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71.
Dr. Nathalie Goudreau René Coulombe Dr. Anne‐Marie Faucher Chantal Grand‐Maître Jean‐Eric Lacoste Dr. Christopher T. Lemke Eric Malenfant Yves Bousquet Dr. Lee Fader Dr. Bruno Simoneau Jean‐François Mercier Steve Titolo Dr. Stephen W. Mason 《ChemMedChem》2013,8(3):405-414
The emergence of resistance to existing classes of antiretroviral drugs underlines the need to find novel human immunodeficiency virus (HIV)‐1 targets for drug discovery. The viral capsid protein (CA) represents one such potential target. Recently, a series of benzodiazepine inhibitors was identified via high‐throughput screening using an in vitro capsid assembly assay (CAA). Here, we demonstrate how a combination of NMR and X‐ray co‐crystallography allowed for the rapid characterization of the early hits from this inhibitor series. Ligand‐based 19F NMR was used to confirm inhibitor binding specificity and reversibility as well as to identify the N‐terminal domain of the capsid (CANTD) as its molecular target. Protein‐based NMR (1H and 15N chemical shift perturbation analysis) identified key residues within the CANTD involved in inhibitor binding, while X‐ray co‐crystallography confirmed the inhibitor binding site and its binding mode. Based on these results, two conformationally restricted cyclic inhibitors were designed to further validate the possible binding modes. These studies were crucial to early hit confirmation and subsequent lead optimization. 相似文献
72.
JJ Braun JP Alabert FB Michel M Quiniou C Rat J Cougnard W Czarlewski J Bousquet 《Canadian Metallurgical Quarterly》1997,52(6):650-655
Recently, it has been recognized that cell-bound heparan sulfate (HS) proteoglycans (HSPG) are able to bind and subsequently initiate degradation of lipoproteins. Two mediators of lipoprotein catabolism, both with HS binding capacity, lipoprotein lipase (LPL) and apolipoprotein E (apoE), are involved in this process. This mechanism is known as the secretion-capture process of apoE. Lipoprotein(a) [Lp(a)] was shown to have a strong binding capacity to cell-associated HSPG. This binding capacity was increased by LPL addition. We investigated the effects of recombinant apoE (r-apoE) enrichment of Lp(a) on the binding to HS. Lp(a), isolated by ultracentrifugation and gel filtration, was incubated with r-apoE and reisolated by ultracentrifugation, resulting in r-apoE-enriched Lp(a). ApoE-enriched Lp(a) and control Lp(a) were coated to microtiter plates. The capacity to bind biotin-conjugated HS (b-HS) in the presence or absence of inactivated bovine LPL was studied. R-apoE-enriched Lp(a) showed increased b-HS binding capacity versus control Lp(a). Addition of LPL resulted in an increased b-HS binding capacity of both control and r-apoE-enriched Lp(a). To investigate whether binding of Lp(a) to endothelial cell HSPG occurred in vivo, 39 volunteers were injected with heparin (50 U/kg) and plasma lipid and Lp(a) levels were determined before and 20 minutes after heparin injection. No significant increase in plasma Lp(a) concentrations was found. The results showed that Lp(a) can be enriched with apoE and that this resulted in increased LPL-enhanced binding to HSPG. From the in vitro studies, it can be concluded that the secretion-capture process of apoE is a possible catabolic route for Lp(a). However, whether this also occurs in vivo remains to be confirmed. 相似文献
73.
A Des Roches L Paradis YH Bougeard P Godard J Bousquet P Chanez 《Canadian Metallurgical Quarterly》1996,98(3):522-527
BACKGROUND: Medications can modulate the results of skin prick tests (SPTs). Short-term corticosteroid therapy does not alter IgE-mediated skin tests, but the impact of long-term oral corticosteroid therapy on SPT results is unclear. A prospective study was carried out in patients with steroid-dependent asthma who received oral corticosteroids for a long period to determine whether this treatment reduced skin test reactivity. METHODS: Thirty-three patients with steroid-dependent asthma (median age, 59 years) were compared with 66 patients with asthma who served as a control group, matched for age, sex, and atopic status. SPTs with codeine phosphate and a screening battery of standardized allergen extracts were performed before commencement and after at least 1 year of daily oral prednisone treatment (median duration, 2 years; median daily dose, 20 mg). RESULTS: Fifteen patients with corticosteroid-dependent asthma were allergic before treatment, and their sensitization was not changed by long-term treatment with oral corticosteroids. The median wheal diameters induced by codeine phosphate were similar in both groups. The median wheal diameters induced by allergens, and more specifically, by Dermatophagoides pteronyssinus and D. farinae were similar in both groups and did not change in the steroid group after treatment. CONCLUSIONS: Systemic corticosteroid therapy (prednisone, 10 to 60 mg/day) for 2 or more years does not seem to alter SPT reactivity. 相似文献
74.
E Bousquet P Pommier S Wessel-Robert H Morvan H Benoit-Valiergue A Laval 《Canadian Metallurgical Quarterly》1998,143(10):269-272
A multicentre, controlled, randomised and blinded study was carried out in three French pig herds to assess the efficacy of doxycycline administered in the feed for the control of pneumonia. About 20 per cent of 363 pigs from the three fattening units were diseased at the start of the study. Pneumonic lesions were found on pigs examined postmortem and Pasteurella multocida was isolated from the lungs of pigs in all the herds. Mycoplasma hyopneumoniae infection was confirmed either by detection in pneumonic lungs or by seroconversion in pigs sampled three weeks apart. P multocida, Bordetella bronchiseptica and Actinobacillus pleuropneumoniae were isolated from 64 per cent, 50 per cent and 2 per cent, respectively, of 148 nasal swabs. The following variables were significantly different between the treated and untreated groups (P < or = 0.001): the incidence of diseased pigs during the three weeks from the start of treatment (8.1 per cent in treated group v 35.4 per cent in control group), mean daily weight gain over the same period (934 g/day in the treated group v 834 g/day in the control group) and the cure rate of pigs which were diseased at the start of treatment (73.5 per cent in treated group v 35.3 per cent in control group). These data demonstrate that an average dose of 11 mg doxycycline/kg bodyweight per day in feed for eight days was effective in controlling pneumonia due to P multocida and M hyopneumoniae in these fattening pigs. 相似文献
75.
76.
M.L. Guzman Castillo F. Di Renzo F. Fajula J. Bousquet 《Microporous and mesoporous materials》2006,90(1-3):221-228
The synthesis of zeolite omega, the synthetic analog of mazzite, was carried out by using commercial reagents and a low amount of tetramethylammonium template. The use of a slow-release source of aluminium allowed to avoid the formation of a precursor gel and to concentrate the nucleation at the beginning of the synthesis. The rates of crystal growth in radial and axial direction depends on the alkalinity and the aluminium concentration. The changes of the aspect ratio and morphology of the crystals can be accounted for by the relative growth rates of different crystal faces. 相似文献
77.
78.
This paper brings forth the experiences and lessons of implementing a participatory modelling process, the Companion Modelling (ComMod) approach, to a natural resource management system in the province of Palawan, Philippines. In this study, we explore the added value of using ComMod in a research and development project, and then we describe the actual modelling process, which includes the use of multiple methods for its evaluation, namely, workshop evaluation exercises, criteria & indicators for the project and the ComMod evaluation protocol. We use the lessons of this evaluation to assess the organisational learning and discuss the role of the modelling process within the development project. 相似文献
79.
Stakeholder engagement, collaboration, or participation, shared learning or fact-finding, have become buzz words and hardly any environmental assessment or modelling effort today can be presented without some kind of reference to stakeholders and their involvement in the process. This is clearly a positive development, but in far too many cases stakeholders have merely been paid lip service and their engagement has consequentially been quite nominal. Nevertheless, it is generally agreed that better decisions are implemented with less conflict and more success when they are driven by stakeholders, that is by those who will be bearing their consequences. Participatory modelling, with its various types and clones, has emerged as a powerful tool that can (a) enhance the stakeholders knowledge and understanding of a system and its dynamics under various conditions, as in collaborative learning, and (b) identify and clarify the impacts of solutions to a given problem, usually related to supporting decision making, policy, regulation or management. In this overview paper we first look at the different types of stakeholder modelling, and compare participatory modelling to other frameworks that involve stakeholder participation. Based on that and on the experience of the projects reported in this issue and elsewhere, we draw some lessons and generalisations. We conclude with an outline of some future directions. 相似文献
80.
Hooper S.E. Kauer M. Bousquet V. Johnson K. Barnes J.M. Heffernan J. 《Electronics letters》2004,40(1):33-34
The first InGaN multiple quantum well laser diodes produced by molecular beam epitaxy are reported. Ridge waveguide lasers have been demonstrated at room temperature under pulsed current injection conditions. The lasers emit at a wavelength of approximately 400 nm with a spectral line-width of less than 0.2 nm, and a threshold current density of /spl sim/30 kA cm/sup -2/. 相似文献