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101.
Nicola Dimitri 《PloS one》2012,7(12)
Neglected diseases are typically characterized as those for which adequate drug treatment is lacking, and the potential return on effort in research and development (R&D), to produce new therapies, is too small for companies to invest significant resources in the field. In recent years various incentives schemes to stimulate R&D by pharmaceutical firms have been considered. Broadly speaking, these can be classified either as ‘push’ or ‘pull’ programs. Hybrid options, that include push and pull incentives, have also become increasingly popular. Supporters and critics of these various incentive schemes have argued in favor of their relative merits and limitations, although the view that no mechanism is a perfect fit for all situations appears to be widely held. For this reason, the debate on the advantages and disadvantages of different approaches has been important for policy decisions, but is dispersed in a variety of sources. With this in mind, the aim of this paper is to contribute to the understanding of the economic determinants behind R&D investments for neglected diseases by comparing the relative strength of different incentive schemes within a simple economic model, based on the assumption of profit maximizing firms. The analysis suggests that co-funded push programs are generally more efficient than pure pull programs. However, by setting appropriate intermediate goals hybrid incentive schemes could further improve efficiency. 相似文献
102.
The exchangeable apolipoprotein ApoC-I promotes membrane fusion of hepatitis C virus 总被引:3,自引:0,他引:3
Dreux M Boson B Ricard-Blum S Molle J Lavillette D Bartosch B Pécheur EI Cosset FL 《The Journal of biological chemistry》2007,282(44):32357-32369
103.
Characterization of fusion determinants points to the involvement of three discrete regions of both E1 and E2 glycoproteins in the membrane fusion process of hepatitis C virus 总被引:1,自引:0,他引:1 下载免费PDF全文
Lavillette D Pécheur EI Donot P Fresquet J Molle J Corbau R Dreux M Penin F Cosset FL 《Journal of virology》2007,81(16):8752-8765
Infection of eukaryotic cells by enveloped viruses requires the merging of viral and cellular membranes. Highly specific viral surface glycoproteins, named fusion proteins, catalyze this reaction by overcoming inherent energy barriers. Hepatitis C virus (HCV) is an enveloped virus that belongs to the genus Hepacivirus of the family Flaviviridae. Little is known about the molecular events that mediate cell entry and membrane fusion for HCV, although significant progress has been made due to recent developments in infection assays. Here, using infectious HCV pseudoparticles (HCVpp), we investigated the molecular basis of HCV membrane fusion. By searching for classical features of fusion peptides through the alignment of sequences from various HCV genotypes, we identified six regions of HCV E1 and E2 glycoproteins that present such characteristics. We introduced conserved and nonconserved amino acid substitutions in these regions and analyzed the phenotype of HCVpp generated with mutant E1E2 glycoproteins. This was achieved by (i) quantifying the infectivity of the pseudoparticles, (ii) studying the incorporation of E1E2 and their capacity to mediate receptor binding, and (iii) determining their fusion capacity in cell-cell and liposome/HCVpp fusion assays. We propose that at least three of these regions (i.e., at positions 270 to 284, 416 to 430, and 600 to 620) play a role in the membrane fusion process. These regions may contribute to the merging of viral and cellular membranes either by interacting directly with lipid membranes or by assisting the fusion process through their involvement in the conformational changes of the E1E2 complex at low pH. 相似文献
104.
Marshall AT Haverkamp RG Davies CE Parsons JG Gardea-Torresdey JL van Agterveld D 《International journal of phytoremediation》2007,9(3):197-206
Enzymatic digestion is proposed as a method for concentrating gold nanoparticles produced in plants. The mild conditions of digestion are used in order to avoid an increase in the gold particle size, which would occur with a high-temperature process, so that material suitable for catalysis may be produced. Gold nanoparticles of a 5-50-nm diameter, as revealed by transmission electron microscopy (TEM), at concentrations 760 and 1120 ppm Au, were produced within Brassica juncea grown on soil with 22-48 mg Au kg(-1). X-ray absorption near edge spectroscopy (XANES) reveals that the plant contained approximately equal quantities of Au in the metallic (Au0) and oxidized (Au+1) states. Enzymatic digestion dissolved 55-60 wt% of the plant matter. Due to the loss of the soluble gold fraction, no significant increase in the total concentration of gold in the samples was observed. However, it is likely that the concentration of the gold nanoparticles increased by a factor of two. To obtain a gold concentration suitable for catalytic reactions, around 95 wt% of the starting dry biomass would need to be solubilized or removed, which has not yet been achieved. 相似文献
105.
Broggi J Joubert N Aucagne V Berteina-Raboin S Diez-Gonzalez S Nolan S Topalis D Deville-Bonne D Balzarini J Neyts J Andrei G Snoeck R Agrofoglio LA 《Nucleosides, nucleotides & nucleic acids》2007,26(10-12):1391-1394
Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxy carbanucleosides were synthesized based on a "click approach." Various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and cellular toxicities were evaluated on vaccinia virus. None of the synthesized compounds exhibited a significant antiviral activity. 相似文献
106.
Roy V Kumamoto H Berteina-Raboin S Nolan SP Topalis D Deville-Bonne D Balzarini J Neyts J Andrei G Snoeck R Agrofoglio LA 《Nucleosides, nucleotides & nucleic acids》2007,26(10-12):1399-1402
With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility, olefin metathesis is now routinely integrated in various syntheses. We will report here the overwhelming power and scope of cross-metathesis in the area of new acyclic nucleoside phosphonates. Scope and limitations of this approach, and especially the E/Z stereocontrol, are discussed on selected examples from our drug discovery group. 相似文献
107.
108.
109.
Saunders HM Gilis D Rooman M Dehouck Y Robertson AL Bottomley SP 《Protein science : a publication of the Protein Society》2011,20(10):1675-1681
Spinocerebellar Ataxia Type 3 (SCA3) is one of nine polyglutamine (polyQ) diseases that are all characterized by progressive neuronal dysfunction and the presence of neuronal inclusions containing aggregated polyQ protein, suggesting that protein misfolding is a key part of this disease. Ataxin-3, the causative protein of SCA3, contains a globular, structured N-terminal domain (the Josephin domain) and a flexible polyQ-containing C-terminal tail, the repeat-length of which modulates pathogenicity. It has been suggested that the fibrillogenesis pathway of ataxin-3 begins with a non-polyQ-dependent step mediated by Josephin domain interactions, followed by a polyQ-dependent step. To test the involvement of the Josephin domain in ataxin-3 fibrillogenesis, we have created both pathogenic and nonpathogenic length ataxin-3 variants with a stabilized Josephin domain, and have both stabilized and destabilized the isolated Josephin domain. We show that changing the thermodynamic stability of the Josephin domain modulates ataxin-3 fibrillogenesis. These data support the hypothesis that the first stage of ataxin-3 fibrillogenesis is caused by interactions involving the non-polyQ containing Josephin domain and that the thermodynamic stability of this domain is linked to the aggregation propensity of ataxin-3. 相似文献
110.
Bolanos-Garcia VM Lischetti T Matak-Vinković D Cota E Simpson PJ Chirgadze DY Spring DR Robinson CV Nilsson J Blundell TL 《Structure (London, England : 1993)》2011,19(11):1691-1700
The maintenance of genomic stability relies on the spindle assembly checkpoint (SAC), which ensures accurate chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bioriented and attached to the mitotic spindle. BUB1 and BUBR1 kinases are central for this process and by interacting with Blinkin, link the SAC with the kinetochore, the macromolecular assembly that connects microtubules with centromeric DNA. Here, we identify the Blinkin motif critical for interaction with BUBR1, define the stoichiometry and affinity of the interaction, and present a 2.2 ? resolution crystal structure of the complex. The structure defines an unanticipated BUBR1 region responsible for the interaction and reveals a novel Blinkin motif that undergoes a disorder-to-order transition upon ligand binding. We also show that substitution of several BUBR1 residues engaged in binding Blinkin leads to defects in the SAC, thus providing the first molecular details of the recognition mechanism underlying kinetochore-SAC signaling. 相似文献