58,711 research outputs found
Majnoni D'Intignano B. et Stephan J. C. : Hippocrate et les technocrates
No full textLévy Emile. Majnoni D'Intignano B. et Stephan J. C. : Hippocrate et les technocrates. In: Politiques et management public, vol. 1, n° 3, 1983. pp. 154-156
A Multi-Language Comparison of Influences on Author Verification using Character N-Grams
No full textWe create a new multi-language corpus for author verification based on Wikipedia talkpages, and evaluate the influence that differences in topic and time have on character n-gram author profiles. Topic alignment between two texts is found to increase author verification precision, and an authors writing style is found to change over time, but not more significantly after 3 years than after 1 year.Information ArchitectureWISElectrical Engineering, Mathematics and Computer Scienc
Towards NMR analysis of the HIV-1 coreceptor CCR5 and its interaction with RANTES
No full textCCR5 is a chemokine receptor together with CD4 used by HIV-1 as a primary gate of cell infection. For this reason CCR5 is of great interest for medicine as a target for the anti-HIV-1 therapies. Since the binding site of its endogenous ligand RANTES overlaps with the binding site of viral envelope glycoprotein gp120, a noninflamatory RANTES derivative 5P12-RANTES has been developed as an anti-HIV-1 infection microbicide. The primary aim of this thesis was to establish an NMR-amenable system to study CCR5 and to understand better the interaction with RANTES.
For this purpose CCR5 expressed in insect cells was characterized in detail with regards to its secondary structure, oligomeric state, particle size, stability, posttranslational modifications and functionality. In contrast to the previous results, carefully performed detergent screening revealed that FosCholine-12, a detergent which allows high yield purification, does not support CCR5 recognition by 2D7 and cannot be used for studying CCR5 interactions with ligands. Therefore for the functional studies the receptor was solubilized with a milder detergent mixture DDM/CHAPS/CHS, which was shown to support native CCR5 tertiary structure.
Using this setup it could be shown by SPR that 5P12-RANTES binds with higher affinity than another potent RANTES variant PSC-RANTES (Morin et al., manuscript in preparation). This explains why 5P12-RANTES, which unlike PSC-RANTES does not cause CCR5 internalization, is an equally effective anti-HIV-1 microbicide. On the other hand, the wild-type RANTES was shown to aggregate on the receptor micelle using a mechanism compatible with the linear oligomerization, a process that is proposed to serve local chemokine preconcentration.
To obtain an access to a cost-efficient source of isotope-labeled samples, an E. coli expression system was established for CCR5 (Wiktor et al., 2012, J Biomol NMR, in revision). The expression was facilitated by fusing the N-terminus of CCR5 to well expressing protein domains e.g. thioredoxin. The C-terminal CCR5 truncation and the mutation of cysteines increased the protein yield up to 10 mg/L and improved the sample stability. Due to the engineered thrombin proteolytic site the N-terminal fusion partner i.e. thioredoxin could be quantitatively cleaved and removed by size exclusion chromatography. The FC-12-purified receptor was abundant in alpha-helical secondary structure but could bind RANTES, MIP-1beta and conformation-dependent antibody 2D7 only when solubilized by a DDM/CHAPS/CHS mixture. Using 15N,13C,2H-labeled CCR5 2D and 3D NMR experiments were recorded but only about 80 backbone resonances could be resolved. The spectral quality was jeopardized by large overlap and line-broadening and needs further improvements to allow the assignment and the structural investigation.
To study 5P12-RANTES by NMR the backbone assignment was completed. The HSQC spectrum revealed that, unlike wild-type RANTES and other chemokines, 5P12-RANTES does not form dimers. The secondary chemical shift analysis suggest that the overall structure of 5P12-RANTES is similar to the wild-type RANTES, with the exception of the mutated N-terminus, which does not participate in the intermolecular beta-sheet and was shown to be highly flexible. Another important observation was that RANTES secondary structure is perturbed by Fos-Choline detergents, whereas maltosides shift the RANTES monomer:dimmer equilibrium towards its monomeric form.
The last part of the thesis present an independent study, where using ubiquitin as an example the mechanism of protein unfolding is studied (Vajpai et al., 2012, Proc Natl Acad Sci USA, in revision) manuscript submitted for publication). The secondary chemical shift analysis showed that the alcohol-denatured ubiquitin structure closely resembles the cold- and pressure denatured structure. This suggests that alcohol, low temperature and pressure unfold proteins by reducing the hydrophobic effect, the cost of exposing hydrophobic residues.
The data of this thesis will be presented in the following publications:
1. Wiktor, M., Morin, S., Sass, H-J., Kebbel, F., Grzesiek, S. (2012) Biophysical and structural investigation of bacterially expressed and engineered CCR5, a G protein-coupled receptor. J Biomol NMR (2012, in revision).
2. Vajpai, N., Nisius, L., Wiktor, M., Grzesiek, S. (2012) High pressure NMR reveals close similarity between cold and alcohol protein denaturation due to a reduction of the hydrophobic effect. Proc Natl Acad Sci USA (in revision).
3. Morin, S., Wiktor, M., Sass, H-J., Hartley, O., Grzesiek, S. (2012) Modulation of RANTES binding to CCR5 by modifications in the N-terminus and C-terminus (in preparation)
Stephan Fichtl, Les Gaulois du nord de la Gaule (150- 20 av. J.-C)., 1994
No full textHanoune Roger. Stephan Fichtl, Les Gaulois du nord de la Gaule (150- 20 av. J.-C)., 1994. In: Revue du Nord, tome 81, n°333,1999. Archéologie de la Picardie et du Nord de la France. pp. 227-228
Vorläuffige Nachricht und wohlgemeynte Anzeige, An (Tit.) Herrn/ Hn. Stephan Christoph Harprecht von Harprechtstein/ auf Kaltenthal/ [et]c. So itzo Professor Juris Primarius bey der Hoch-Fürstl. Universitaet Kiel/ Wie und wo derselbe den unbenan[n]ten Verfasser der gegenseitigen/ über den Non-Usum modernum Speculi Suevici & Juris Feudalis Alemannici gemachten/ Anmerckungen/ gantz gewiß könne antreffen
No full textVORLÄUFFIGE NACHRICHT UND WOHLGEMEYNTE ANZEIGE, AN (TIT.) HERRN/ HN. STEPHAN CHRISTOPH HARPRECHT VON HARPRECHTSTEIN/ AUF KALTENTHAL/ [ET]C. SO ITZO PROFESSOR JURIS PRIMARIUS BEY DER HOCH-FÜRSTL. UNIVERSITAET KIEL/ WIE UND WO DERSELBE DEN UNBENAN[N]TEN VERFASSER DER GEGENSEITIGEN/ ÜBER DEN NON-USUM MODERNUM SPECULI SUEVICI & JURIS FEUDALIS ALEMANNICI GEMACHTEN/ ANMERCKUNGEN/ GANTZ GEWISS KÖNNE ANTREFFEN
Vorläuffige Nachricht und wohlgemeynte Anzeige, An (Tit.) Herrn/ Hn. Stephan Christoph Harprecht von Harprechtstein/ auf Kaltenthal/ [et]c. So itzo Professor Juris Primarius bey der Hoch-Fürstl. Universitaet Kiel/ Wie und wo derselbe den unbenan[n]ten Verfasser der gegenseitigen/ über den Non-Usum modernum Speculi Suevici & Juris Feudalis Alemannici gemachten/ Anmerckungen/ gantz gewiß könne antreffen ( - )
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Hoch-Edel-Gebohrner/ Besonders zu ehrender Herr Professor! ( - )
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Horst Stephan und Hans Leube, Handbuch der Kirchengeschichte, IV. Die Neuzeit, 2e éd. refondue, J. C. B. Mohr, Tübingen, 1932
No full textPatry Raoul. Horst Stephan und Hans Leube, Handbuch der Kirchengeschichte, IV. Die Neuzeit, 2e éd. refondue, J. C. B. Mohr, Tübingen, 1932. In: Revue d'histoire et de philosophie religieuses, 13e année n°6, Novembre-décembre 1933. pp. 556-558
Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: A meta-analysis of randomized trials
No full textAIMS:
Current evidence on dyslipidaemia management has expanded to novel treatments and very low achieved levels of low-density lipoprotein cholesterol (LDL-C). We sought to compare the clinical impact of more-intensive vs. less-intensive LDL-C lowering by means of statins and currently recommended non-statin medications in secondary prevention.
METHODS AND RESULTS:
We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials of statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, or bile acid sequestrants with >500 patients followed for ≥1 year. We employed random-effects models using risk ratios (RRs) with 95% confidence intervals (CIs) to compare outcomes. We included 19 trials (15 of statins, 3 of PCSK9 inhibitors, and 1 of ezetimibe) with 152 507 patients randomly assigned to more-intensive (n = 76 678) or less-intensive treatment (n = 75 829). More-intensive treatment was associated with 19% relative risk reduction for the primary outcome, major vascular events (MVEs; RR 0.81, 95% CI 0.77-0.86). Risk reduction was greater across higher baseline levels and greater achieved reductions of LDL-C. The clinical benefit was significant across varying types of more-intensive treatment and was consistent for statins (RR 0.81, 95% CI 0.76-0.86) and non-statin agents (PCSK9 inhibitors and ezetimibe; RR 0.85, 95% CI 0.77-0.94) as active (more-intensive) intervention (P-interaction = 0.38). Each 1.0 mmol/L reduction in LDL-C was associated with 19% relative decrease in MVE. Death, cardiovascular death, myocardial infarction, stroke, and coronary revascularization also favoured more-intensive treatment.
CONCLUSION:
Reduction of MVE is proportional to the magnitude of LDL-C lowering across a broad spectrum of on-treatment levels in secondary prevention. Statin intensification and add-on treatment with PCSK9 inhibitors or ezetimibe are associated with significant reduction of cardiovascular morbidity in this very high-risk population
Catalytic P-H activation by Ti and Zr catalysts
No full textCatalytic dehydrocoupling of phosphines was investigated using the anionic zirconocene trihydride salts [Cp*Zr-2(mu-H)(3)Li](3) (1a) or [Cp*Zr-2(mu-H)(3)K(thf)(4)] (1b), and the metallocycles [CpTi(NPtBu3)(CH2)(4)] (6) and [Cp*M(NPtBu3)(CH2)(4)] (M = Ti 20, Zr 21) as catalyst precursors. Dehydrocoupling of primary phosphines RPH2 (R = Ph, C6H2Me3, Cy, C10H7) gave both dehydrocoupled dimers RP(H)P(H)R or cyclic oligophosphines (RP)(n) (n = 4, 5) while reaction of tBu(3)C(6)H(2)PH(2) gave the phosphaindoline tBu(2)(Me2CCH2)C6H2PH (9). Stoichiometric reactions of these catalyst precursors with primary phosphines afforded [Cp*Zr-2((PR)(2))H][K(thf)(4)] (R = Ph 2, Cy 3, C6H2Me3 4), [Cp*Zr-2((PPh)(3))H] [K(thf)(4)] (5), [CpTi(NPtBu3)(PPh)(3)] (7) and [CpTi(NPtBu3)(mu-PHPh)](2) (8), while reaction of 6 with (C(6)H(2)tBu3)PH2 in the presence of PMe3 afforded [CpTi(NPtBu3)(PMe3)(p(C(6)H(2)tBu(3))] (10). The secondary phosphines Ph2PH and (PhHPCH2)(2)CH2 also undergo dehydrocoupling affording (Ph2P)(2) and (PhPCH2)(2)CH2. The bisphosphines (CH2PH2)(2) and C6H4(PH2)(2) are dehydrocoupled to give (PCH2CH2PH)(2) (12) and (C6H4P(PH))(2) (13) while prolonged reaction of 13 gave (C6H4P2)(8) (14). The analogous bisphosphine Me2C6H4(PH)(2) (17) was prepared and dehydrocoupling catalysis afforded (Me2C6H2P(PH))(2) (18) and subsequently [(Me2C6H2P2)(2)(mu-Me2C6H2P2)](2) (19). Stoichiometric reactions with these bisphosphines gave [Cp*Zr-2(H)(PH)(2)C6H4] [Li(thf)(4)] (22), [Cp*Ti(NPtBu3)(PH)(2)C6H4](2) (23) and [Cp*Ti(NPtBu3)(PH)(2)C6H4] (24). 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Fast implementation of iterative adaptive approach for wideband unambiguous radar detection
No full textAccepted author manuscriptMicrowave Sensing, Signals & System
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