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61.
62.
Jeff A. O'Meara Christopher T. Lemke Cédrickx Godbout George Kukolj Lisette Lagacé Beno?t Moreau Diane Thibeault Peter W. White Montse Llinàs-Brunet 《The Journal of biological chemistry》2013,288(8):5673-5681
Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms. 相似文献
63.
Magali Moreau Timothy Westlake Giulio Zampogna George Popescu Miaoying Tian Christos Noutsos Sorina Popescu 《The Plant journal : for cell and molecular biology》2013,76(4):603-614
Salicylic acid (SA) is a small phenolic molecule with hormonal properties, and is an essential component of the immune response. SA exerts its functions by interacting with protein targets; however, the specific cellular components modulated by SA and critical for immune signal transduction are largely unknown. To uncover cellular activities targeted by SA, we probed Arabidopsis protein microarrays with a functional analog of SA. We demonstrate that thimet oligopeptidases (TOPs) constitute a class of SA‐binding enzymes. Biochemical evidence demonstrated that SA interacts with TOPs and inhibits their peptidase activities to various degrees both in vitro and in plant extracts. Functional characterization of mutants with altered TOP expression indicated that TOP1 and TOP2 mediate SA‐dependent signaling and are necessary for the immune response to avirulent pathogens. Our results support a model whereby TOP1 and TOP2 act in separate pathways to modulate SA‐mediated cellular processes. 相似文献
64.
Anne Décor Chantal Grand-Maître Oliver Hucke Jeff O’Meara Cyrille Kuhn Léa Constantineau -Forget Christian Brochu Eric Malenfant Mégan Bertrand-Laperle Josée Bordeleau Elise Ghiro Marc Pesant Gulrez Fazal Vida Gorys Michael Little Colette Boucher Sylvain Bordeleau Pascal Turcotte Annick Gauthier 《Bioorganic & medicinal chemistry letters》2013,23(13):3841-3847
We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. 相似文献
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66.
Junior physicians mainly learn during their observation in the operative room. The senior physicians evaluate them based on the same kind of observation. Knowledge transfer evaluation is thus done without quantitative methods and it mainly lies on a subjective assessment. In this paper, we present some recent techniques used to objectively evaluate medical gestures. The classical techniques used are Hidden Markov Models (HMM) or Dynamic Time Warping (DTW). Both techniques lies on the temporal analysis of the gestures. We proposed here a technique based on the arc length parametrization in order to analyze the gestures in space which is more appropriate because it gives information about the shape of the gestures independently of the chosen coordinate system. 相似文献
67.
Pascal Hingamp Nigel Grimsley Silvia G Acinas Camille Clerissi Lucie Subirana Julie Poulain Isabel Ferrera Hugo Sarmento Emilie Villar Gipsi Lima-Mendez Karoline Faust Shinichi Sunagawa Jean-Michel Claverie Hervé Moreau Yves Desdevises Peer Bork Jeroen Raes Colomban de Vargas Eric Karsenti Stefanie Kandels-Lewis Olivier Jaillon Fabrice Not Stéphane Pesant Patrick Wincker Hiroyuki Ogata 《The ISME journal》2013,7(9):1678-1695
Nucleo-cytoplasmic large DNA viruses (NCLDVs) constitute a group of eukaryotic viruses that can have crucial ecological roles in the sea by accelerating the turnover of their unicellular hosts or by causing diseases in animals. To better characterize the diversity, abundance and biogeography of marine NCLDVs, we analyzed 17 metagenomes derived from microbial samples (0.2–1.6 μm size range) collected during the Tara Oceans Expedition. The sample set includes ecosystems under-represented in previous studies, such as the Arabian Sea oxygen minimum zone (OMZ) and Indian Ocean lagoons. By combining computationally derived relative abundance and direct prokaryote cell counts, the abundance of NCLDVs was found to be in the order of 104–105 genomes ml−1 for the samples from the photic zone and 102–103 genomes ml−1 for the OMZ. The Megaviridae and Phycodnaviridae dominated the NCLDV populations in the metagenomes, although most of the reads classified in these families showed large divergence from known viral genomes. Our taxon co-occurrence analysis revealed a potential association between viruses of the Megaviridae family and eukaryotes related to oomycetes. In support of this predicted association, we identified six cases of lateral gene transfer between Megaviridae and oomycetes. Our results suggest that marine NCLDVs probably outnumber eukaryotic organisms in the photic layer (per given water mass) and that metagenomic sequence analyses promise to shed new light on the biodiversity of marine viruses and their interactions with potential hosts. 相似文献
68.
Bryche Jean-François Gillibert Raymond Barbillon Grégory Gogol Philippe Moreau Julien Lamy de la Chapelle Marc Bartenlian Bernard Canva Michael 《Plasmonics (Norwell, Mass.)》2016,11(2):601-608
Plasmonics - In this paper, we report on an improved enhancement of the surface-enhanced Raman scattering (SERS) effect. Such improvement is obtained by using a continuous gold film (underlayer),... 相似文献
69.
We evaluated the cost-effectiveness of capsaicin 8% patch (QUTENZA™) versus pregabalin in patients with PNP from the perspective of the National Health Service (NHS) and Personal and Social Services in Scotland, UK. A decision-tree cost-effectiveness model was developed for non-diabetic patients with peripheral neuropathic pain (PNP) who were pregabalin-naïve and had not achieved adequate pain relief or tolerated conventional first- or second-line treatments. Patients entering the model received either a single application of capsaicin 8% patch or titrated daily dosing with pregabalin; after 8 weeks patients were classified as responders, non-responders, or were assumed to discontinue treatment due to intolerable adverse events. Responders continued to receive baseline treatment at intervals observed in clinical practice. Non-responders and those who discontinued treatment were assumed to receive last-line therapy (duloxetine). The base-case time horizon was 2 years. Model inputs for effectiveness, discontinuations and health-state utilities were taken from a head-to-head non-inferiority study (ELEVATE, ). Other inputs were obtained from published sources or clinical expert opinion. Costs were expressed in GBP 2013/14. Results were presented as incremental cost-effectiveness ratios (ICER), i.e. cost per quality-adjusted life-year (QALY) gained. Model assumptions were tested with scenario analyses. Parameter uncertainty was tested using one-way and probabilistic sensitivity analyses. Compared with dose-optimized pregabalin, capsaicin 8% patch was the dominant treatment strategy (total cost difference, –£11; total QALY gain, 0.049). Capsaicin 8% patch was also the dominant treatment strategy versus pregabalin in 6 out of 7 scenario analyses. The model was most sensitive to variation in time to capsaicin 8% patch retreatment (maximum ICER, £7,951/QALY at lower-bound 95% confidence interval). At a willingness-to-pay threshold of £20,000/QALY, the probability of capsaicin 8% patch being cost-effective versus pregabalin was 97%. Capsaicin 8% patch is a cost-effective treatment option compared with dose-optimized pregabalin in patients with PNP who have failed one or more previous systemic treatments. NCT01713426相似文献
70.
Hyong Woo Choi Murli Manohar Patricia Manosalva Miaoying Tian Magali Moreau Daniel F. Klessig 《PLoS pathogens》2016,12(3)
Damage-associated molecular pattern molecules (DAMPs) signal the presence of tissue damage to induce immune responses in plants and animals. Here, we report that High Mobility Group Box 3 (HMGB3) is a novel plant DAMP. Extracellular HMGB3, through receptor-like kinases BAK1 and BKK1, induced hallmark innate immune responses, including i) MAPK activation, ii) defense-related gene expression, iii) callose deposition, and iv) enhanced resistance to Botrytis cinerea. Infection by necrotrophic B. cinerea released HMGB3 into the extracellular space (apoplast). Silencing HMGBs enhanced susceptibility to B. cinerea, while HMGB3 injection into apoplast restored resistance. Like its human counterpart, HMGB3 binds salicylic acid (SA), which results in inhibition of its DAMP activity. An SA-binding site mutant of HMGB3 retained its DAMP activity, which was no longer inhibited by SA, consistent with its reduced SA-binding activity. These results provide cross-kingdom evidence that HMGB proteins function as DAMPs and that SA is their conserved inhibitor. 相似文献