118 resultados para price discovery
Resumo:
This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M-1). An M-1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M-1 versus M-4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC50 = 130 nM) and selective (>75-fold vs. M-2-M-5 and >10 mu M vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M-1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (Brain(AUC)/Plasma(AUC) of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/MLPCN probe molecule for studying and dissecting M-1 function.
Resumo:
Porcine circoviruses (PCVs) belong to the genus Circovirus, family Circoviridae. and are the smallest non-enveloped, single stranded, negative sense, circular DNA viruses that replicate autonomously in mammalian cells. Two types of PCV have been characterised, PCV1 and PCV2 and these two viruses show 83% sequence identity at open reading frame (ORF) 1 and 67% identity at ORF2. PCV1 is a nonpathogenic virus of pigs. In contrast, PCV2 has emerged as a major pathogen of swine around the world. The discovery of PCV1 and how the subsequent studies on this virus eventually led to the recognition and characterisation of PCV2, and the disease scenarios associated with PCV2, serve as a model of how multidisciplinary collaboration among field veterinarians, diagnosticians and researchers can lead to the rapid characterisation and control of a globally important emerging disease. (C) 2011 Elsevier B.V. All rights reserved.
Resumo:
The concept of exospace, as an alternative liveable structure, is discussed in this article to improve our comprehension of architectural space. Exospace is a man-made space designed for living beyond Earth’s atmosphere. Humankind has developed outerspace technologies to build the International Space Station as a significant experiment in exospace design. The ISS is a new building type for scientific experiments and for testing human existence in outerspace.
A fictional example of exospace, on the other hand, is Discovery 1 spaceship in Stanley Kubrick’s legendary science fiction film 2001: A Space Odyssey (1968). It is a ship travelling to Jupiter with a crew of five astronauts and HAL9000, the artificial intelligence controlling the ship. I will first discuss the ISS, and the space stations built before, from a spatial point of view. A spatial study of Discovery 1 will follow. Finally, through an understanding of exospace, I will return to architectural space with a critical appraisal. The comparison of architectural space with exospace will add to the discussion of space theories from a technological approach.
Exospace creates an alternative reality to architectural space. Architects cannot consider exospaces without comparing them with the spaces they design on Earth. The different context of outerspace shows that a work of terrestrial architecture is very much dependent on its context. A building is not an ‘object’ that can be located anywhere; it is designed for its site. Architectural space is a real, material, continuous, static and extroverted habitable space designed for and used in the specific physical context of Earth. The existence of exospace in science opens a new discussion in architectural theory, both terrestrial and extraterrestrial.
Resumo:
Increasingly infrastructure providers are supplying the cloud marketplace with storage and on-demand compute resources to host cloud applications. From an application user's point of view, it is desirable to identify the most appropriate set of available resources on which to execute an application. Resource choice can be complex and may involve comparing available hardware specifications, operating systems, value-added services, such as network configuration or data replication, and operating costs, such as hosting cost and data throughput. Providers' cost models often change and new commodity cost models, such as spot pricing, have been introduced to offer significant savings. In this paper, a software abstraction layer is used to discover infrastructure resources for a particular application, across multiple providers, by using a two-phase constraints-based approach. In the first phase, a set of possible infrastructure resources are identified for a given application. In the second phase, a heuristic is used to select the most appropriate resources from the initial set. For some applications a cost-based heuristic is most appropriate; for others a performance-based heuristic may be used. A financial services application and a high performance computing application are used to illustrate the execution of the proposed resource discovery mechanism. The experimental result shows the proposed model could dynamically select an appropriate set of resouces that match the application's requirements.
Resumo:
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.
Resumo:
Burkholderia cenocepacia is a Gram-negative aerobic bacterium that belongs to a group of opportunistic pathogens displaying diverse environmental and pathogenic lifestyles. B. cenocepacia is known for its ability to cause lung infections in people with cystic fibrosis and it possesses a large 8?Mb multireplicon genome encoding a wide array of pathogenicity and fitness genes. Transcriptomic profiling across nine growth conditions was performed to identify the global gene expression changes made when B. cenocepacia changes niches from an environmental lifestyle to infection. In comparison to exponential growth, the results demonstrated that B. cenocepacia changes expression of over one-quarter of its genome during conditions of growth arrest, stationary phase and surprisingly, under reduced oxygen concentrations (6% instead of 20.9% normal atmospheric conditions). Multiple virulence factors are upregulated during these growth arrest conditions. A unique discovery from the comparative expression analysis was the identification of a distinct, co-regulated 50-gene cluster that was significantly upregulated during growth under low oxygen conditions. This gene cluster was designated the low-oxygen-activated (lxa) locus and encodes six universal stress proteins and proteins predicted to be involved in metabolism, transport, electron transfer and regulation. Deletion of the lxa locus resulted in B. cenocepacia mutants with aerobic growth deficiencies in minimal medium and compromised viability after prolonged incubation in the absence of oxygen. In summary, transcriptomic profiling of B. cenocepacia revealed an unexpected ability of aerobic Burkholderia to persist in the absence of oxygen and identified the novel lxa locus as key determinant of this important ecophysiological trait.
Resumo:
A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
Resumo:
This paper identifies and analyses the means of accessing and collecting foreign-based evidence in transnational antitrust cases. It makes an original contribution to the existing scholarship by critically addressing the available mechanisms of judicial cooperation, the possibility of reliance on domestic discovery in transnational context, as well as the existing instruments allowing for cooperation between antitrust agencies. It identifies the shortcomings of the current regulatory framework and points out to the existing good practices in those jurisdictions which provide their antitrust agencies with more leeway in sharing confidential information with foreign counterparts.