肝纤维化有效剂量与用药频次

    Institute of Scientific and Technical Information of China (English)

    唐东; 吴建新; 陆伟跃; 陈源文; 葛文松; 朱长红; 周韵斓; 熊敏莉; 范建高

    2011-01-01

    Objective To investigate whether cRGD-NL-OM could reduce the effective dosage and administration frequency of oxymatrine on carbon tetrachloride ( CCl4)-induced hepatic fibrosis in rats by structuring cyclic RGD-pep-tide modified nanoliposome (cRGD-NL) to encapsulate oxymatrine and comparing the antifibrotic effect between low dosage OM (2 mg/kg, q2w) alone and oxymatrine nanoliposome ( with or without cRGD modification) delivering similiar amount of oxymatrine. Methods Sprague-Dawely rats were divided into 6 groups (n = 8 per group): normal group,model (CCl4) group, NL-treated (CCl4 + NL) group, OM-treated ( CCl4 + OM) group, NL-OM-treated (CCl4 + NL-OM) group and cRGD-NL-OM-treated ( CCl4 + cRGD-NL-OM) group. After modeling for 4 weeks, corresponding drugs or vehicles were given twice a week for another 4 weeks in each group (OM 2 mg/kg body mass). At the end of 8th week, all animals were sacrificed to sample serum and livers. HE and Masson staining were performed for evaluation of liver histopathological changes;liver function and collagen metabolism status were determined by biochemical analysis and ELISA respectively; collagen type 1 alpha 2 (COL1 A2) mRNA was measured by quantitative real-time PCR; the expression of α-smooth muscle actin (α-SMA) was detected by Western blot. Results Compared with model group,cRGD-NL-OM group and NL-OM treatment group significantly improved the serum indexes and liver histopathology,COL1A2 mRNA expression and α-SMA protein level also significantly decreased in the two groups. Moreover, cRGD-NL-OM treatment group showed further improvement than NL-OM-treated group. In contrast, NL-treated group and OM-treated group showed no significant improvement compared with model group. Conclusion cRGD-NL-OM could significantly reduce the effective antifibrotic dosage and administration frequency of oxymatrine. This new compound may be promising for clinical application.%目的构建RGD环肽修饰纳米脂质体(cRGD-NL),利用其包

  1. 探讨抗环瓜氨酸肽抗体和类风湿因子对类风湿关节炎的诊断价值%Evaluate the value of anti -cyclic citrullinated peptide antibody and rheumatoid factor in the diagnosis of rheumatoid ar-thritis

    Institute of Scientific and Technical Information of China (English)

    莫巧璇; 张间霞; 张劲丰; 苏荣

    2013-01-01

    Objective Evaluate the diagnosis value of anti-cyclic citrullinated antibody (anti CCP antibody ) combined with rheumatoid factor (RF) for rheumatoid arthritis (RA) .Methods From May 2011 to September 2011 ,202 patients with rheumatic disease were selected ,including RA group ,and non-RA group .The quantitative chemiluminescence method to detect anti-CCP antibody ,immune turbidimetric assay to test RF ,and the results were analyzed statistically .Results The diagnostic test sensitivity of anti-CCP antibody ,specificity ,positive and the nega-tive predictive value were ,78% ,80 .6% ,82 .5% ,75 .8% ;RF :89 .9% ,52 .7% ,69% ,81 .7% .To analyze parallel and series test after anti-CCP antibody combined with RF detection ,The above indexes were ,parallel:93 .6% ,51 .6% , 69 .4% ,87 .3% ;series :74 .3% ,81 .7% ,82 .7% ,73 .1% ;The result of comparison in the RA group sensitivity :RF and anti-CCP antibody+RF series testing compared to individual CCP testing was significantly different (P<0 .05) , Beside ,Anti-CCP antibody+RF parallel testing and RF testing was significantly different (P<0 .05) .In the mean of anti-CCP antibody and RF positive results ,RA group and RA group was significantly difference .Conclusion Detec-tion of anti CCP antibody Combined with RF could provide clinical diagnosis for RA than individual testing .It could avoid leakage diagnosis caused by the low anti-CCP antibody sensitivity ,and misdiagnosis caused by RF low specifici-ty ,and provided the basis for clinical early diagnosis .%  目的探讨抗环瓜氨酸肽抗体(抗CCP抗体)、类风湿因子(RF)联合检测对类风湿关节炎(RA)的诊断价值。方法收集2011年5~9月RA和非RA患者202例,分别采用电化学发光法定量检测抗CCP抗体,免疫比浊法检测RF并进行统计学处理。结果抗CCP抗体诊断试验的灵敏度、特异性和阳性、阴性预测值分别为:78.0%、80.6%、82.5%、75.8%;RF为:89.9%、52.7

  2. Easy and Efficient 111Indium Labeling of Long-Term Stored DTPA Conjugated Protein

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Buch, Inge; Hesse, Birger

    2011-01-01

    targeting vehicles such as monoclonal antibodies and receptor directed peptides. The purpose of this study was to monitor the labelling efficiency of a DTPA-conjugate on long-term storage using 111In-chloride at two different temperatures and incubation times for the In-labelling. Method: Cyclic......-diethylene-triamine-pentaacetic acid (cDTAP) was conjugated to a polyclonal immunoglobulin-G (IgG) in borate buffer, pH 8.2 at +4?C for 4 hours. Then the DTPA-conjugate was dialyzed against 50 mmol/l sodium citrate buffer saline, pH 6.0 and stored at -80° C in aliquots of 1 mg/0.5 ml. The DTPA-conjugate was labeled with 111In...... months. Conclusion: Our study shows that 111In-labelling can easily be performed within 30 min at RT for thermo-stable proteins like polyclonal, DTPA-conjugated IgG stored long-term at -80°C with a high 111In-labelling efficiency....

  3. Easy and efficient (111)Indium labeling of long-term stored DTPA conjugated protein

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Buch, Inge; Hesse, Birger

    2011-01-01

    targeting vehicles such as monoclonal antibodies and receptor directed peptides. The purpose of this study was to monitor the labelling efficiency of a DTPA-conjugate on long-term storage using 111In-chloride at two different temperatures and incubation times for the In-labelling. Method: Cyclic......-diethylene-triamine-pentaacetic acid (cDTAP) was conjugated to a polyclonal immunoglobulin-G (IgG) in borate buffer, pH 8.2 at +4oC for 4 hours. Then the DTPA-conjugate was dialyzed against 50 mmol/l sodium citrate buffer saline, pH 6.0 and stored at -80o C in aliquots of 1 mg/0.5 ml. The DTPA-conjugate was labeled with 111In...... months. Conclusion: Our study shows that 111In-labelling can easily be performed within 30 min at RT for thermo-stable proteins like polyclonal, DTPA-conjugated IgG stored long-term at -80oC with a high 111In-labelling effi- ciency....

  4. Peptides whose uptake by cells is controllable

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Tao; Olson, Emilia S.; Whitney, Michael; Tsien, Roger

    2015-07-07

    A generic structure for the peptides of the present invention includes A-X-B-C, where C is a cargo moiety, the B portion includes basic amino acids, X is a cleavable linker sequence, and the A portion includes acidic amino acids. The intact structure is not significantly taken up by cells; however, upon extracellular cleavage of X, the B-C portion is taken up, delivering the cargo to targeted cells. Cargo may be, for example, a contrast agent for diagnostic imaging, a chemotherapeutic drug, or a radiation-sensitizer for therapy. X may be cleaved extracellularly or intracellularly. The molecules of the present invention may be linear, cyclic, branched, or have a mixed structure.

  5. Peptides whose uptake by cells is controllable

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Tao (San Diego, CA); Olson, Emilia S. (La Jolla, CA); Whitney, Michael (San Diego, CA); Tsien, Roger (La Jolla, CA)

    2011-07-26

    A generic structure for the peptides of the present invention includes A-X-B-C, where C is a cargo moiety, the B portion includes basic amino acids, X is a cleavable linker sequence, and the A portion includes acidic amino acids. The intact structure is not significantly taken up by cells; however, upon extracellular cleavage of X, the B-C portion is taken up, delivering the cargo to targeted cells. Cargo may be, for example, a contrast agent for diagnostic imaging, a chemotherapeutic drug, or a radiation-sensitizer for therapy. X may be cleaved extracellularly or intracellularly. The molecules of the present invention may be linear, cyclic, branched, or have a mixed structure.

  6. Sequence dependent proton conduction in self-assembled peptide nanostructures

    Science.gov (United States)

    Lerner Yardeni, Jenny; Amit, Moran; Ashkenasy, Gonen; Ashkenasy, Nurit

    2016-01-01

    The advancement of diverse electrochemistry technologies depends on the development of novel proton conducting polymers. Inspired by the efficacy of proton transport through proteins, we show in this work that self-assembling peptide nanostructures may be a promising alternative for such organic proton conducting materials. We demonstrate that aromatic amino acids, which participate in charge transport in nature, unprecedentedly promote proton conduction under both high and low relative humidity conditions for d,l α-cyclic peptide nanotubes. For dehydrated networks long-range order of the assemblies, induced by the aromatic side chains, is shown to be a dominating factor for promoting conductivity. However, for hydrated networks this order of effect is less significant and conductivity can be improved by the introduction of proton donating carboxylic acid peptide side chains in addition to the aromatic side chains despite the lower order of the assemblies. Based on these observations, a novel cyclic peptide that incorporates non-natural naphthyl side chains was designed. Self-assembled nanotubes of this peptide show greatly improved dehydrated conductivity, while maintaining high conductivity under hydrated conditions. We envision that the demonstrated modularity and versatility of these bio inspired nanostructures will make them extremely attractive building blocks for the fabrication of devices for energy conversion and storage applications, as well as other applications that involve proton transport, whether dry or wet conductivity is desired.The advancement of diverse electrochemistry technologies depends on the development of novel proton conducting polymers. Inspired by the efficacy of proton transport through proteins, we show in this work that self-assembling peptide nanostructures may be a promising alternative for such organic proton conducting materials. We demonstrate that aromatic amino acids, which participate in charge transport in nature

  7. Cyclic Cratonic Carbonates and Phanerozoic Calcite Seas.

    Science.gov (United States)

    Wilkinson, Bruce H.

    1982-01-01

    Discusses causes of cyclicity in cratonic carbonate sequences and evidence for and potential significance of postulated primary calcite sediment components in past Paleozoic seas, outlining problems, focusing on models explaining existing data, and identifying background. Future sedimentary geologists will need to address these and related areas…

  8. Cyclic viscoelastoplasticity of polypropylene/nanoclay composites

    DEFF Research Database (Denmark)

    Drozdov, A.; Christiansen, Jesper de Claville

    2012-01-01

    Observations are reported on isotactic polypropylene/organically modified nanoclay hybrids with concentrations of filler ranging from 0 to 5 wt.% in cyclic tensile tests with a stress–controlled program (oscillations between various maximum stresses and the zero minimum stress). A pronounced effect...

  9. Steady state oxygen reduction and cyclic voltammetry

    DEFF Research Database (Denmark)

    Rossmeisl, Jan; Karlberg, Gustav; Jaramillo, Thomas;

    2008-01-01

    The catalytic activity of Pt and Pt3Ni for the oxygen reduction reaction is investigated by applying a Sabatier model based on density functional calculations. We investigate the role of adsorbed OH on the activity, by comparing cyclic voltammetry obtained from theory with previously published...

  10. Hopf Algebroids and Their Cyclic Theory

    NARCIS (Netherlands)

    Kowalzig, N.

    2009-01-01

    The main objective of this thesis is to clarify concepts of generalised symmetries in noncommutative geometry (i.e., the noncommutative analogue of groupoids and Lie algebroids) and their associated (co)homologies. These ideas are incorporated by the notion of Hopf algebroids and Hopf-cyclic (co)hom

  11. STUDY OF CYCLIC AMP IN HUMAN SEMEN

    Institute of Scientific and Technical Information of China (English)

    JIANGNing

    1989-01-01

    It had been observed that there was a close relationship between cyclic AMP and the motility, energy metabolism, capaeitation and acrosome reaction of spermatozoa. In this study a radio-immunoassay procedure for measuring cAMP concentration in sperm and

  12. Strongly Cyclic and Strongly Irreducible Decomposition

    Institute of Scientific and Technical Information of China (English)

    纪友清; 韩黎明

    2001-01-01

    Let W be an injective unilateral weighted shift, and let W(n) be the orthogonal direct sum of n copies of W. In this paper, we prove that, if the commutant of W is strictly cyclic, then W(n) has a unique (SI) decomposition with respect to similarity for every natural number n.

  13. Cyclic Plastic Deformation and Welding Simulation

    NARCIS (Netherlands)

    Ten Horn, C.H.L.J.

    2003-01-01

    One of the concerns of a fitness for purpose analysis is the quantification of the relevant material properties. It is known from experiments that the mechanical properties of a material can change due to a monotonic plastic deformation or a cyclic plastic deformation. For a fitness for purpose anal

  14. Cyclic electron flow: facts and hypotheses.

    Science.gov (United States)

    Finazzi, Giovanni; Johnson, Giles N

    2016-09-01

    Over the last 15 years, research into the process of cyclic electron flow in photosynthesis has seen a huge resurgence. Having been considered by some in the early 1990s as a physiologically unimportant artefact, it is now recognised as essential to normal plant growth. Here, we provide an overview of the major developments covered in this special issue of photosynthesis research.

  15. Monopod bucket foundations under cyclic lateral loading

    DEFF Research Database (Denmark)

    Foglia, Aligi; Ibsen, Lars Bo

    The monopod bucket foundation can be a cost-reducing sub-structure for offshore wind turbines. To avoid problems during the turbine operation, the long-term effect of cyclic loading must be considered in the design of the foundation. In this paper a 1g testing rig is adopted to extend the knowled...

  16. Cyclic Triaxial Loading of Cohesionless Silty Sand

    DEFF Research Database (Denmark)

    Sabaliauskas, Tomas; Ibsen, Lars Bo

    2015-01-01

    To engineer efficient structures offshore, we need to extend our knowledge of soil response. Cyclic loading and high water pressure encountered offshore greatly influence cohesionless soil performance. Silty sand from Frederikshavn wind turbine farm was tested using single diameter height samples...

  17. Monopod Bucket Foundations Under Cyclic Lateral Loading

    DEFF Research Database (Denmark)

    Foglia, Aligi; Ibsen, Lars Bo

    2016-01-01

    The monopod bucket foundation has the potential to become a cost-reducing substructure for offshore wind turbines. To avoid problems during the energy converter operation, the long-term effect of cyclic loading must be considered in the design of the foundation. In this paper, a 1-g testing rig i...

  18. Scale invariant density perturbations from cyclic cosmology

    Science.gov (United States)

    Frampton, Paul Howard

    2016-04-01

    It is shown how quantum fluctuations of the radiation during the contraction era of a comes back empty (CBE) cyclic cosmology can provide density fluctuations which re-enter the horizon during the subsequent expansion era and at lowest order are scale invariant, in a Harrison-Zel’dovich-Peebles sense. It is necessary to be consistent with observations of large scale structure.

  19. Synthetic Peptides Derived from Bovine Lactoferricin Exhibit Antimicrobial Activity against E. coli ATCC 11775, S. maltophilia ATCC 13636 and S. enteritidis ATCC 13076

    Directory of Open Access Journals (Sweden)

    Nataly De Jesús Huertas Méndez

    2017-03-01

    Full Text Available Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B–containing non-natural amino acids and the RWQWR motif were synthesized, purified, and characterized using RP-HPLC, MALDI-TOF mass spectrometry, and circular dichroism. The antibacterial activity of peptides against Escherichia coli ATCC 11775, Stenotrophomonas maltophilia ATCC 13636, and Salmonella enteritidis ATCC 13076 was evaluated. The minimum inhibitory concentration (MIC and minimum bactericidal concentration (MBC were determined. The synthetic bovine lactoferricin exhibited antibacterial activity against E. coli ATCC 11775 and S. enteritidis ATCC 13076. The dimeric peptide (RRWQWR2K-Ahx exhibited the highest antibacterial activity against the tested bacterial strain. The monomeric, cyclic, tetrameric, and palindromic peptides containing the RWQWR motif exhibited high and specific activity against E. coli ATCC 11775. The results suggest that short peptides derived from lactoferricin B could be considered as potential candidates for the development of antibacterial agents against infections caused by E. coli.

  20. Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome

    OpenAIRE

    Abdul-Sater, Ali A.; Tattoli, Ivan; Jin, Lei; Grajkowski, Andrzej; Levi, Assaf; Koller, Beverly H.; Irving C Allen; Beaucage, Serge L.; Fitzgerald, Katherine A.; Ting, Jenny P.-Y.; Cambier, John C.; Stephen E Girardin; Schindler, Christian

    2013-01-01

    Cyclic dinucleotides have been recently shown to induce type I interferon secretion. This study shows they also activate the NLRP3 inflammasome to stimulate robust IL-1b secretion through a novel pathway that does not generate mitochondrial ROS.

  1. Anti-antimicrobial Peptides

    Science.gov (United States)

    Ryan, Lloyd; Lamarre, Baptiste; Diu, Ting; Ravi, Jascindra; Judge, Peter J.; Temple, Adam; Carr, Matthew; Cerasoli, Eleonora; Su, Bo; Jenkinson, Howard F.; Martyna, Glenn; Crain, Jason; Watts, Anthony; Ryadnov, Maxim G.

    2013-01-01

    Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance. PMID:23737519

  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. Immunotherapy with Allergen Peptides

    OpenAIRE

    Larché Mark

    2007-01-01

    Specific allergen immunotherapy (SIT) is disease-modifying and efficacious. However, the use of whole allergen preparations is associated with frequent allergic adverse events during treatment. Many novel approaches are being designed to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity. One approach is the use of short synthetic peptides which representing dominant T cell epitopes of the allergen. Short peptides exhibit markedly reduced capacity to cro...

  4. Antimicrobial Peptides in Echinoderms

    OpenAIRE

    Li, C; Haug, T; K Stensvåg

    2010-01-01

    Antimicrobial peptides (AMPs) are important immune effector molecules for invertebrates, including echinoderms, which lack a vertebrate-type adaptive immune system. Here we summarize the knowledge of such peptides in echinoderms. Strongylocins are a novel family of cysteine-rich AMPs, recently identified in the sea urchins, Strongylocentrotus droebachiensis and S. purpuratus. Although these molecules present diverse amino acid sequences, they share an identical cysteine arrangement pattern, d...

  5. Interdigitated lamella and bicontinuous cubic phases formation from natural cyclic surfactin and its linear derivative.

    Science.gov (United States)

    Imura, Tomohiro; Ikeda, Shintaro; Aburai, Kenichi; Taira, Toshiaki; Kitamoto, Dai

    2013-01-01

    The lyotropic phase behavior of the cyclic form surfactin (CS) produced by Bacillus subtilis and its linear derivative in aqueous solution was evaluated for the first time by using polarized light microscopy and small-angle X-ray scattering (SAXS). By polarized light microscopy, the aqueous solutions of CS at the concentrations above 50 wt% were optically anisotropic and gave mosaic textures, suggesting the formation of lamella structures, while those of the linear surfactin (LS) were optically isotropic and no distinctive textures were observed. SAXS diffractograms of the CS solution above 50 wt% clearly gave the three peaks whose spacing ratio of 1: 2: 3, indicating the presence of the lamellar (L(α)) phase, while those of the LS solution gave multiple peaks whose spacing ratios of √2: √3: √4: √6: √8, confirming the bicontinuous cubic (V₂) phase of the symmetry Pn3m. It was also found that the lamellar phase with CS was composed of not ordinary bilayer but interdigitated bilayer with the unusual packing of the acyl chain region. These results clearly demonstrated that the cyclic peptide structure plays a key role in regulating their self-assembly, and naturally occurring CS is likely to form lamellar structure by balancing bulky peptide headgroups with interdigitated packing of their acyl chains.

  6. Design, synthesis, and biological evaluation of (S)-valine thiazole-derived cyclic and noncyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1).

    Science.gov (United States)

    Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E; Patel, Bhargav A; Ambudkar, Suresh V; Talele, Tanaji T

    2014-01-01

    Multidrug resistance caused by ATP binding cassette transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure in cancer chemotherapy. Previously, selenazole-containing cyclic peptides were reported as P-gp inhibitors and were also used for co-crystallization with mouse P-gp, which has 87 % homology to human P-gp. It has been reported that human P-gp can simultaneously accommodate two to three moderately sized molecules at the drug binding pocket. Our in silico analysis, based on the homology model of human P-gp, spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at the drug binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity, and structural form (linear or cyclic) of valine-derived thiazole peptides that can be accommodated in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear (13) and cyclic trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 =1.5 μM). As the cyclic trimer and linear trimer compounds are equipotent, future studies should focus on noncyclic counterparts of cyclic peptides maintaining linear trimer length. A binding model of the linear trimer 13 within the drug binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the noncyclic form.

  7. Synthesis and evaluation of amphiphilic peptides as nanostructures and drug delivery tools

    Science.gov (United States)

    Sayeh, Naser Ali

    conjugates although one limitation lies in the effort of controlling the rate of drug release. The encapsulated or complexed drugs tend to be released rapidly (before reaching the target site) and in the dendrimer--drug conjugates, it is the chemical linkage that controls the drug release. Thus, future studies in this field are urgently required to create more efficient and stable biomaterials. Peptides are considered as efficient vectors for achieving optimal cellular uptake. The potential use of peptides as drug delivery vectors received much attention by the discovery of several cell-penetrating peptides (CPPs). The first CPPs discovered in 1988, that were sequences from HIV-1 encoded TAT protein, TAT (48--60), and penetrated very efficiently through cell membranes of cultured mammalian cells. CPPs are a class of diverse peptides, typically with 8--25 amino acids, and unlike most peptides, they can cross the cellular membrane with more efficiency. CPPs have also shown to undergo self-assembly and generate nanostructures. The generation of self-assembled peptides and nanostructures occur through various types of interactions between functional groups of amino acid residues, such as electrostatic, hydrophobic, and hydrogen bonding. Appropriate design and functionalization of peptides are critical for generating nanostructures. Chemically CPPs are classified into two major groups: linear and cyclic peptides. It has been previously reported that linear peptides containing hydrophilic and hydrophobic amino acids could act as membrane protein stabilizers. These compounds are short hydrophilic or amphiphilic peptides that have positively charged amino acids, such as arginine, lysine or histidine, which can interact with the negative charge phospholipids layer on the cell membrane and translocate the cargo into the cells. Conjugation to cationic linear CPPs, such as TAT, penetratin, or oligoarginine efficiently improves the cellular uptake of large hydrophilic molecules, but the

  8. SCATTERING BY CYCLIC POLYMERS AND COPOLYMERS AT LARGE SCATTERING VECTORS

    NARCIS (Netherlands)

    KOSMAS, M; BENOIT, H; HADZIIOANNOU, G

    1994-01-01

    General formulae allowing the evaluation of the form factors of cyclic block copolymers are established and graphs for cyclic copolymers of the form (A-B)(N) are shown. When N is large, the linear and the cyclic copolymer have the same behaviour. It is possible to extend at large angle an analytical

  9. Cyclic cocycles on deformation quantizations and higher index theorems

    NARCIS (Netherlands)

    Pflaum, M.J.; Posthuma, H.; Tang, X.

    2010-01-01

    We construct a nontrivial cyclic cocycle on the Weyl algebra of a symplectic vector space. Using this cyclic cocycle we construct an explicit, local, quasi-isomorphism from the complex of differential forms on a symplectic manifold to the complex of cyclic cochains of any formal deformation quantiza

  10. Transient Spectroscopic Properties of [60]Fullerene-Containing Cyclic Sulphoxide

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The properties of the triplet excited state of [60]fullerene-containing cyclic sulphoxide have been investigated by time-resolved absorption spectroscopy. Transient absorption bands of [60]fullerene-containing cyclic sulphoxide showed two decay-components, which were attributed to triplet excited states of different spin multiplicity. The properties of photoexcited states of [60]fullerene-containing cyclic sulphoxide are also reported.

  11. Natriuretic Peptides, Diagnostic and Prognostic Biomarkers

    NARCIS (Netherlands)

    J.H.W. Rutten (Joost)

    2010-01-01

    textabstractIn humans, the natriuretic peptide family consists of three different types of peptides: atrial natriuretic peptide (synonym: atrial natriuretic factor), B-type natriuretic peptide (synonym: brain natriuretic peptide) and C-natriuretic peptide.1 Atrial natriuretic peptide (ANP) was the f

  12. Natriuretic Peptides, Diagnostic and Prognostic Biomarkers

    OpenAIRE

    Rutten, Joost

    2010-01-01

    textabstractIn humans, the natriuretic peptide family consists of three different types of peptides: atrial natriuretic peptide (synonym: atrial natriuretic factor), B-type natriuretic peptide (synonym: brain natriuretic peptide) and C-natriuretic peptide.1 Atrial natriuretic peptide (ANP) was the fi rst natriuretic peptide to be discovered and in humans ANP is predominantly formed in the cardiomyocytes of the atria.2 B-type natriuretic peptide (BNP) was fi rst discovered in porcine brain hen...

  13. The Hall Algebra of Cyclic Serial Algebra

    Institute of Scientific and Technical Information of China (English)

    郭晋云

    1994-01-01

    In this paper, orders <1 and <2 on ((Z)+)nm are introduced and also regarded as orders on the isomorphism classes of finite modules of finite .cyclic algebra R with n simple modules and all the indecomposable projective modules have length m through a one-to-one correspondence between ((Z)+)nm and the isomorphism classes of finite R modules. Using this we prove that the Hall algebra of a cyclic serial algebra is identified with its Loewy subalgebra, and its rational extension has a basis of BPW type, and is a (((Z)+)nm, <2) filtered ring with the associated graded ring as an iterated skew polynomial ring. These results are also generalized to the Hall algebra of a tube over a finite field.

  14. Generalized Toeplitz operators and cyclic vectors

    CERN Document Server

    Gassier, G; Zerouali, E H

    2003-01-01

    We give in this paper some asymptotic Von Neumann inequalities for power bounded operators in the class C subrho intersection C sub 1. and some spacial von Neumann inequalities associated with non zero elements of the point spectrum, when it is non void, of generalized Toeplitz operators. Introducing perturbed kernel, we consider classes C sub R which extend the classical classes C subrho. We give results about absolute continuity with respect to the Haar measure for operators in class C sub R intersection C sub 1. This allows us to give new results on cyclic vectors for such operators and provides invariant subspaces for their powers. Relationships between cyclic vectors for T and T* involving generalized Toeplitz operators are given and the commutativity of left brace T right brace', the commutant of T is discussed.

  15. Detecting highly cyclic structure with complex eigenpairs

    CERN Document Server

    Klymko, Christine

    2016-01-01

    Many large, real-world complex networks have rich community structure that a network scientist seeks to understand. These communities may overlap or have intricate internal structure. Extracting communities with particular topological structure, even when they overlap with other communities, is a powerful capability that would provide novel avenues of focusing in on structure of interest. In this work we consider extracting highly-cyclic regions of directed graphs (digraphs). We demonstrate that embeddings derived from complex-valued eigenvectors associated with stochastic propagator eigenvalues near roots of unity are well-suited for this purpose. We prove several fundamental theoretic results demonstrating the connection between these eigenpairs and the presence of highly-cyclic structure and we demonstrate the use of these vectors on a few real-world examples.

  16. Cyclic Nucleotide Signalling in Kidney Fibrosis

    Directory of Open Access Journals (Sweden)

    Elisabeth Schinner

    2015-01-01

    Full Text Available Kidney fibrosis is an important factor for the progression of kidney diseases, e.g., diabetes mellitus induced kidney failure, glomerulosclerosis and nephritis resulting in chronic kidney disease or end-stage renal disease. Cyclic adenosine monophosphate (cAMP and cyclic guanosine monophosphate (cGMP were implicated to suppress several of the above mentioned renal diseases. In this review article, identified effects and mechanisms of cGMP and cAMP regarding renal fibrosis are summarized. These mechanisms include several signalling pathways of nitric oxide/ANP/guanylyl cyclases/cGMP-dependent protein kinase and cAMP/Epac/adenylyl cyclases/cAMP-dependent protein kinase. Furthermore, diverse possible drugs activating these pathways are discussed. From these diverse mechanisms it is expected that new pharmacological treatments will evolve for the therapy or even prevention of kidney failure.

  17. Universal Cyclic Topology in Polymer Networks.

    Science.gov (United States)

    Wang, Rui; Alexander-Katz, Alfredo; Johnson, Jeremiah A; Olsen, Bradley D

    2016-05-01

    Polymer networks invariably possess topological defects: loops of different orders which have profound effects on network properties. Here, we demonstrate that all cyclic topologies are a universal function of a single dimensionless parameter characterizing the conditions for network formation. The theory is in excellent agreement with both experimental measurements of hydrogel loop fractions and Monte Carlo simulations without any fitting parameters. We demonstrate the superposition of the dilution effect and chain-length effect on loop formation. The one-to-one correspondence between the network topology and primary loop fraction demonstrates that the entire network topology is characterized by measurement of just primary loops, a single chain topological feature. Different cyclic defects cannot vary independently, in contrast to the intuition that the densities of all topological species are freely adjustable. Quantifying these defects facilitates studying the correlations between the topology and properties of polymer networks, providing a key step in overcoming an outstanding challenge in polymer physics.

  18. Helical Two-Revolutional Cyclical Surface

    Directory of Open Access Journals (Sweden)

    Tatiana Olejníková

    2009-12-01

    Full Text Available Paper presents a family of helical two-revolutional cyclical surfaces, which arecreated by movement of the circle alongside the helical cycloidal curve, where circle islocated in the curve normal plane and its centre is on this curve. Helical cycloidal curvecan be created by simultaneous revolution of a point about two different axes 3o, 2o and byscrewing about axis 1o in the space. Form of the helical cycloidal curve and also of thehelical two-revolutional cyclical surface is dependent on the relative position of the threeaxes of revolutions, on multiples of angular velocities and orientations of separaterevolutions. Analytic representation, classification of surfaces and some of their geometricproperties are derived.

  19. Cyclic sieving, promotion, and representation theory

    CERN Document Server

    Rhoades, Brendon

    2010-01-01

    We prove a collection of conjectures of D. White \\cite{WComm}, as well as some related conjectures of Abuzzahab-Korson-Li-Meyer \\cite{AKLM} and of Reiner and White \\cite{ReinerComm}, \\cite{WComm}, regarding the cyclic sieving phenomenon of Reiner, Stanton, and White \\cite{RSWCSP} as it applies to jeu-de-taquin promotion on rectangular tableaux. To do this, we use Kazhdan-Lusztig theory and a characterization of the dual canonical basis of $\\mathbb{C}[x_{11}, ..., x_{nn}]$ due to Skandera \\cite{SkanNNDCB}. Afterwards, we extend our results to analyzing the fixed points of a dihedral action on rectangular tableaux generated by promotion and evacuation, suggesting a possible sieving phenomenon for dihedral groups. Finally, we give applications of this theory to cyclic sieving phenomena involving reduced words for the long elements of hyperoctohedral groups and noncrossing partitions.

  20. Cyclic and Quasi-Cyclic LDPC Codes on Row and Column Constrained Parity-Check Matrices and Their Trapping Sets

    CERN Document Server

    Huang, Qin; Lin, Shu; Abdel-Ghaffar, Khaled

    2010-01-01

    This paper is concerned with construction and structural analysis of both cyclic and quasi-cyclic codes, particularly LDPC codes. It consists of three parts. The first part shows that a cyclic code given by a parity-check matrix in circulant form can be decomposed into descendant cyclic and quasi-cyclic codes of various lengths and rates. Some fundamental structural properties of these descendant codes are developed, including the characterizations of the roots of the generator polynomial of a cyclic descendant code. The second part of the paper shows that cyclic and quasi-cyclic descendant LDPC codes can be derived from cyclic finite geometry LDPC codes using the results developed in first part of the paper. This enlarges the repertoire of cyclic LDPC codes. The third part of the paper analyzes the trapping sets of regular LDPC codes whose parity-check matrices satisfy a certain constraint on their rows and columns. Several classes of finite geometry and finite field cyclic and quasi-cyclic LDPC codes with l...

  1. Breaking antidunes: Cyclic behavior due to hysteresis

    DEFF Research Database (Denmark)

    Deigaard, Rolf

    2006-01-01

    The cyclic behavior of breaking antidunes (growth, breaking of surface wave, obliteration) is investigated by use of a numerical model. The model includes the transition between supercritical and transcritical flow. As the antidune grows the flow becomes transcritical and a hydraulic jump is form...... upstream of the antidune crest. The relation between growth of the antidune and supercritical flow and between decay and transcritical flow is shown, and the significance of hysteresis in the flow conditions is investigated....

  2. Transversality for Cyclic Negative Feedback Systems

    OpenAIRE

    2014-01-01

    Transversality of stable and unstable manifolds of hyperbolic periodic trajectories is proved for monotone cyclic systems with negative feedback. Such systems in general are not in the category of monotone dynamical systems in the sense of Hirsch. Our main tool utilized in the proofs is the so-called cone of high rank. We further show that stable and unstable manifolds between a hyperbolic equilibrium and a hyperbolic periodic trajectory, or between two hyperbolic equilibria with different di...

  3. Past Eras In Cyclic Cosmological Models

    CERN Document Server

    Frampton, Paul H

    2009-01-01

    In infinitely cyclic cosmology past eras are discussed using set theory and transfinite numbers. One consistent scenario, already in the literature, is where there is always a countably infinite number, $\\aleph_0$, of universes and no big bang. I describe here an alternative where the present number of universes is $\\aleph_0$ and in the infinite past there was only a finite number of universes. In this alternative model it is also possible that there was no big bang.

  4. Cyclic Strain Enhances Cellular Uptake of Nanoparticles

    OpenAIRE

    Jia Hu; Yaling Liu

    2015-01-01

    Nanoparticles (NPs) have gained increasing interest in recent years due to their potential use as drug carrier, imaging, and diagnostic agents in pharmaceutical and biomedical applications. While many cells in vivo experience mechanical forces, little is known about the correlation of the mechanical stimulation and the internalization of NPs into cells. This paper investigates the effects of applied cyclic strain on NP uptake by cells. Bovine aortic endothelial cells (BAECs) were cultured on ...

  5. Synthesis of a Cyclic Analogue of Galardin

    Institute of Scientific and Technical Information of China (English)

    马大为; 吴问根; 钱静; 郎深慧; 叶其壮

    2001-01-01

    A cyclic analogue 4 of galardin,a known MMP inhibitor,is designed to improve its selectivity.The synthesis of 4starts from dimethyl(S)-malate using diaselective alkylation and subsequent cyclization and amide formation as key steps.The compound 4 showed MMP inhibitory activity on all MMPs tested with IC50 ranging from 20.1 μM to 104 μM.

  6. General solution of the cyclic Leibniz rule

    Science.gov (United States)

    Kadoh, Daisuke; Ukita, Naoya

    2015-10-01

    We study the cyclic Leibniz rule (CLR) which was recently proposed as a new approach to the realization of supersymmetric quantum mechanics on the lattice. The CLR has an infinite number of solutions that give the different definitions of the lattice supersymmetric quantum mechanics. We show the general form of the solution for the naive symmetric difference operator and reveal the differences between the lattice models.

  7. Simple Current Actions of Cyclic Groups

    OpenAIRE

    Varga, Tamas

    2004-01-01

    Permutation actions of simple currents on the primaries of a Rational Conformal Field Theory are considered in the framework of admissible weighted permutation actions. The solution of admissibility conditions is presented for cyclic quadratic groups: an irreducible WPA corresponds to each subgroup of the quadratic group. As a consequence, the primaries of a RCFT with an order n integral or half-integral spin simple current may be arranged into multiplets of length k^2 (where k is a divisor o...

  8. Cyclical Variability of Prominences, CMEs and Flares

    Indian Academy of Sciences (India)

    J. L. Ballester

    2000-09-01

    Solar flares, prominences and CMEs are well known manifestations of solar activity. For many years, qualitative studies were made about the cyclical behaviour of such phenomena. Nowadays, more quantitative studies have been undertaken with the aim to understand the solar cycle dependence of such phenomena as well as peculiar behaviour, such as asymmetries and periodicities, occurring within the solar cycle. Here, we plan to review the more recent research concerning all these topics.

  9. Peptide synthesis triggered by comet impacts: A possible method for peptide delivery to the early Earth and icy satellites

    Science.gov (United States)

    Sugahara, Haruna; Mimura, Koichi

    2015-09-01

    We performed shock experiments simulating natural comet impacts in an attempt to examine the role that comet impacts play in peptide synthesis. In the present study, we selected a mixture of alanine (DL-alanine), water ice, and silicate (forsterite) to make a starting material for the experiments. The shock experiments were conducted under cryogenic conditions (77 K), and the shock pressure range achieved in the experiments was 4.8-25.8 GPa. The results show that alanine is oligomerized into peptides up to tripeptides due to the impact shock. The synthesized peptides were racemic, indicating that there was no enantioselective synthesis of peptides from racemic amino acids due to the impact shock. We also found that the yield of linear peptides was a magnitude higher than those of cyclic diketopiperazine. Furthermore, we estimated the amount of cometary-derived peptides to the early Earth based on two models (the Lunar Crating model and the Nice model) during the Late Heavy Bombardment (LHB) using our experimental data. The estimation based on the Lunar Crating model gave 3 × 109 mol of dialanine, 4 × 107 mol of trialanine, and 3 × 108 mol of alanine-diketopiperazine. Those based on the Nice model, in which the main impactor of LHB is comets, gave 6 × 1010 mol of dialanine, 1 × 109 mol of trialanine, and 8 × 109 mol of alanine-diketopiperazine. The estimated amounts were comparable to those originating from terrestrial sources (Cleaves, H.J., Aubrey, A.D., Bada, J.L. [2009]. Orig. Life Evol. Biosph. 39, 109-126). Our results indicate that comet impacts played an important role in chemical evolution as a supplier of linear peptides, which are important for further chemical evolution on the early Earth. Our study also highlights the importance of icy satellites, which were formed by comet accumulation, as prime targets for missions searching for extraterrestrial life.

  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 powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides...... 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. Cyclical period changes in Z Chamaeleontis

    CERN Document Server

    Baptista, R; Oliveira, E; Vrielmann, S; Woudt, P A; Catalan, M S

    2002-01-01

    We report the identification of cyclical changes in the orbital period of the eclipsing dwarf nova Z Cha. We used times of mid-eclipse collected from the literature and our new eclipse timings to construct an observed-minus-calculated diagram covering 30 years of observations (1972-2002). The data present cyclical variations that can be fitted by a linear plus sinusoidal function with period 28+/-2 yr and amplitude 1.0+/-0.2 minute. The statistical significance of this period by an F-test is larger than 99.9%. The derived fractional period change, Delta P/P= 4.4 x 10^{-7}, is comparable to that of other short-period cataclysmic variables (CVs), but is one order of magnitude smaller than those of the long-period CVs. Separate fits to the first and second half of the data lead to ephemerides with quite different cycle periods and amplitudes, indicating that the variation is not sinusoidal or, most probably, is not strictly periodic. The observed cyclical period change is possibly caused by a solar-type magnetic...

  12. Cyclic dominance in evolutionary games: A review

    CERN Document Server

    Szolnoki, Attila; Jiang, Luo-Luo; Szczesny, Bartosz; Rucklidge, Alastair M; Perc, Matjaz

    2014-01-01

    Rock is wrapped by paper, paper is cut by scissors, and scissors are crushed by rock. This simple game is popular among children and adults to decide on trivial disputes that have no obvious winner, but cyclic dominance is also at the heart of predator-prey interactions, the mating strategy of side-blotched lizards, the overgrowth of marine sessile organisms, and the competition in microbial populations. Cyclical interactions also emerge spontaneously in evolutionary games entailing volunteering, reward, punishment, and in fact are common when the competing strategies are three or more regardless of the particularities of the game. Here we review recent advances on the rock-paper-scissors and related evolutionary games, focusing in particular on pattern formation, the impact of mobility, and the spontaneous emergence of cyclic dominance. We also review mean-field and zero-dimensional rock-paper-scissors models and the application of the complex Ginzburg-Landau equation, and we highlight the importance and use...

  13. Visualization of cyclic nucleotide dynamics in neurons

    Directory of Open Access Journals (Sweden)

    Kirill eGorshkov

    2014-12-01

    Full Text Available The second messengers cAMP and cGMP transduce many neuromodulatory signals from hormones and neurotransmitters into specific functional outputs. Their production, degradation and signaling are spatiotemporally regulated to achieve high specificity in signal transduction. The development of genetically encodable fluorescent biosensors has provided researchers with useful tools to study these versatile second messengers and their downstream effectors with unparalleled spatial and temporal resolution in cultured cells and living animals. In this review, we introduce the general design of these fluorescent biosensors and describe several of them in more detail. Then we discuss a few examples of using cyclic nucleotide fluorescent biosensors to study regulation of neuronal function and finish with a discussion of advances in the field. Although there has been significant progress made in understanding how the specific signaling of cyclic nucleotide second messengers is achieved, the mechanistic details in complex cell types like neurons are only just beginning to surface. Current and future fluorescent protein reporters will be essential to elucidate the role of cyclic nucleotide signaling dynamics in the functions of individual neurons and their networks.

  14. Scale factor duality for conformal cyclic cosmologies

    Science.gov (United States)

    Camara da Silva, U.; Alves Lima, A. L.; Sotkov, G. M.

    2016-11-01

    The scale factor duality is a symmetry of dilaton gravity which is known to lead to pre-big-bang cosmologies. A conformal time version of the scale factor duality (SFD) was recently implemented as a UV/IR symmetry between decelerated and accelerated phases of the post-big-bang evolution within Einstein gravity coupled to a scalar field. The problem investigated in the present paper concerns the employment of the conformal time SFD methods to the construction of pre-big-bang and cyclic extensions of these models. We demonstrate that each big-bang model gives rise to two qualitatively different pre-big-bang evolutions: a contraction/expansion SFD model and Penrose's Conformal Cyclic Cosmology (CCC). A few examples of SFD symmetric cyclic universes involving certain gauged Kähler sigma models minimally coupled to Einstein gravity are studied. We also describe the specific SFD features of the thermodynamics and the conditions for validity of the generalized second law in the case of Gauss-Bonnet (GB) extension of these selected CCC models.

  15. Scale Factor Duality for Conformal Cyclic Cosmologies

    CERN Document Server

    dS, U Camara; Sotkov, G M

    2016-01-01

    The scale factor duality is a symmetry of dilaton gravity which is known to lead to pre-big-bang cosmologies. A conformal time version of the scale factor duality (SFD) was recently implemented as a UV/IR symmetry between decelerated and accelerated phases of the post-big-bang evolution within Einstein gravity coupled to a scalar field. The problem investigated in the present paper concerns the employment of the conformal time SFD methods to the construction of pre-big-bang and cyclic extensions of these models. We demonstrate that each big-bang model gives rise to two qualitatively different pre-big-bang evolutions: a contraction/expansion SFD model and Penrose's Conformal Cyclic Cosmology (CCC). A few examples of SFD symmetric cyclic universes involving certain gauged K\\"ahler sigma models minimally coupled to Einstein gravity are studied. We also describe the specific SFD features of the thermodynamics and the conditions for validity of the generalized second law in the case of Gauss-Bonnet (GB) extension ...

  16. Cosmology and Cosmogony in a Cyclic Universe

    Indian Academy of Sciences (India)

    Jayant V. Narlikar; Geoffrey Burbidge; R. G. Vishwakarma

    2007-06-01

    In this paper we discuss the properties of the quasi-steady state cosmological model (QSSC) developed in 1993 in its role as a cyclic model of the universe driven by a negative energy scalar field. We discuss the origin of such a scalar field in the primary creation process first described by F. Hoyle & J. V. Narlikar forty years ago. It is shown that the creation processes which take place in the nuclei of galaxies are closely linked to the high energy and explosive phenomena, which are commonly observed in galaxies at all redshifts. The cyclic nature of the universe provides a natural link between the places of origin of the microwave background radiation (arising in hydrogen burning in stars), and the origin of the lightest nuclei (H, D, He3 and He4). It also allows us to relate the large scale cyclic properties of the universe to events taking place in the nuclei of galaxies. Observational evidence shows that ejection of matter and energy from these centers in the form of compact objects, gas and relativistic particles is responsible for the population of quasi-stellar objects (QSOs) and gamma-ray burst sources in the universe. In the later parts of the paper we briefly discuss the major unsolved problems of this integrated cosmological and cosmogonical scheme – the understanding of the origin of the intrinsic redshifts, and the periodicities in the redshift distribution of the QSOs.

  17. Electron transfer in peptides.

    Science.gov (United States)

    Shah, Afzal; Adhikari, Bimalendu; Martic, Sanela; Munir, Azeema; Shahzad, Suniya; Ahmad, Khurshid; Kraatz, Heinz-Bernhard

    2015-02-21

    In this review, we discuss the factors that influence electron transfer in peptides. We summarize experimental results from solution and surface studies and highlight the ongoing debate on the mechanistic aspects of this fundamental reaction. Here, we provide a balanced approach that remains unbiased and does not favor one mechanistic view over another. Support for a putative hopping mechanism in which an electron transfers in a stepwise manner is contrasted with experimental results that support electron tunneling or even some form of ballistic transfer or a pathway transfer for an electron between donor and acceptor sites. In some cases, experimental evidence suggests that a change in the electron transfer mechanism occurs as a result of donor-acceptor separation. However, this common understanding of the switch between tunneling and hopping as a function of chain length is not sufficient for explaining electron transfer in peptides. Apart from chain length, several other factors such as the extent of the secondary structure, backbone conformation, dipole orientation, the presence of special amino acids, hydrogen bonding, and the dynamic properties of a peptide also influence the rate and mode of electron transfer in peptides. Electron transfer plays a key role in physical, chemical and biological systems, so its control is a fundamental task in bioelectrochemical systems, the design of peptide based sensors and molecular junctions. Therefore, this topic is at the heart of a number of biological and technological processes and thus remains of vital interest.

  18. Fractional Fourier domain analysis of cyclic multirate signal processing

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The cyclic filter banks, which are used widely in the image subband coding, refer to signal processing on the finite field. This study investigates the fractional Fourier domain (FRFD) analysis of cyclic multirate systems based on the fractional circular convolution and chirp period. The proposed theorems include the fractional Fourier domain analysis of cyclic decimation and cyclic interpolation, the noble identities of cyclic decimation and cyclic interpolation in the FRFD, the polyphase represen-tation of cyclic signal in the FRFD, and the perfect reconstruction condition for the cyclic filter banks in the FRFD. Furthermore, this paper proposes the design methods for perfect reconstruction cyclic filter bank and cyclic filter bank with chirp modulation in the FRFD. The proposed theorems extend the multirate signal processing in the FRFD, which also advance the applications of the theorems of filter bank in the FRFD on the finite signal field, such as digital image processing. At last, the proposed design methods for the cyclic filter banks in the FRFD are validated by simulations.

  19. Multiaxial elastoplastic cyclic loading of austenitic 316L steel

    Directory of Open Access Journals (Sweden)

    V. Mazánová

    2017-04-01

    Full Text Available Cyclic stress-strain response and fatigue damage character has been investigated in austenitic stainless steel 316L. Hollow cylindrical specimens have been cyclically deformed in combined tension-compression and torsion under constant strain rate condition and different constant strain and shear strain amplitudes. In-phase and 90° out-of-phase cyclic straining was applied and the stress response has been monitored. Cyclic hardening/softening curves were assessed in both channels. Cyclic softening followed for higher strain amplitudes by long-term cyclic hardening was observed. Cyclic stress-strain curves were determined. Study of the surface damage in fractured specimens revealed the types and directions of principal cracks and the sources of fatigue crack initiation in slip bands.

  20. Electrochemical properties of tyrosine phenoxy and tryptophan indolyl radicals in peptides and amino acid analogues

    Energy Technology Data Exchange (ETDEWEB)

    DeFelippis, M.R.; Murthy, C.P.; Klapper, M.H. (Ohio State Univ., Columbus (United States)); Broitman, F.; Weinraub, D.; Faraggi, M. (Nuclear Research Centre-Negev, Beer Sheva (Israel))

    1991-04-18

    Reported here are the redox potentials of the tyrosine phenoxy (tyrO{sup {sm bullet}}) and tryptophan indolyl (trp{sup {sm bullet}}) radicals in peptides containing tyrosine or tryptophan residues. These were determined with pulse radiolysis, and the electrochemical techniques of cyclic voltammetry and differential pulse polarography. The pulse radiolytic and electrochemical methods yield comparable results. There are small differences (relative to the free amino acid) in redox potentials among the different tryptophan and tyrosine containing peptides; in the case of tryptophan these changes may correlate with the position of amino acid in the peptide. The authors also present the redox potentials of some tyrosine and tryptophan derivatives and the acid/base properties of the tryptophan radical cation, when both free and peptide bound.

  1. Detection of cancer cells using a peptide nanotube–folic acid modified graphene electrode

    DEFF Research Database (Denmark)

    Castillo, John J.; Svendsen, Winnie Edith; Rozlosnik, Noemi

    2013-01-01

    This article describes the preparation of a graphene electrode modified with a new conjugate of peptide nanotubes and folic acid for the selective detection of human cervical cancer cells over-expressing folate receptors. The functionalization of peptide nanotubes with folic acid was confirmed......–folic acid modified electrode lowered the electron transfer resulting in a decrease in the measured current. A detection limit of 250 human cervical cancer cells per mL was obtained. Control experiments confirmed that the peptide nanotube–folic acid electrode specifically recognized folate receptors....... The human cervical cancer cells were bound to the modified electrode through the folic acid–folate receptor interaction. Cyclic voltammograms in the presence of [Fe(CN)6]3/4 as a redox species demonstrated that the binding of the folate receptor from human cervical cancer cells to the peptide nanotube...

  2. CXCR4-antagonist Peptide R-liposomes for combined therapy against lung metastasis

    Science.gov (United States)

    Ieranò, Caterina; Portella, Luigi; Lusa, Sara; Salzano, Giuseppina; D'Alterio, Crescenzo; Napolitano, Maria; Buoncervello, Maria; Macchia, Daniele; Spada, Massimo; Barbieri, Antonio; Luciano, Antonio; Barone, Maria Vittoria; Gabriele, Lucia; Caraglia, Michele; Arra, Claudio; De Rosa, Giuseppe; Scala, Stefania

    2016-03-01

    The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide R were developed (PL-Peptide R). In vitro PL-Peptide R efficiently inhibited CXCR4-dependent migration and in vivo it significantly reduced lung metastases and increased overall survival in B16-CXCR4 injected C57BL/6 mice. To evaluate if PL-Peptide R could also be a drug delivery system for CXCR4 expressing tumors, the PL-Peptide R was loaded with doxorubicin (DOX) (PL-Peptide R-DOX). PL-Peptide R-DOX efficiently delivered DOX to CXCR4 expressing cell lines with a consequent decrease in the DOX IC50 efficient dose. In vivo, B16-CXCR4 injected C57BL/6 mice treated with PL-Peptide R-DOX developed fewer lung metastases compared to PL-DOX treated mice. This work provides the proof-of-concept to prevent metastasis by using combined nanomedicine.The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide

  3. Structural organization and spectroscopy of peptide-actinide(IV) complexes; Organisation structurale et spectroscopie de peptides susceptibles de complexer les actinides(IV)

    Energy Technology Data Exchange (ETDEWEB)

    Dahou, S.

    2010-11-05

    The contamination of living organisms by actinide elements is at the origin of both radiological and chemical toxicity that may lead to severe dysfunction. Most of the data available on the actinide interaction with biological systems are macroscopic physiological measurements and are lacking a molecular description of the systems. Because of the intricacy of these systems, classical biochemical methods are difficult to implement. Our strategy consisted in designing simplified biomimetic peptides, and describing the corresponding intramolecular interactions with actinides. A carboxylic pentapeptide of the form DDPDD has been at the starting point of this work in order to further assess the influence of the peptide sequence on the topology of the complexes.To do so, various linear (Asp/Ala permutations, peptoids) and cyclic analogues have been synthesized. Furthermore, in order to include the hydroxamic function (with a high affinity for Fe(III)) in the peptide, both desferrioxamine and acetohydroxamic acid have been investigated. However because of difficulties in synthesis, we have not been able to test these peptides. Three actinide cations have been considered at oxidation state +IV (Th, Np, Pu) and compared to Fe(III), often considered as a biological surrogate of Pu(IV). The spatial arrangement of the peptide around the cation has been probed by spectrophotometry and X-ray Absorption Spectroscopy. The spectroscopic data and EXAFS data adjustment lead us to rationalize the topology of the complexes as a function of the peptide sequence: mix hydroxy polynuclear species for linear and cyclic peptides, mononuclear for the desferrioxamine complexes. Furthermore, significant differences have appeared between Fe(III) and actinide(IV), related to differences of reactivity in aqueous medium. (author)

  4. Immunotherapy with Allergen Peptides

    Directory of Open Access Journals (Sweden)

    Larché Mark

    2007-06-01

    Full Text Available Specific allergen immunotherapy (SIT is disease-modifying and efficacious. However, the use of whole allergen preparations is associated with frequent allergic adverse events during treatment. Many novel approaches are being designed to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity. One approach is the use of short synthetic peptides which representing dominant T cell epitopes of the allergen. Short peptides exhibit markedly reduced capacity to cross link IgE and activate mast cells and basophils, due to lack of tertiary structure. Murine pre-clinical studies have established the feasibility of this approach and clinical studies are currently in progress in both allergic and autoimmune diseases.

  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. β-PEPTIDES CYCLOBUTANIQUES

    OpenAIRE

    Fernandez, Carlos

    2008-01-01

    The synthesis of β-amino acids, structural analogues of?-Amino acids, is an issue essential in the development of oligopeptides. A lot of work has been conducted on the behavior of β-peptide (sequence of β-amino acids) as well as peptides mixed (mixed β-and β- amino acids). As a result, the conformational preference of β-amino acids will induce the appearance of a three-dimensional structure of the oligopeptide ordered. Thus, several types of helices, sheets and elbows were observed in β-olig...

  7. Invertebrate FMRFamide related peptides.

    Science.gov (United States)

    Krajniak, Kevin G

    2013-06-01

    In 1977 the neuropeptide FMRFamide was isolated from the clam, Macrocallista nimbosa. Since then several hundred FMRFamide-related peptides (FaRPs) have been isolated from invertebrate animals. Precursors to the FaRPs likely arose in the cnidarians. With the transition to a bilateral body plan FaRPs became a fixture in the invertebrate phyla. They have come to play a critical role as neurotransmitters, neuromodulators, and neurohormones. FaRPs regulate a variety of body functions including, feeding, digestion, circulation, reproduction, movement. The evolution of the molecular form and function of these omnipresent peptides will be considered.

  8. Dicyclopropylmethyl peptide backbone protectant.

    Science.gov (United States)

    Carpino, Louis A; Nasr, Khaled; Abdel-Maksoud, Adel Ali; El-Faham, Ayman; Ionescu, Dumitru; Henklein, Peter; Wenschuh, Holger; Beyermann, Michael; Krause, Eberhard; Bienert, Michael

    2009-08-20

    The N-dicyclopropylmethyl (Dcpm) residue, introduced into amino acids via reaction of dicyclopropylmethanimine hydrochloride with an amino acid ester followed by sodium cyanoborohydride or triacetoxyborohydride reduction, can be used as an amide bond protectant for peptide synthesis. Examples which demonstrate the amelioration of aggregation effects include syntheses of the alanine decapeptide and the prion peptide (106-126). Avoidance of cyclization to the aminosuccinimide followed substitution of Fmoc-(Dcpm)Gly-OH for Fmoc-Gly-OH in the assembly of sequences containing the sensitive Asp-Gly unit.

  9. Efficient Synthesis of Cyclic Block Copolymers by Rotaxane Protocol by Linear/Cyclic Topology Transformation.

    Science.gov (United States)

    Valentina, Stephanie; Ogawa, Takahiro; Nakazono, Kazuko; Aoki, Daisuke; Takata, Toshikazu

    2016-06-20

    High-yielding synthesis of cyclic block copolymer (CBC) using the rotaxane protocol by linear-cyclic polymer topology transformation was first demonstrated. Initial complexation of OH-terminated sec-ammonium salt and a crown ether was followed by the successive living ring-opening polymerizations of two lactones to a linear block copolymer having a rotaxane structure by the final capping of the propagation end. CBC was obtained in a high yield by an exploitation of the mechanical linkage through the translational movement of the rotaxane component to transform polymer structure from linear to cyclic. Furthermore, the change of the polymer topology was translated into a macroscopic change in crystallinity of the block copolymer.

  10. [Natriuretic peptides: a new lipolytic pathway in human fat cells].

    Science.gov (United States)

    Sengenes, Coralie; Moro, Cédric; Galitzky, Jean; Berlan, Michel; Lafontan, Max

    2005-12-01

    Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity.

  11. Uptake of 111In-labeled fully human monoclonal antibody TSP-A18 reflects transferrin receptor expression in normal organs and tissues of mice.

    Science.gov (United States)

    Sugyo, Aya; Tsuji, Atsushi B; Sudo, Hitomi; Nomura, Fumiko; Satoh, Hirokazu; Koizumi, Mitsuru; Kurosawa, Gene; Kurosawa, Yoshikazu; Saga, Tsuneo

    2017-03-01

    Transferrin receptor (TfR) is an attractive molecule for targeted therapy of cancer. Various TfR-targeted therapeutic agents such as anti-TfR antibodies conjugated with anticancer agents have been developed. An antibody that recognizes both human and murine TfR is needed to predict the toxicity of antibody-based agents before clinical trials, there is no such antibody to date. In this study, a new fully human monoclonal antibody TSP-A18 that recognizes both human and murine TfR was developed and the correlation analysis of the radiolabeled antibody uptake and TfR expression in two murine strains was conducted. TSP-A18 was selected using extracellular portions of human and murine TfR from a human antibody library. The cross-reactivity of TSP-A18 with human and murine cells was confirmed by flow cytometry. Cell binding and competitive inhibition assays with [111In]TSP-A18 showed that TSP-A18 bound highly to TfR-expressing MIAPaCa-2 cells with high affinity. Biodistribution studies of [111In]TSP-A18 and [67Ga]citrate (a transferrin-mediated imaging probe) were conducted in C57BL/6J and BALB/c-nu/nu mice. [111In]TSP-A18 was accumulated highly in the spleen and bone containing marrow component of both strains, whereas high [67Ga]citrate uptake was only observed in bone containing marrow component and not in the spleen. Western blotting indicated the spleen showed the strongest TfR expression compared with other organs in both strains. There was significant correlation between [111In]TSP-A18 uptake and TfR protein expression in both strains, whereas there was significant correlation of [67Ga]citrate uptake with TfR expression only in C57BL/6J. These findings suggest that the difference in TfR expression between murine strains should be carefully considered when testing for the toxicity of anti-TfR antibody in mice and the uptake of anti-TfR antibody could reflect tissue TfR expression more accurately compared with that of transferrin-mediated imaging probe such as [67Ga]citrate.

  12. Chronic bacterial osteomyelitis: prospective comparison of {sup 18}F-FDG imaging with a dual-head coincidence camera and {sup 111}In-labelled autologous leucocyte scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Meller, J.; Siefker, U.; Lehmann, K.; Meyer, I.; Schreiber, K.; Altenvoerde, G.; Becker, W. [Goettingen Univ. (Germany). Abt. fuer Nuklearmedizin; Koester, G. [Dept. of Orthopedics, Goettingen Univ. (Germany); Liersch, T. [Dept. of Traumatic Surgery, Goettingen Univ. (Germany)

    2002-01-01

    Indium-111-labelled white blood cells ({sup 111}In-WBCs) are currently considered the tracer of choice in the diagnostic work-up of suspected active chronic osteomyelitis (COM). Previous studies in a limited number of patients, performed with dedicated PET systems, have shown that [{sup 18}F]2'-deoxy-2-fluoro-D-glucose (FDG) imaging may offer at least similar diagnostic accuracy. The aim of this prospective study was to compare FDG imaging with a dual-head coincidence camera (DHCC) and {sup 111}In-WBC imaging in patients with suspected COM. Thirty consecutive non-diabetic patients with possible COM underwent combined skeletal scintigraphy (30/30 patients), {sup 111}In-WBC imaging (28/30 patients) and FDG-PET with a DHCC (30/30 patients). During diagnostic work-up, COM was proven in 11/36 regions of suspected skeletal infection and subsequently excluded in 25/36 regions. In addition, soft tissue infection was present in five patients and septic arthritis in three. {sup 111}In-WBC imaging in 28 patients was true positive in 2/11 regions with proven COM and true negative in 21/23 regions without further evidence of COM. False-positive results occurred in two regions and false-negative results in nine regions suspected for COM. Most of the false-negative results (7/9) occurred in the central skeleton. If the analysis was restricted to the 18 regions with available histology (n=17) or culture (n=1), {sup 111}In-WBC imaging was true positive in 2/18 regions, true negative in 8/18 regions, false negative in 7/18 regions and false positive in 1/18 regions. FDG-DHCC imaging was true positive in 11/11 regions with proven COM and true negative in 23/25 regions without further evidence of COM. False-positive results occurred in two regions. If the analysis was restricted to the 19 regions with available histology (n=18) or culture (n=1), FDG-DHCC imaging was true positive in 9/9 regions with proven COM and true negative in 10/10 regions without further evidence of COM. It is concluded that FDG-DHCC imaging is superior to {sup 111}In-WBC scintigraphy in the diagnosis of COM in the central skeleton and therefore should be considered the method of choice for this indication. This seems to hold true for peripheral lesions as well, but in our series the number of cases with proven infection was too small to permit a final conclusion. (orig.)

  13. Meta-Analysis: Diagnostic Accuracy of Anti-Cyclic Citrullinated Peptide Antibody for Juvenile Idiopathic Arthritis

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2015-01-01

    Full Text Available Objective. To estimate the diagnostic accuracy of the anti-CCP test in JIA and to evaluate factors associated with higher accuracy. Methods. Two investigators performed an extensive search of the literature published between January 2000 and January 2014. The included articles were assessed by the Quality Assessment of Diagnostic Accuracy Studies tool. The meta-analysis was performed using a summary ROC (SROC curve and a bivariate random-effect model to estimate sensitivity and specificity across studies. Results. The bivariate meta-analysis yielded a pooled sensitivity and specificity of 10% (95% confidence interval (CI: 6.0%–15.0% and 99.0% (95% CI: 98.0%–100.0%. The area under the SROC curve was 0.96. Sensitivity estimates were highly heterogeneous, which was partially explained by the higher sensitivity in the rheumatoid factor-positive polyarthritis (RF+ PA subtype (48.0%; 95% CI: 31.0%–65.0% than in the other subtypes (17.0%; 95% CI: 14.0%–20.0% and the higher sensitivity of the Inova assay (17.0%; 95% CI: 14.0%–20.%% than the other assays (0.05%; 95% CI: 2.0%–11.0%. Conclusions. Anti-CCP antibody test has a high specificity for the diagnosis of JIA. The sensitivity of this test is low and varies across populations but is higher in RF+ PA than in other JIA subtypes.

  14. THE CLINICAL AND DIAGNOSTIC VALUE OF ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODIES IN EARLY JUVENILEARTHRITIS

    Directory of Open Access Journals (Sweden)

    S O Salugina

    2009-01-01

    Conclusion. In patients with early JA, the detection rate of CCPA is significantly higher than that in healthy children and comparable with that of RF. CCPAs have a high specificity for the diagnosis of JRA (an independent nosological entity within JA are a risk factor of polyarthritis. The early detection of CCPA alone or in combination with RF in JA patients may serve the basis for the early use of active, frequently aggressive therapy.

  15. Peptidyl prolyl isomerase Pin1-inhibitory activity of D-glutamic and D-aspartic acid derivatives bearing a cyclic aliphatic amine moiety.

    Science.gov (United States)

    Nakagawa, Hidehiko; Seike, Suguru; Sugimoto, Masatoshi; Ieda, Naoya; Kawaguchi, Mitsuyasu; Suzuki, Takayoshi; Miyata, Naoki

    2015-12-01

    Pin1 is a peptidyl prolyl isomerase that specifically catalyzes cis-trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity.

  16. Vascular Endothelial Growth Factor Peptide Ligands Explored by Competition Assay and Isothermal Titration Calorimetry.

    Science.gov (United States)

    Reille-Seroussi, Marie; Gaucher, Jean-François; Desole, Claudia; Gagey-Eilstein, Nathalie; Brachet, Franck; Broutin, Isabelle; Vidal, Michel; Broussy, Sylvain

    2015-08-25

    The v114* cyclic peptide has been identified as a tight vascular endothelial growth factor (VEGF) ligand. Here we report on the use of isothermal titration calorimetry (ITC), 96-well plate competition assay, and circular dichroism (CD) to explore the binding determinants of a new set of related peptides. Anti-VEGF antibodies are currently used in the clinic for regulating angiogenesis in cancer and age-related macular degeneration treatment. In this context, our aim is to develop smaller molecular entities with high affinity for the growth factor by a structure activity relationship approach. The cyclic disulfide peptide v114* was modified in several ways, including truncation, substitution, and variation of the size and nature of the cycle. The results indicated that truncation or substitution of the four N-terminal amino acids did not cause severe loss in affinity, allowing potential peptide labeling. Increase of the cycle size or substitution of the disulfide bridge with a thioether linkage drastically decreased the affinity, due to an enthalpy penalty. The leucine C-terminal residue positively contributed to affinity. Cysteine N-terminal acetylation induced favorable ΔΔG° and ΔΔH° of binding, which correlated with free peptide CD spectra changes. We also propose a biochemical model to extrapolate Ki from IC50 values measured in the displacement assay. These calculated Ki correlate well with the Kd values determined by extensive direct and reverse ITC measurements.

  17. Signatures of Mechanically Interlocked Topology of Lasso Peptides by Ion Mobility-Mass Spectrometry: Lessons from a Collection of Representatives

    Science.gov (United States)

    Fouque, Kevin Jeanne Dit; Lavanant, Hélène; Zirah, Séverine; Hegemann, Julian D.; Zimmermann, Marcel; Marahiel, Mohamed A.; Rebuffat, Sylvie; Afonso, Carlos

    2016-11-01

    Lasso peptides are characterized by a mechanically interlocked structure, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. Their compact and stable structures have a significant impact on their biological and physical properties and make them highly interesting for drug development. Ion mobility - mass spectrometry (IM-MS) has shown to be effective to discriminate the lasso topology from their corresponding branched-cyclic topoisomers in which the C-terminal tail is unthreaded. In fact, previous comparison of the IM-MS data of the two topologies has yielded three trends that allow differentiation of the lasso fold from the branched-cyclic structure: (1) the low abundance of highly charged ions, (2) the low change in collision cross sections (CCS) with increasing charge state and (3) a narrow ion mobility peak width. In this study, a three-dimensional plot was generated using three indicators based on these three trends: (1) mean charge divided by mass (ζ), (2) relative range of CCS covered by all protonated molecules (ΔΩ/Ω) and (3) mean ion mobility peak width (δΩ). The data were first collected on a set of twenty one lasso peptides and eight branched-cyclic peptides. The indicators were obtained also for eight variants of the well-known lasso peptide MccJ25 obtained by site-directed mutagenesis and further extended to five linear peptides, two macrocyclic peptides and one disulfide constrained peptide. In all cases, a clear clustering was observed between constrained and unconstrained structures, thus providing a new strategy to discriminate mechanically interlocked topologies.

  18. Signatures of Mechanically Interlocked Topology of Lasso Peptides by Ion Mobility-Mass Spectrometry: Lessons from a Collection of Representatives

    Science.gov (United States)

    Fouque, Kevin Jeanne Dit; Lavanant, Hélène; Zirah, Séverine; Hegemann, Julian D.; Zimmermann, Marcel; Marahiel, Mohamed A.; Rebuffat, Sylvie; Afonso, Carlos

    2017-02-01

    Lasso peptides are characterized by a mechanically interlocked structure, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. Their compact and stable structures have a significant impact on their biological and physical properties and make them highly interesting for drug development. Ion mobility - mass spectrometry (IM-MS) has shown to be effective to discriminate the lasso topology from their corresponding branched-cyclic topoisomers in which the C-terminal tail is unthreaded. In fact, previous comparison of the IM-MS data of the two topologies has yielded three trends that allow differentiation of the lasso fold from the branched-cyclic structure: (1) the low abundance of highly charged ions, (2) the low change in collision cross sections (CCS) with increasing charge state and (3) a narrow ion mobility peak width. In this study, a three-dimensional plot was generated using three indicators based on these three trends: (1) mean charge divided by mass (ζ), (2) relative range of CCS covered by all protonated molecules (ΔΩ/Ω) and (3) mean ion mobility peak width (δΩ). The data were first collected on a set of twenty one lasso peptides and eight branched-cyclic peptides. The indicators were obtained also for eight variants of the well-known lasso peptide MccJ25 obtained by site-directed mutagenesis and further extended to five linear peptides, two macrocyclic peptides and one disulfide constrained peptide. In all cases, a clear clustering was observed between constrained and unconstrained structures, thus providing a new strategy to discriminate mechanically interlocked topologies.

  19. Vasoactive intestinal peptide stimulates tracheal submucosal gland secretion in ferret

    Energy Technology Data Exchange (ETDEWEB)

    Peatfield, A.C.; Barnes, P.J.; Bratcher, C.; Nadel, J.A.; Davis, B.

    1983-07-01

    We studied the effect of vasoactive intestinal peptide (VIP) on the output of 35S-labeled macromolecules from ferret tracheal explants either placed in beakers or suspended in modified Ussing chambers. In Ussing chamber experiments, the radiolabel precursor, sodium (35S)sulfate, and all drugs were placed on the submucosal side of the tissue. Washings were collected at 30-min intervals from the luminal side and were dialyzed to remove unbound 35S, leaving radiolabeled macromolecules. Vasoactive intestinal peptide at 3 X 10(-7) M stimulated bound 35S output by a mean of + 252.6% (n . 14). The VIP response was dose-dependent with a near maximal response and a half maximal response at approximately 10(-6) M and 10(-8), M, respectively. The VIP effect was not inhibited by a mixture of tetrodotoxin, atropine, I-propranolol, and phentolamine. Vasoactive intestinal peptide had no effect on the electrical properties of the of the tissues. We conclude that VIP stimulates output of sulfated-macromolecules from ferret tracheal submucosal glands without stimulating ion transport. Our studies also suggest that VIP acts on submucosal glands via specific VIP receptors. Vasoactive intestinal peptide has been shown to increase intracellular levels of cyclic AMP, and we suggest that this may be the mechanism for its effect on the output of macromolecules. This mechanism may be important in the neural regulation of submucosal gland secretion.

  20. Disulfide Bridges: Bringing Together Frustrated Structure in a Bioactive Peptide.

    Science.gov (United States)

    Zhang, Yi; Schulten, Klaus; Gruebele, Martin; Bansal, Paramjit S; Wilson, David; Daly, Norelle L

    2016-04-26

    Disulfide bridges are commonly found covalent bonds that are usually believed to maintain structural stability of proteins. Here, we investigate the influence of disulfide bridges on protein dynamics through molecular dynamics simulations on the cysteine-rich trypsin inhibitor MCoTI-II with three disulfide bridges. Correlation analysis of the reduced cyclic peptide shows that two of the three disulfide distances (Cys(11)-Cys(23) and Cys(17)-Cys(29)) are anticorrelated within ∼1 μs of bridge formation or dissolution: when the peptide is in nativelike structures and one of the distances shortens to allow bond formation, the other tends to lengthen. Simulations over longer timescales, when the denatured state is less structured, do not show the anticorrelation. We propose that the native state contains structural elements that frustrate one another's folding, and that the two bridges are critical for snapping the frustrated native structure into place. In contrast, the Cys(4)-Cys(21) bridge is predicted to form together with either of the other two bridges. Indeed, experimental chromatography and nuclear magnetic resonance data show that an engineered peptide with the Cys(4)-Cys(21) bridge deleted can still fold into its near-native structure even in its noncyclic form, confirming the lesser role of the Cys(4)-Cys(21) bridge. The results highlight the importance of disulfide bridges in a small bioactive peptide to bring together frustrated structure in addition to maintaining protein structural stability.

  1. Stable right- and left-handed peptide helices containing C(alpha)-tetrasubstituted alpha-amino acids.

    Science.gov (United States)

    Grauer, Andreas A; Cabrele, Chiara; Zabel, Manfred; König, Burkhard

    2009-05-15

    Short peptidomimetics with stable secondary structures in solution are of interest for applications in chemistry, biology, and medicine. One way to rigidify the backbone of a peptide is the use of cyclic C(alpha)-tetrasubstituted alpha-amino acids (TAAs) like compound 14. The structures resulting from the incorporation of this unnatural amino acid into peptides were investigated. In total, 13 different peptides with a length of up to eight residues and alternating sequences of TAA 14 and (S)- or (R)-valine were synthesized. Their structures were characterized by X-ray diffraction analysis and NMR and CD measurements showing that the all-S-backbone-configured peptides 5 and 6 (SS)(2-3) form right-handed 3(10)-helices, while the all-R-configured peptides 11-13 (RR)(2-4) form left-handed 3(10)-helices in the solid state and solution.

  2. Biosynthesis of cardiac natriuretic peptides

    DEFF Research Database (Denmark)

    Goetze, Jens Peter

    2010-01-01

    . An inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly...

  3. Isolation of a Cyclic (Alkyl(aminogermylene

    Directory of Open Access Journals (Sweden)

    Liliang Wang

    2016-07-01

    Full Text Available A 1,4-addition of a dichlorogermylene dioxane complex with α,β-unsaturated imine 1 gave a dichlorogermane derivative 2 bearing a GeC3N five-membered ring skeleton. By reducing 2 with KC8, cyclic (alkyl(aminogermylene 3 was synthesized and fully characterized. Germylene 3 readily reacted with TEMPO, N2O and S8, producing the 1:2 adduct 4, the oxo-bridged dimer 5 and the sulfido-bridged dimer 6, respectively.

  4. Periodic cyclic homology of affine Hecke algebras

    CERN Document Server

    Solleveld, Maarten

    2009-01-01

    This is the author's PhD-thesis, which was written in 2006. The version posted here is identical to the printed one. Instead of an abstract, the short list of contents: Preface 5 1 Introduction 9 2 K-theory and cyclic type homology theories 13 3 Affine Hecke algebras 61 4 Reductive p-adic groups 103 5 Parameter deformations in affine Hecke algebras 129 6 Examples and calculations 169 A Crossed products 223 Bibliography 227 Index 237 Samenvatting 245 Curriculum vitae 253

  5. Cyclic groups and quantum logic gates

    Science.gov (United States)

    Pourkia, Arash; Batle, J.; Raymond Ooi, C. H.

    2016-10-01

    We present a formula for an infinite number of universal quantum logic gates, which are 4 by 4 unitary solutions to the Yang-Baxter (Y-B) equation. We obtain this family from a certain representation of the cyclic group of order n. We then show that this discrete family, parametrized by integers n, is in fact, a small sub-class of a larger continuous family, parametrized by real numbers θ, of universal quantum gates. We discuss the corresponding Yang-Baxterization and related symmetries in the concomitant Hamiltonian.

  6. A cyclic universe approach to fine tuning

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, Stephon, E-mail: stephon.alexander@dartmouth.edu [Department of Physics and Astronomy, Dartmouth College, Hanover, NH 03755 (United States); Department of Physics, Brown University, Providence, RI 02906 (United States); Cormack, Sam, E-mail: samuel.c.cormack.gr@dartmouth.edu [Department of Physics and Astronomy, Dartmouth College, Hanover, NH 03755 (United States); Gleiser, Marcelo, E-mail: marcelo.gleiser@dartmouth.edu [Department of Physics and Astronomy, Dartmouth College, Hanover, NH 03755 (United States)

    2016-06-10

    We present a closed bouncing universe model where the value of coupling constants is set by the dynamics of a ghost-like dilatonic scalar field. We show that adding a periodic potential for the scalar field leads to a cyclic Friedmann universe where the values of the couplings vary randomly from one cycle to the next. While the shuffling of values for the couplings happens during the bounce, within each cycle their time-dependence remains safely within present observational bounds for physically-motivated values of the model parameters. Our model presents an alternative to solutions of the fine tuning problem based on string landscape scenarios.

  7. Simple Current Actions of Cyclic Groups

    CERN Document Server

    Varga, T

    2004-01-01

    Permutation actions of simple currents on the primaries of a Rational Conformal Field Theory are considered in the framework of admissible weighted permutation actions. The solution of admissibility conditions is presented for cyclic quadratic groups: an irreducible WPA corresponds to each subgroup of the quadratic group. As a consequence, the primaries of a RCFT with an order n integral or half-integral spin simple current may be arranged into multiplets of length k^2 (where k is a divisor of n) or 3k^2 if the spin of the simple current is half-integral and k is odd.

  8. Peptide vectors for gene delivery: from single peptides to multifunctional peptide nanocarriers.

    Science.gov (United States)

    Raad, Markus de; Teunissen, Erik A; Mastrobattista, Enrico

    2014-07-01

    The therapeutic use of nucleic acids relies on the availability of sophisticated delivery systems for targeted and intracellular delivery of these molecules. Such a gene delivery should possess essential characteristics to overcome several extracellular and intracellular barriers. Peptides offer an attractive platform for nonviral gene delivery, as several functional peptide classes exist capable of overcoming these barriers. However, none of these functional peptide classes contain all the essential characteristics required to overcome all of the barriers associated with successful gene delivery. Combining functional peptides into multifunctional peptide vectors will be pivotal for improving peptide-based gene delivery systems. By using combinatorial strategies and high-throughput screening, the identification of multifunctional peptide vectors will accelerate the optimization of peptide-based gene delivery systems.

  9. 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.

  10. CyclicCO2R: production of cyclic carbonates from CO2 using renewable feedstocks

    NARCIS (Netherlands)

    Kimball, E.; Schuurbiers, C.A.H.; Zevenbergen, J.F.; Håkonsen, S.F.; Heyn, R.; Offermans, W.; Leitner, W.; Ostapowicz, T.; Müller, T. E.; Mul, G.; North, M.; Ngomsik-Fanselow, A.F.; Sarron, E.; Sigurbjörnsson, O.; Schäffner, B.

    2013-01-01

    The consortium behind CyclicCO2R wants to kick-start the implementation of CO2 utilization technologies by converting CO2 into a high value-added product, thus providing a showcase that inspires industry to further develop technologies utilizing CO2 as a sustainable raw material and valorizing CO2 i

  11. Effects of cationic antimicrobial peptides on liquid-preserved boar spermatozoa.

    Science.gov (United States)

    Schulze, Martin; Junkes, Christof; Mueller, Peter; Speck, Stephanie; Ruediger, Karin; Dathe, Margitta; Mueller, Karin

    2014-01-01

    Antibiotics are mandatory additives in semen extenders to control bacterial contamination. The worldwide increase in resistance to conventional antibiotics requires the search for alternatives not only for animal artificial insemination industries, but also for veterinary and human medicine. Cationic antimicrobial peptides are of interest as a novel class of antimicrobial additives for boar semen preservation. The present study investigated effects of two synthetic cyclic hexapeptides (c-WFW, c-WWW) and a synthetic helical magainin II amide derivative (MK5E) on boar sperm during semen storage at 16 °C for 4 days. The standard extender, Beltsville Thawing Solution (BTS) containing 250 µg/mL gentamicin (standard), was compared to combinations of BTS with each of the peptides in a split-sample procedure. Examination revealed peptide- and concentration-dependent effects on sperm integrity and motility. Negative effects were more pronounced for MK5E than in hexapeptide-supplemented samples. The cyclic hexapeptides were partly able to stimulate a linear progressive sperm movement. When using low concentrations of cyclic hexapeptides (4 µM c-WFW, 2 µM c-WWW) sperm quality was comparable to the standard extender over the course of preservation. C-WFW-supplemented boar semen resulted in normal fertility rates after AI. In order to investigate the interaction of peptides with the membrane, electron spin resonance spectroscopic measurements were performed using spin-labeled lipids. C-WWW and c-WFW reversibly immobilized an analog of phosphatidylcholine (PC), whereas MK5E caused an irreversible increase of PC mobility. These results suggest testing the antimicrobial efficiency of non-toxic concentrations of selected cyclic hexapeptides as potential candidates to supplement/replace common antibiotics in semen preservation.

  12. Effects of cationic antimicrobial peptides on liquid-preserved boar spermatozoa.

    Directory of Open Access Journals (Sweden)

    Martin Schulze

    Full Text Available Antibiotics are mandatory additives in semen extenders to control bacterial contamination. The worldwide increase in resistance to conventional antibiotics requires the search for alternatives not only for animal artificial insemination industries, but also for veterinary and human medicine. Cationic antimicrobial peptides are of interest as a novel class of antimicrobial additives for boar semen preservation. The present study investigated effects of two synthetic cyclic hexapeptides (c-WFW, c-WWW and a synthetic helical magainin II amide derivative (MK5E on boar sperm during semen storage at 16 °C for 4 days. The standard extender, Beltsville Thawing Solution (BTS containing 250 µg/mL gentamicin (standard, was compared to combinations of BTS with each of the peptides in a split-sample procedure. Examination revealed peptide- and concentration-dependent effects on sperm integrity and motility. Negative effects were more pronounced for MK5E than in hexapeptide-supplemented samples. The cyclic hexapeptides were partly able to stimulate a linear progressive sperm movement. When using low concentrations of cyclic hexapeptides (4 µM c-WFW, 2 µM c-WWW sperm quality was comparable to the standard extender over the course of preservation. C-WFW-supplemented boar semen resulted in normal fertility rates after AI. In order to investigate the interaction of peptides with the membrane, electron spin resonance spectroscopic measurements were performed using spin-labeled lipids. C-WWW and c-WFW reversibly immobilized an analog of phosphatidylcholine (PC, whereas MK5E caused an irreversible increase of PC mobility. These results suggest testing the antimicrobial efficiency of non-toxic concentrations of selected cyclic hexapeptides as potential candidates to supplement/replace common antibiotics in semen preservation.

  13. A cyclically actuated electrolytic drug delivery device

    KAUST Repository

    Yi, Ying

    2015-01-01

    This work, focusing on an implantable drug delivery system, presents the first prototype electrolytic pump that combines a catalytic reformer and a cyclically actuated mode. These features improve the release performance and extend the lifetime of the device. Using our platinum (Pt)-coated carbon fiber mesh that acts as a catalytic reforming element, the cyclical mode is improved because the faster recombination rate allows for a shorter cycling time for drug delivery. Another feature of our device is that it uses a solid-drug-in-reservoir (SDR) approach, which allows small amounts of a solid drug to be dissolved in human fluid, forming a reproducible drug solution for long-term therapies. We have conducted proof-of-principle drug delivery studies using such an electrolytic pump and solvent blue 38 as the drug substitute. These tests demonstrate power-controlled and pulsatile release profiles of the chemical substance, as well as the feasibility of this device. A drug delivery rate of 11.44 ± 0.56 μg min-1 was achieved by using an input power of 4 mW for multiple pulses, which indicates the stability of our system. © The Royal Society of Chemistry 2015.

  14. Cyclic integrals and reduction of rotational relativistic Birkhoffian system

    Institute of Scientific and Technical Information of China (English)

    罗绍凯

    2003-01-01

    The order reduction method of the rotational relativistic Birkhoffian equations is studied. For a rotational relativistic Birkhoffian system, the cyclic integrals can be found by using the perfect differential method. Through these cyclic integrals, the order of the system can be reduced. If the rotational relativistic Birkhoffian system has a cyclic integral, then the Birkhoffian equations can be reduced at least two degrees and the Birkhoffian form can be kept. An example is given to illustrate the application of the results.

  15. Cyclic Voltammetry of Polysulfide (Thiokol) Prepolymers and Related Compounds

    Science.gov (United States)

    1983-12-01

    low scan rates suqges t that A and B are unstable and undergo chesical reactions on the cyclic voltametry time scale. A more detailed examination is...REPOR CYCLIC VOLTAq4ETRY OF POLYSIILF!OE (THIOKOL) PREPOLYMERS AND~ RELATED COMPODWS Waldemar Nazurek ThE UPrEDT STATES NATIONAL. CZTECMNNCAL...DEPARTMENT OF DEFENCE MATERIALS RESEARCH LABORATORIES REPORT MRL-R.911 CYCLIC VOLTAP,4ETRY OF POLYSULFIDE (THIOKOL) PREPOLYMERS AND RELATEn COMPOUNDS 𔃻

  16. Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients

    Science.gov (United States)

    Wang, Conan K.; Northfield, Susan E.; Colless, Barbara; Chaousis, Stephanie; Hamernig, Ingrid; Lohman, Rink-Jan; Nielsen, Daniel S.; Schroeder, Christina I.; Liras, Spiros; Price, David A.; Fairlie, David P.; Craik, David J.

    2014-01-01

    Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog. PMID:25416591

  17. Abiotic Formation of Valine Peptides Under Conditions of High Temperature and High Pressure

    Science.gov (United States)

    Furukawa, Yoshihiro; Otake, Tsubasa; Ishiguro, Takato; Nakazawa, Hiromoto; Kakegawa, Takeshi

    2012-12-01

    We investigated the oligomerization of solid valine and the stabilities of valine and valine peptides under conditions of high temperature (150-200 °C) and high pressure (50-150 MPa). Experiments were performed under non-aqueous condition in order to promote dehydration reaction. After prolonged exposure of monomeric valine to elevated temperatures and pressures, the products were analyzed by liquid chromatography mass spectrometry comparing their retention times and masses. We identified linear peptides that ranged in size from dimer to hexamer, as well as a cyclic dimer. Previous studies that attempted abiotic oligomerization of valine in the absence of a catalyst have never reported valine peptides larger than a dimer. Increased reaction temperature increased the dissociative decomposition of valine and valine peptides to products such as glycine, β-alanine, ammonia, and amines by processes such as deamination, decarboxylation, and cracking. The amount of residual valine and peptide yields was greater at higher pressures at a given temperature, pressure, and reaction time. This suggests that dissociative decomposition of valine and valine peptides is reduced by pressure. Our findings are relevant to the investigation of diagenetic processes in prebiotic marine sediments where similar pressures occur under water-poor conditions. These findings also suggest that amino acids, such as valine, could have been polymerized to peptides in deep prebiotic marine sediments within a few hundred million years.

  18. Abiotic formation of valine peptides under conditions of high temperature and high pressure.

    Science.gov (United States)

    Furukawa, Yoshihiro; Otake, Tsubasa; Ishiguro, Takato; Nakazawa, Hiromoto; Kakegawa, Takeshi

    2012-12-01

    We investigated the oligomerization of solid valine and the stabilities of valine and valine peptides under conditions of high temperature (150-200 °C) and high pressure (50-150 MPa). Experiments were performed under non-aqueous condition in order to promote dehydration reaction. After prolonged exposure of monomeric valine to elevated temperatures and pressures, the products were analyzed by liquid chromatography mass spectrometry comparing their retention times and masses. We identified linear peptides that ranged in size from dimer to hexamer, as well as a cyclic dimer. Previous studies that attempted abiotic oligomerization of valine in the absence of a catalyst have never reported valine peptides larger than a dimer. Increased reaction temperature increased the dissociative decomposition of valine and valine peptides to products such as glycine, β-alanine, ammonia, and amines by processes such as deamination, decarboxylation, and cracking. The amount of residual valine and peptide yields was greater at higher pressures at a given temperature, pressure, and reaction time. This suggests that dissociative decomposition of valine and valine peptides is reduced by pressure. Our findings are relevant to the investigation of diagenetic processes in prebiotic marine sediments where similar pressures occur under water-poor conditions. These findings also suggest that amino acids, such as valine, could have been polymerized to peptides in deep prebiotic marine sediments within a few hundred million years.

  19. Probing the bioactive conformation of an archetypal natural product HDAC inhibitor with conformationally homogeneous triazole-modified cyclic tetrapeptides.

    Science.gov (United States)

    Horne, W Seth; Olsen, Christian A; Beierle, John M; Montero, Ana; Ghadiri, M Reza

    2009-01-01

    Fooling enzymes with mock amides: Analogues of apicidin, a cyclic-tetrapeptide inhibitor of histone deacetylase (HDAC), were designed with a 1,4- or 1,5-disubstituted 1,2,3-triazole in place of a backbone amide bond to fix the bond in question in either a trans-like or a cis-like configuration. Thus, the binding affinity of distinct peptide conformations (see picture) could be probed. One analogue proved in some cases to be superior to apicidin as an HDAC inhibitor.

  20. cis-Apa: a practical linker for the microwave-assisted preparation of cyclic pseudopeptides via RCM cyclative cleavage.

    Science.gov (United States)

    Baron, Alice; Verdié, Pascal; Martinez, Jean; Lamaty, Frédéric

    2011-02-04

    A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.

  1. APD: the Antimicrobial Peptide Database.

    Science.gov (United States)

    Wang, Zhe; Wang, Guangshun

    2004-01-01

    An antimicrobial peptide database (APD) has been established based on an extensive literature search. It contains detailed information for 525 peptides (498 antibacterial, 155 antifungal, 28 antiviral and 18 antitumor). APD provides interactive interfaces for peptide query, prediction and design. It also provides statistical data for a select group of or all the peptides in the database. Peptide information can be searched using keywords such as peptide name, ID, length, net charge, hydrophobic percentage, key residue, unique sequence motif, structure and activity. APD is a useful tool for studying the structure-function relationship of antimicrobial peptides. The database can be accessed via a web-based browser at the URL: http://aps.unmc.edu/AP/main.html.

  2. Cyclic cocycles on deformation quantizations and higher index theorems

    CERN Document Server

    Pflaum, M; Tang, X

    2008-01-01

    We construct a nontrivial cyclic cocycle on the Weyl algebra of a symplectic vector space. Using this cyclic cocycle we construct an explicit, local, quasi-isomorphism from the complex of differential forms on a symplectic manifold to the complex of cyclic cochains of any formal deformation quantization thereof. We prove an algebraic higher index theorem by computing the pairing between such cyclic cocycles and the $K$-theory of the formal deformation quantization. As an application, we obtain the analytic higher index theorem of Connes--Moscovici.

  3. Cyclic structures in algebraic (co)homology theories

    CERN Document Server

    Kowalzig, Niels

    2010-01-01

    This note discusses the cyclic cohomology of a left Hopf algebroid ($\\times_A$-Hopf algebra) with coefficients in a right module-left comodule, defined using a straightforward generalisation of the original operators given by Connes and Moscovici for Hopf algebras. Lie-Rinehart homology is a special case of this theory. A generalisation of cyclic duality that makes sense for arbitrary para-cyclic objects yields a dual homology theory. The twisted cyclic homology of an associative algebra provides an example of this dual theory that uses coefficients that are not necessarily stable anti Yetter-Drinfel'd modules.

  4. 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.

  5. Antimicrobial peptides in Echinoderms

    Directory of Open Access Journals (Sweden)

    C Li

    2010-05-01

    Full Text Available Antimicrobial peptides (AMPs are important immune effector molecules for invertebrates, including echinoderms, which lack a vertebrate-type adaptive immune system. Here we summarize the knowledge of such peptides in echinoderms. Strongylocins are a novel family of cysteine-rich AMPs, recently identified in the sea urchins, Strongylocentrotus droebachiensis and S. purpuratus. Although these molecules present diverse amino acid sequences, they share an identical cysteine arrangement pattern, dissimilar to other known AMPs. A family of heterodimeric AMPs, named centrocins, are also present in S. droebachiensis. Lysozymes and fragments of larger proteins, such as beta-thymocins, actin, histone 2A and filamin A have also been shown to display antimicrobial activities in echinoderms. Future studies on AMPs should be aimed in revealing how echinoderms use these AMPs in the immune response against microbial pathogens.

  6. Avian host defense peptides.

    Science.gov (United States)

    Cuperus, Tryntsje; Coorens, Maarten; van Dijk, Albert; Haagsman, Henk P

    2013-11-01

    Host defense peptides (HDPs) are important effector molecules of the innate immune system of vertebrates. These antimicrobial peptides are also present in invertebrates, plants and fungi. HDPs display broad-spectrum antimicrobial activities and fulfill an important role in the first line of defense of many organisms. It is becoming increasingly clear that in the animal kingdom the functions of HDPs are not confined to direct antimicrobial actions. Research in mammals has indicated that HDPs have many immunomodulatory functions and are also involved in other physiological processes ranging from development to wound healing. During the past five years our knowledge about avian HDPs has increased considerably. This review addresses our current knowledge on the evolution, regulation and biological functions of HDPs of birds.

  7. Peptides and Food Intake

    OpenAIRE

    Carmen Sobrino Crespo; Aranzazu Perianes Cachero; Lilian Puebla Jiménez; Vicente eBarrios; Eduardo eArilla

    2014-01-01

    The mechanisms for controlling food intake involve mainly an interplay between gut, brain, and adipose tissue (AT), among the major organs. Parasympathetic, sympathetic, and other systems are required for communication between the brain satiety center, gut, and AT. These neuronal circuits include a variety of peptides and hormones, being ghrelin the only orexigenic molecule known, whereas the plethora of other factors are inhibitors of appetite, suggesting its physiological relevance in the r...

  8. Interaction between integrin a Ⅱbβ 3 and synthesized cyclic hexapeptide containing RGD

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The RGD sequence generally exists in the extracellular matrix proteins and can be recognized by many integrin proteins. The binding ability of immobilized biotinylated cyclic hexapeptide [cyclo(-Arg-Gly-Asp-D-Phe-Lys-Gly-)] containing RGD to integrin a ab β3 was tested by the methods of ELISA and SPR. Results showed that a spacer of 1.48-2.2 nm between the peptide and the biotin residue was long enough to send the RGD sequence into the binding center embedded within a Ⅱbβ 3, and the equilibrium dissociation constant was 1.1 μm. The work provides an ideal model system for the research of cell adhesion on solid surfaces.

  9. Synthesis and structure-activity relationship study of organometallic bioconjugates of the cyclic octapeptide octreotate.

    Science.gov (United States)

    Gross, Annika; Habig, Daniel; Metzler-Nolte, Nils

    2013-12-16

    The chemically stabilized somatostatin-derived cyclic octapeptide octreotate has a number of interesting applications in medicinal chemistry. Here, a number of different organometallic derivatives of octreotate were prepared, and their properties were investigated. Specifically, we report the synthesis and characterization of ruthenocene, ferrocene, and cobaltocenium octreotate derivatives and their fluorophore-labeled conjugates as well as a dicobalt hexacarbonyl alkyne functionalized octreotate. To provide further insights into their characteristics, the log P values and electrochemical properties of the novel metal conjugates were compared. For biological activity, we determined their toxicity in three different cell lines. Cellular uptake and colocalization of selected compounds were studied by fluorescence microscopy with particular focus on efficiency and specificity of their uptake through the somatostatin receptor SSTR to elucidate the value of the metallocene head group for its potential use as a nontoxic and universal peptide label.

  10. [C-peptide physiological effects].

    Science.gov (United States)

    Shpakov, A O; Granstrem, O K

    2013-02-01

    In the recent years there were numerous evidences that C-peptide, which was previously considered as a product of insulin biosynthesis, is one of the key regulators of physiological processes. C-peptide via heterotrimeric G(i/o) protein-coupled receptors activates a wide range of intracellular effector proteins and transcription factors and, thus, controls the inflammatory and neurotrophic processes, pain sensitivity, cognitive function, macro- and microcirculation, glomerular filtration. These effects of C-peptide are mainly expressed in its absolute or relative deficiency occurred in type 1 diabetes mellitus and they are less pronounced when the level of C-peptide is close to normal. Replacement therapy with C-peptide prevents many complications of type 1 diabetes, such as atherosclerosis, diabetic peripheral neuropathy, and nephropathy. C-peptide interacts with the insulin hexamer complexes and induces their dissociation and, as a result, regulates the functional activity of the insulin signaling system. At the same time, C-peptide at the concentrations above physiological may demonstrate pro-inflammatory effects on the endothelial cells and cause atherosclerotic changes in the vessels, which should be considered in the study of pathogenic mechanisms of complications of type 2 diabetes mellitus, where the level of C peptide is increased, as well as in the development of approaches for C-peptide application in clinic. This review is devoted contemporary achievements and unsolved problems in the study of C-peptide, as an important regulator of physiological and biochemical processes.

  11. Corrosive electrochemistry of jamesonite by cyclic voltammetry

    Institute of Scientific and Technical Information of China (English)

    余润兰; 胡岳华; 邱冠周; 覃文庆

    2004-01-01

    The corrosive electrochemistry of jamesonite was studied by cyclic voltammetry. Every peak in voltammograms was identified through thermodynamic calculation. The results show an irreversible electrode process by the strong adsorption of oxidation elemental sulfur on jamesonite. A deficient-metal and sulfur-rich compound is formed under the potential of 80 mV at pH 6.86. The passive action by elemental sulfur occurs from 80 to 470 mV and S2O23- , SO24- are produced at potential over 470 mV. The anodic peak producing SO24- is inhibited due to the deposition of PbSO4 at higher potential in Na2SO4 solution. The corrosive action of jamesonite becomes strong and the redox characterization similar to PbS, FeS and Sb2 S3 appears at pH 9.18.

  12. Bucket foundations under lateral cyclic loading

    DEFF Research Database (Denmark)

    Foglia, Aligi

    -competitive in the energy market. This thesis addresses issues concerning monopod bucket foundations in the hope of providing tools and ideas that could be used to optimize the design of this sub-structure. The work is focussed on the behaviour of bucket foundations under lateral cyclic loading. Other related......To enable a prosperous development of offshore wind energy, economically feasible technologies must be developed. The monopod bucket foundation is likely to become a cost-effective sub-structure for offshore wind turbines and has the potential to make offshore wind more cost...... and propaedeutic topics, such as bucket foundations under transient lateral loading and under monotonic lateral loading, are also investigated. All the scientific work is fundamentally based on small-scale experimental tests of bucket foundations in dense water-saturated sand. The most important scientific...

  13. Numerical Simulation of Cyclic Thermodynamic Processes

    DEFF Research Database (Denmark)

    Andersen, Stig Kildegård

    2006-01-01

    This thesis is on numerical simulation of cyclic thermodynamic processes. A modelling approach and a method for finding periodic steady state solutions are described. Examples of applications are given in the form of four research papers. Stirling machines and pulse tube coolers are introduced...... and a brief overview of the current state of the art in methods for simulating such machines is presented. It was found that different simulation approaches, which model the machines with different levels of detail, currently coexist. Methods using many simplifications can be easy to use and can provide...... results quickly, but they are limited with respect to the phenomena that can be studied. More comprehensive methods can be used to study and optimise machines or components in more detail, but they usually require more time and computer resources. In this work the focus was on methods that are fast enough...

  14. Extinction in four species cyclic competition

    Science.gov (United States)

    Intoy, Ben; Pleimling, Michel

    2013-08-01

    When four species compete stochastically in a cyclic way, the formation of two teams of mutually neutral partners is observed. In this paper we study through numerical simulations the extinction processes that can take place in this system both in the well mixed case as well as on different types of lattices. The different routes to extinction are revealed by the probability distribution of the domination time, i.e. the time needed for one team to fully occupy the system. If swapping is allowed between neutral partners, then the probability distribution is dominated by very long-lived states where a few very large domains persist, each domain being occupied by a mix of individuals from species that form one of the teams. Many aspects of the possible extinction scenarios are lost when only considering averaged quantities, such as for example the mean domination time.

  15. Pyroelectric Harvesters for Generating Cyclic Energy

    Directory of Open Access Journals (Sweden)

    Chun-Ching Hsiao

    2015-04-01

    Full Text Available Pyroelectric energy conversion is a novel energy process which directly transforms waste heat energy from cyclic heating into electricity via the pyroelectric effect. Application of a periodic temperature profile to pyroelectric cells is necessary to achieve temperature variation rates for generating an electrical output. The critical consideration in the periodic temperature profile is the frequency or work cycle which is related to the properties and dimensions of the air layer; radiation power and material properties, as well as the dimensions and structure of the pyroelectric cells. This article aims to optimize pyroelectric harvesters by matching all these requirements. The optimal induced charge per period increases about 157% and the efficient period band decreases about 77%, when the thickness of the PZT cell decreases from 200 μm to 50 μm, about a 75% reduction. Moreover, when using the thinner PZT cell for harvesting the pyroelectric energy it is not easy to focus on a narrow band with the efficient period. However, the optimal output voltage and stored energy per period decrease about 50% and 74%, respectively, because the electrical capacitance of the 50 μm thick pyroelectric cell is about four times greater than that of the 200 μm thick pyroelectric cell. In addition, an experiment is used to verify that the work cycle to be able to critically affect the efficiency of PZT pyroelectric harvesters. Periods in the range between 3.6 s and 12.2 s are useful for harvesting thermal cyclic energy by pyroelectricity. The optimal frequency or work cycle can be applied in the design of a rotating shutter in order to control the heated and unheated periods of the pyroelectric cells to further enhance the amount of stored energy.

  16. Oxidation of Disulfides to Thiolsulfinates with Hydrogen Peroxide and a Cyclic Seleninate Ester Catalyst.

    Science.gov (United States)

    McNeil, Nicole M R; McDonnell, Ciara; Hambrook, Miranda; Back, Thomas G

    2015-06-11

    Cyclic seleninate esters function as mimetics of the antioxidant selenoenzyme glutathione peroxidase. They catalyze the reduction of harmful peroxides with thiols, which are converted to disulfides in the process. The possibility that the seleninate esters could also catalyze the further oxidation of disulfides to thiolsulfinates and other overoxidation products under these conditions was investigated. This has ramifications in potential medicinal applications of seleninate esters because of the possibility of catalyzing the unwanted oxidation of disulfide-containing spectator peptides and proteins. A variety of aryl and alkyl disulfides underwent facile oxidation with hydrogen peroxide in the presence of catalytic benzo-1,2-oxaselenolane Se-oxide affording the corresponding thiolsulfinates as the principal products. Unsymmetrical disulfides typically afforded mixtures of regioisomers. Lipoic acid and N,N'-dibenzoylcystine dimethyl ester were oxidized readily under similar conditions. Although isolated yields of the product thiolsulfinates were generally modest, these experiments demonstrate that the method nevertheless has preparative value because of its mild conditions. The results also confirm the possibility that cyclic seleninate esters could catalyze the further undesired oxidation of disulfides in vivo.

  17. Classifying Spaces with Virtually Cyclic Stabilisers for Certain Infinite Cyclic Extensions

    CERN Document Server

    Fluch, Martin

    2010-01-01

    Let G be an infinite cyclic extension, 1 -> B -> G -> Z -> 1, of a group B where the action of Z on the set of conjugacy classes of non-trivial elements of B is free. This class of groups includes certain ascending HNN-extensions with abelian or free base groups, certain wreath products by Z and the soluble Baumslag--Solitar groups BS(1,m) with |m|> 1. We construct a model for Evc(G), the classifying space of G for the family of virtually cyclic subgroups of G, and give bounds for the minimum dimension of Evc(G). We construct a 2-dimensional model for Evc(G) where G is a soluble Baumslag-Solitar BS(1,m) group with |m|>1 and we show that this model for Evc(G) is of minimal dimension.

  18. CYCLIC VECTORS AND CELLULAR INDECOMPOSABLE OPERATORS ON Qp SPACES

    Institute of Scientific and Technical Information of China (English)

    Ye Shanli; Lou Zengjian

    2011-01-01

    We identify the functions whose polynomial multiples are weak* dense in Qp spaces and prove that if |f(z)|≥|g(z)| and g is cyclic in Qp, then f is cyclic in Qp. We also show that the multiplication operator Mz on Qp spaces is cellular indecomposable.

  19. Classifying spaces with virtually cyclic stabilizers for linear groups

    DEFF Research Database (Denmark)

    Degrijse, Dieter Dries; Köhl, Ralf; Petrosyan, Nansen

    2015-01-01

    We show that every discrete subgroup of GL(n, ℝ) admits a finite-dimensional classifying space with virtually cyclic stabilizers. Applying our methods to SL(3, ℤ), we obtain a four-dimensional classifying space with virtually cyclic stabilizers and a decomposition of the algebraic K-theory of its...

  20. Development of Pore Pressure and Material Damping during Cyclic Loading

    DEFF Research Database (Denmark)

    Ibsen, Lars Bo

    1994-01-01

    The behaviour of sand during cyclic loading can be characterized as "stabilization", "instant stabilization". "pore pressure buildup" and "liquefaction". The terminologies can be defined exactly by a simple mathematical formulation based on the existence of a cyclic stable state. By introducing a...

  1. Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome.

    Science.gov (United States)

    Abdul-Sater, Ali A; Tattoli, Ivan; Jin, Lei; Grajkowski, Andrzej; Levi, Assaf; Koller, Beverly H; Allen, Irving C; Beaucage, Serge L; Fitzgerald, Katherine A; Ting, Jenny P-Y; Cambier, John C; Girardin, Stephen E; Schindler, Christian

    2013-10-01

    The cyclic dinucleotides 3'-5'diadenylate (c-diAMP) and 3'-5' diguanylate (c-diGMP) are important bacterial second messengers that have recently been shown to stimulate the secretion of type I Interferons (IFN-Is) through the c-diGMP-binding protein MPYS/STING. Here, we show that physiologically relevant levels of cyclic dinucleotides also stimulate a robust secretion of IL-1β through the NLRP3 inflammasome. Intriguingly, this response is independent of MPYS/STING. Consistent with most NLRP3 inflammasome activators, the response to c-diGMP is dependent on the mobilization of potassium and calcium ions. However, in contrast to other NLRP3 inflammasome activators, this response is not associated with significant changes in mitochondrial potential or the generation of mitochondrial reactive oxygen species. Thus, cyclic dinucleotides activate the NLRP3 inflammasome through a unique pathway that could have evolved to detect pervasive bacterial pathogen-associated molecular patterns associated with intracellular infections.

  2. Conformational analysis of PKI(5-22)amide, the active inhibitory fragment of the inhibitor protein of the cyclic AMP-dependent protein kinase.

    Science.gov (United States)

    Reed, J; De Ropp, J S; Trewhella, J; Glass, D B; Liddle, W K; Bradbury, E M; Kinzel, V; Walsh, D A

    1989-12-01

    Fourier-transform i.r. spectroscopy, 1H-n.m.r. spectroscopy and X-ray scattering were used to study the conformation and shape of the peptide PKI(5-22)amide, which contains the active site of the inhibitor protein of the cyclic AMP-dependent protein kinase [Cheng, Van Pattern, Smith & Walsh (1985) Biochem. J. 231, 655-661]. The X-ray-scattering solution studies show that the peptide has a compact structure with Rg 0.9 nm (9.0 A) and a linear maximum dimension of 2.5 nm (25A). Compatible with this, Fourier-transform i.r. and n.m.r. determinations indicate that the peptide contains approx. 26% alpha-helix located in the N-terminal one-third of the molecule. This region contains the phenylalanine residue that is one essential recognition determinant for high-affinity binding to the protein kinase catalytic site.

  3. 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...

  4. Improving Peptide Applications Using Nanotechnology.

    Science.gov (United States)

    Narayanaswamy, Radhika; Wang, Tao; Torchilin, Vladimir P

    2016-01-01

    Peptides are being successfully used in various fields including therapy and drug delivery. With advancement in nanotechnology and targeted delivery carrier systems, suitable modification of peptides has enabled achievement of many desirable goals over-riding some of the major disadvantages associated with the delivery of peptides in vivo. Conjugation or physical encapsulation of peptides to various nanocarriers, such as liposomes, micelles and solid-lipid nanoparticles, has improved their in vivo performance multi-fold. The amenability of peptides to modification in chemistry and functionalization with suitable nanocarriers are very relevant aspects in their use and have led to the use of 'smart' nanoparticles with suitable linker chemistries that favor peptide targeting or release at the desired sites, minimizing off-target effects. This review focuses on how nanotechnology has been used to improve the number of peptide applications. The paper also focuses on the chemistry behind peptide conjugation to nanocarriers, the commonly employed linker chemistries and the several improvements that have already been achieved in the areas of peptide use with the help of nanotechnology.

  5. Antitumor Peptides from Marine Organisms

    Directory of Open Access Journals (Sweden)

    Mi Sun

    2011-10-01

    Full Text Available The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides.

  6. The Pig PeptideAtlas

    DEFF Research Database (Denmark)

    Hesselager, Marianne Overgaard; Codrea, Marius; Sun, Zhi;

    2016-01-01

    underrepresented in existing repositories. We here present a significantly improved build of the Pig PeptideAtlas, which includes pig proteome data from 25 tissues and three body fluid types mapped to 7139 canonical proteins. The content of the Pig PeptideAtlas reflects actively ongoing research within...... the veterinary proteomics domain, and this article demonstrates how the expression of isoform-unique peptides can be observed across distinct tissues and body fluids. The Pig PeptideAtlas is a unique resource for use in animal proteome research, particularly biomarker discovery and for preliminary design of SRM...

  7. 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.......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....

  8. Isolation and Partial Characterization of a Cyclic GMP-Dependent Cyclic GMP-Specific Phosphodiesterase from Dictyostelium discoideum

    NARCIS (Netherlands)

    Bulgakov, Roman; Haastert, Peter J.M. van

    1983-01-01

    The cellular slime mold, Dictyostelium discoideum, contains at least two classes of phosphodiesterase activity. One class of enzymes hydrolyses cyclic AMP (cAMP) and cyclic GMP (cGMP) with approximately equal rates. Another enzyme, which is less than 5% of the total activity, specifically hydrolyses

  9. Inter-rater reliability of cyclic and non-cyclic task assessment using the hand activity level in appliance manufacturing.

    Science.gov (United States)

    Paulsen, Robert; Schwatka, Natalie; Gober, Jennifer; Gilkey, David; Anton, Dan; Gerr, Fred; Rosecrance, John

    2014-01-01

    This study evaluated the inter-rater reliability of the American Conference of Governmental Industrial Hygienists (ACGIH(®)) hand activity level (HAL), an observational ergonomic assessment method used to estimate physical exposure to repetitive exertions during task performance. Video recordings of 858 cyclic and non-cyclic appliance manufacturing tasks were assessed by sixteen pairs of raters using the HAL visual-analog scale. A weighted Pearson Product Moment-Correlation Coefficient was used to evaluate the agreement between the HAL scores recorded by each rater pair, and the mean weighted correlation coefficients for cyclic and non-cyclic tasks were calculated. Results indicated that the HAL is a reliable exposure assessment method for cyclic (r̄-bar w = 0.69) and non-cyclic work tasks (r̄-bar w = 0.68). When the two reliability scores were compared using a two-sample Student's t-test, no significant difference in reliability (p = 0.63) between these work task categories was found. This study demonstrated that the HAL may be a useful measure of exposure to repetitive exertions during cyclic and non-cyclic tasks.

  10. Synthesis and biological properties of amino acids and peptides containing a tetrazolyl moiety

    Science.gov (United States)

    Popova, E. A.; Trifonov, R. E.

    2015-09-01

    Literature data published mainly in the last 15 years on the synthesis and biological properties of amino acid analogues and derivatives containing tetrazolyl moieties are analyzed. Tetrazolyl analogues and derivatives of amino acids and peptides are shown to be promising for medicinal chemistry. Being polynitrogen heterocyclic systems comprising four endocyclic nitrogen atoms, tetrazoles can behave as acids and bases and form strong hydrogen bonds with proton donors (more rarely, with acceptors). They have high metabolic stability and are able to penetrate biological membranes. The review also considers the synthesis and properties of linear and cyclic peptides based on modified amino acids incorporating a tetrazolyl moiety. A special issue is the discussion of the biological properties of tetrazole-containing amino acids and peptides, which exhibit high biological activity and can be used to design new drugs. The bibliography includes 200 references.

  11. Anticancer peptides from bacteria

    Directory of Open Access Journals (Sweden)

    Tomasz M. Karpiński

    2013-08-01

    Full Text Available Cancer is a leading cause of death in the world. The rapid development of medicine and pharmacology allows to create new and effective anticancer drugs. Among modern anticancer drugs are bacterial proteins. Until now has been shown anticancer activity among others azurin and exotoxin A from Pseudomonas aeruginosa, Pep27anal2 from Streptococcus pneumoniae, diphtheria toxin from Corynebacterium diphtheriae, and recently discovered Entap from Enterococcus sp. The study presents the current data regarding the properties, action and anticancer activity of listed peptides.

  12. Peptides and Food Intake

    Science.gov (United States)

    Sobrino Crespo, Carmen; Perianes Cachero, Aránzazu; Puebla Jiménez, Lilian; Barrios, Vicente; Arilla Ferreiro, Eduardo

    2014-01-01

    The mechanisms for controlling food intake involve mainly an interplay between gut, brain, and adipose tissue (AT), among the major organs. Parasympathetic, sympathetic, and other systems are required for communication between the brain satiety center, gut, and AT. These neuronal circuits include a variety of peptides and hormones, being ghrelin the only orexigenic molecule known, whereas the plethora of other factors are inhibitors of appetite, suggesting its physiological relevance in the regulation of food intake and energy homeostasis. Nutrients generated by food digestion have been proposed to activate G-protein-coupled receptors on the luminal side of enteroendocrine cells, e.g., the L-cells. This stimulates the release of gut hormones into the circulation such as glucagon-like peptide-1 (GLP-1), oxyntomodulin, pancreatic polypeptides, peptide tyrosine tyrosine, and cholecystokinin, which inhibit appetite. Ghrelin is a peptide secreted from the stomach and, in contrast to other gut hormones, plasma levels decrease after a meal and potently stimulate food intake. Other circulating factors such as insulin and leptin relay information regarding long-term energy stores. Both hormones circulate at proportional levels to body fat content, enter the CNS proportionally to their plasma levels, and reduce food intake. Circulating hormones can influence the activity of the arcuate nucleus (ARC) neurons of the hypothalamus, after passing across the median eminence. Circulating factors such as gut hormones may also influence the nucleus of the tractus solitarius (NTS) through the adjacent circumventricular organ. On the other hand, gastrointestinal vagal afferents converge in the NTS of the brainstem. Neural projections from the NTS, in turn, carry signals to the hypothalamus. The ARC acts as an integrative center, with two major subpopulations of neurons influencing appetite, one of them coexpressing neuropeptide Y and agouti-related protein (AgRP) that increases food

  13. Cyclic nucleotide specific phosphodiesterases of Leishmania major

    Directory of Open Access Journals (Sweden)

    Linder Markus

    2006-03-01

    Full Text Available Abstract Background Leishmania represent a complex of important human pathogens that belong to the systematic order of the kinetoplastida. They are transmitted between their human and mammalian hosts by different bloodsucking sandfly vectors. In their hosts, the Leishmania undergo several differentiation steps, and their coordination and optimization crucially depend on numerous interactions between the parasites and the physiological environment presented by the fly and human hosts. Little is still known about the signalling networks involved in these functions. In an attempt to better understand the role of cyclic nucleotide signalling in Leishmania differentiation and host-parasite interaction, we here present an initial study on the cyclic nucleotide-specific phosphodiesterases of Leishmania major. Results This paper presents the identification of three class I cyclic-nucleotide-specific phosphodiesterases (PDEs from L. major, PDEs whose catalytic domains exhibit considerable sequence conservation with, among other, all eleven human PDE families. In contrast to other protozoa such as Dictyostelium, or fungi such as Saccharomyces cerevisiae, Candida ssp or Neurospora, no genes for class II PDEs were found in the Leishmania genomes. LmjPDEA contains a class I catalytic domain at the C-terminus of the polypeptide, with no other discernible functional domains elsewhere. LmjPDEB1 and LmjPDEB2 are coded for by closely related, tandemly linked genes on chromosome 15. Both PDEs contain two GAF domains in their N-terminal region, and their almost identical catalytic domains are located at the C-terminus of the polypeptide. LmjPDEA, LmjPDEB1 and LmjPDEB2 were further characterized by functional complementation in a PDE-deficient S. cerevisiae strain. All three enzymes conferred complementation, demonstrating that all three can hydrolyze cAMP. Recombinant LmjPDEB1 and LmjPDEB2 were shown to be cAMP-specific, with Km values in the low micromolar range

  14. Exploring Protein-Peptide Binding Specificity through Computational Peptide Screening.

    Directory of Open Access Journals (Sweden)

    Arnab Bhattacherjee

    2013-10-01

    Full Text Available The binding of short disordered peptide stretches to globular protein domains is important for a wide range of cellular processes, including signal transduction, protein transport, and immune response. The often promiscuous nature of these interactions and the conformational flexibility of the peptide chain, sometimes even when bound, make the binding specificity of this type of protein interaction a challenge to understand. Here we develop and test a Monte Carlo-based procedure for calculating protein-peptide binding thermodynamics for many sequences in a single run. The method explores both peptide sequence and conformational space simultaneously by simulating a joint probability distribution which, in particular, makes searching through peptide sequence space computationally efficient. To test our method, we apply it to 3 different peptide-binding protein domains and test its ability to capture the experimentally determined specificity profiles. Insight into the molecular underpinnings of the observed specificities is obtained by analyzing the peptide conformational ensembles of a large number of binding-competent sequences. We also explore the possibility of using our method to discover new peptide-binding pockets on protein structures.

  15. Phosphorylated Peptide Functionalization of Lanthanide Upconversion Nanoparticles for Tuning Nanomaterial-Cell Interactions.

    Science.gov (United States)

    Yao, Chi; Wei, Caiyi; Huang, Zhi; Lu, Yiqing; El-Toni, Ahmed Mohamed; Ju, Dianwen; Zhang, Xiangmin; Wang, Wenning; Zhang, Fan

    2016-03-23

    Peptide modification of nanoparticles with high efficiency is critical in determining the properties and bioapplications of nanoparticles, but the methodology remains a challenging task. Here, by using the phosphorylated linear and cyclic peptide with the arginine-glycine-aspartic acid (RGD) targeting motifs as typical examples, the peptides binding efficiency for the inorganic metal compound nanoparticles was increased significantly after the phosphorylation treatment, and the modification allowed for improving the selectivity and signal-to-noise ratio for cancer targeting and reduced the toxicity derived from nonspecific interactions of nanoparticles with cells owing to the higher amount of phosphopeptide binding. In addition, molecular dynamics (MD) simulations of various peptides on inorganic metal compound surfaces revealed that the peptide adsorption on the surface is mainly driven by electrostatic interactions between phosphate oxygen and the polarized interfacial water layer, consistent with the experimental observation of the strong binding propensity of phosphorylated peptides. Significantly, with the RGD phosphopeptide surface modification, these nanoparticles provide a versatile tool for tuning material-cell interactions to achieve the desired level of autophagy and may prove useful for various diagnostic and therapeutic applications.

  16. Charge transport in vertically aligned, self-assembled peptide nanotube junctions

    Science.gov (United States)

    Mizrahi, Mordechay; Zakrassov, Alexander; Lerner-Yardeni, Jenny; Ashkenasy, Nurit

    2012-01-01

    The self-assembly propensity of peptides has been extensively utilized in recent years for the formation of supramolecular nanostructures. In particular, the self-assembly of peptides into fibrils and nanotubes makes them promising building blocks for electronic and electro-optic applications. However, the mechanisms of charge transfer in these wire-like structures, especially in ambient conditions, are not yet fully understood. We describe here a layer-by-layer deposition methodology of short self-assembled cyclic peptide nanotubes, which results in vertically oriented nanotubes on gold substrates. Using this novel deposition methodology, we have fabricated molecular junctions with a conductive atomic force microscopy tip as a second electrode. Studies of the junctions' current-voltage characteristics as a function of the nanotube length revealed an efficient charge transfer in these supramolecular structures, with a low current attenuation constant of 0.1 Å-1, which indicate that electron transfer is dominated by hopping. Moreover, the threshold voltage to field-emission dominated transport was found to increase with peptide length in a manner that depends on the nature of the contact with the electrodes. The flexibility in the design of the peptide monomers and the ability to control their sequential order over the nanotube by means of the layer-by-layer assembly process, which is demonstrated in this work, can be used to engineer the electronic properties of self-assembled peptide nanotubes toward device applications.

  17. Effect of the Peptidic Scaffold in Copper(II) Coordination and the Redox Properties of Short Histidine-Containing Peptides.

    Science.gov (United States)

    Fragoso, Ana; Carvalho, Tiago; Rousselot-Pailley, Pierre; Correia Dos Santos, Margarida M; Delgado, Rita; Iranzo, Olga

    2015-09-07

    A linear decapeptide containing three His and one Asp residues and a β-turn-inducing dProPro unit was synthesised. A detailed potentiometric, mass spectrometric and spectroscopic study showed that at a 1:1 ratio of CCu /Cpeptide this peptide formed a major [CuH(O(dPro)-Asp)](2+) species (pH range 5.5-7.0), in which the Cu(2+) ion was bound to the His and Asp residues in square-planar or square-pyramidal geometries. The stability constant corrected for protonated species (log K* CuH(O dPro-Asp)=9.33) is almost equal to the value obtained for the parent [CuH(OAsp)](2+) species (log K*CuH(O-Asp) =9.28), but lower than that obtained for the cyclic [CuH(C-Asp)](2+) complex (log K*CuH(C-Asp) =10.79) previously published. Thus, the replacement of the ProGly unit by the stronger β-turn-inducing dProPro unit did not generate a more stable copper(II) species, although the O(dPro)-Asp peptide was structured in solution, as shown by circular dichroism (CD) spectroscopy. Interestingly, the calculated value of Keff showed that this peptide behaved similarly to the O-Asp or C-Asp counterparts, depending on the pH value. The cyclic voltammetry data indicated that the most easily reducible species were [CuH(O-Asp)](2+) (E'(0) =262 mV versus a normal hydrogen electrode (NHE)) and [CuH(O(dPro)-Asp)](2+) (E'(0) =294 mV versus NHE) complexes, the peptidic scaffolds of which are open. A lower value was obtained for [CuH(C-Asp)](2+) (E'(0) =24 mV versus NHE). A different degree of non-reversibility was observed for the three copper(II) complexes; this could reflect a different degree of flexibility in their respective peptidic scaffolds.

  18. Genome-based discovery, structure prediction and functional analysis of cyclic lipopeptide antibiotics in Pseudomonas species.

    Science.gov (United States)

    de Bruijn, Irene; de Kock, Maarten J D; Yang, Meng; de Waard, Pieter; van Beek, Teris A; Raaijmakers, Jos M

    2007-01-01

    Analysis of microbial genome sequences have revealed numerous genes involved in antibiotic biosynthesis. In Pseudomonads, several gene clusters encoding non-ribosomal peptide synthetases (NRPSs) were predicted to be involved in the synthesis of cyclic lipopeptide (CLP) antibiotics. Most of these predictions, however, are untested and the association between genome sequence and biological function of the predicted metabolite is lacking. Here we report the genome-based identification of previously unknown CLP gene clusters in plant pathogenic Pseudomonas syringae strains B728a and DC3000 and in plant beneficial Pseudomonas fluorescens Pf0-1 and SBW25. For P. fluorescens SBW25, a model strain in studying bacterial evolution and adaptation, the structure of the CLP with a predicted 9-amino acid peptide moiety was confirmed by chemical analyses. Mutagenesis confirmed that the three identified NRPS genes are essential for CLP synthesis in strain SBW25. CLP production was shown to play a key role in motility, biofilm formation and in activity of SBW25 against zoospores of Phytophthora infestans. This is the first time that an antimicrobial metabolite is identified from strain SBW25. The results indicate that genome mining may enable the discovery of unknown gene clusters and traits that are highly relevant in the lifestyle of plant beneficial and plant pathogenic bacteria.

  19. Champacyclin, a New Cyclic Octapeptide from Streptomyces Strain C42 Isolated from the Baltic Sea

    Directory of Open Access Journals (Sweden)

    Alexander Pesic

    2013-12-01

    Full Text Available New isolates of Streptomyces champavatii were isolated from marine sediments of the Gotland Deep (Baltic Sea, from the Urania Basin (Eastern Mediterranean, and from the Kiel Bight (Baltic Sea. The isolates produced several oligopeptidic secondary metabolites, including the new octapeptide champacyclin (1a present in all three strains. Herein, we report on the isolation, structure elucidation and determination of the absolute stereochemistry of this isoleucine/leucine (Ile/Leu = Xle rich cyclic octapeptide champacyclin (1a. As 2D nuclear magnetic resonance (NMR spectroscopy could not fully resolve the structure of (1a, additional information on sequence and configuration of stereocenters were obtained by a combination of multi stage mass spectrometry (MSn studies, amino acid analysis, partial hydrolysis and subsequent enantiomer analytics with gas chromatography positive chmical ionization/electron impact mass spectrometry (GC-PCI/EI-MS supported by comparison to reference dipeptides. Proof of the head-to-tail cyclization of (1a was accomplished by solid phase peptide synthesis (SPPS compared to an alternatively side chain cyclized derivative (2. Champacyclin (1a is likely synthesized by a non-ribosomal peptide synthetase (NRPS, because of its high content of (d-amino acids. The compound (1a showed antimicrobial activity against the phytopathogen Erwinia amylovora causing the fire blight disease of certain plants.

  20. Metal-binding and redox properties of substituted linear and cyclic ATCUN motifs.

    Science.gov (United States)

    Neupane, Kosh P; Aldous, Amanda R; Kritzer, Joshua A

    2014-10-01

    The amino-terminal copper and nickel binding (ATCUN) motif is a short peptide sequence found in human serum albumin and other proteins. Synthetic ATCUN-metal complexes have been used to oxidatively cleave proteins and DNA, cross-link proteins, and damage cancer cells. The ATCUN motif consists of a tripeptide that coordinates Cu(II) and Ni(II) ions in a square planar geometry, anchored by chelation sites at the N-terminal amine, histidine imidazole and two backbone amides. Many studies have shown that the histidine is required for tight binding and square planar geometry. Previously, we showed that macrocyclization of the ATCUN motif can lead to high-affinity binding with altered metal ion selectivity and enhanced Cu(II)/Cu(III) redox cycling (Inorg. Chem. 2013, 52, 2729-2735). In this work, we synthesize and characterize several linear and cyclic ATCUN variants to explore how substitutions at the histidine alter the metal-binding and catalytic properties. UV-visible spectroscopy, EPR spectroscopy and mass spectrometry indicate that cyclization can promote the formation of ATCUN-like complexes even in the absence of imidazole. We also report several novel ATCUN-like complexes and quantify their redox properties. These findings further demonstrate the effects of conformational constraints on short, metal-binding peptides, and also provide novel redox-active metallopeptides suitable for testing as catalysts for stereoselective or regioselective oxidation reactions.