Discovery and characterization of two types of liver-expressed antimicrobial peptide 2 (LEAP-2) genes in rainbow trout

The sequences and gene organisation of two LEAP-2 molecules (LEAP-2A and LEAP-2B) from rainbow trout, Oncorhynchus mykiss are presented. Both genes consist of a 3 exon/2 intron structure, with exon sizes comparable to known mammalian genes. LEAP-2A notably differs from LEAP-2B in having larger introns and a larger 3'UTR. The predicted proteins contain a signal peptide and prodomain, followed by a mature peptide of 41 aa containing four conserved cysteines. The RXXR cleavage site to release the mature peptide was also conserved. Both genes were found to be constitutively expressed in the liver, with expression in the intestine, and to a lesser extent the skin, evident after bacterial challenge. (C) 2004 Elsevier B.V. All rights reserved.

Expressed sequence tags from the zhikong scallop (Chlamys farreri): Discovery and annotation of host-defense genes

A high-quality cDNA library was constructed from whole body tissues of the zhikong scallop, Chlamys farreri, challenged by Listonella anguillarum. A total of 5720 clones were sequenced, yielding 5123 expressed sequence tags (ESTs). Among the 3326 unique genes identified, 2289 (69%) genes had no significant (E-value < 1e-5) matches to known sequences in public databases and 194 (6%) matched proteins of unknown functions. The remaining 843 (25%) genes that exhibited homology with genes of known functions, showed broad involvement in metabolic processes (31%), cell structure and motility (20%), gene and protein expression (12%), cell signaling and cell communication (8%), cell division (4%), and notably, 25% of those genes were related to immune function. They included stress response genes, complement-like genes, proteinase and proteinase inhibitors, immune recognition receptors and immune effectors. The EST collection obtained in this study provides a useful resource for gene discovery and especially for the identification of host-defense genes and systems in scallops and other molluscs. (C) 2009 Elsevier Ltd. All rights reserved.

TYPICAL: A Knowledge Representation System for Automated Discovery and Inference

TYPICAL is a package for describing and making automatic inferences about a broad class of SCHEME predicate functions. These functions, called types following popular usage, delineate classes of primitive SCHEME objects, composite data structures, and abstract descriptions. TYPICAL types are generated by an extensible combinator language from either existing types or primitive terminals. These generated types are located in a lattice of predicate subsumption which captures necessary entailment between types; if satisfaction of one type necessarily entail satisfaction of another, the first type is below the second in the lattice. The inferences make by TYPICAL computes the position of the new definition within the lattice and establishes it there. This information is then accessible to both later inferences and other programs (reasoning systems, code analyzers, etc) which may need the information for their own purposes. TYPICAL was developed as a representation language for the discovery program Cyrano; particular examples are given of TYPICAL's application in the Cyrano program.

Delivering mobile cloud services to the user: description, discovery, and consumption

The mobile cloud computing paradigm can offer relevant and useful services to the users of smart mobile devices. Such public services already exist on the web and in cloud deployments, by implementing common web service standards. However, these services are described by mark-up languages, such as XML, that cannot be comprehended by non-specialists. Furthermore, the lack of common interfaces for related services makes discovery and consumption difficult for both users and software. The problem of service description, discovery, and consumption for the mobile cloud must be addressed to allow users to benefit from these services on mobile devices. This paper introduces our work on a mobile cloud service discovery solution, which is utilised by our mobile cloud middleware, Context Aware Mobile Cloud Services (CAMCS). The aim of our approach is to remove complex mark-up languages from the description and discovery process. By means of the Cloud Personal Assistant (CPA) assigned to each user of CAMCS, relevant mobile cloud services can be discovered and consumed easily by the end user from the mobile device. We present the discovery process, the architecture of our own service registry, and service description structure. CAMCS allows services to be used from the mobile device through a user's CPA, by means of user defined tasks. We present the task model of the CPA enabled by our solution, including automatic tasks, which can perform work for the user without an explicit request.

Outposts of Empire: Scientific Discovery and Colonial Displacement in Gaskell's Wives and Daughters

This article offers a fresh consideration of Elizabeth Gaskell's unfinished Wives and Daughters (1864–6), in terms of what this metropolitan novelist knew about contemporary scientific debates and imperial exploration of Africa, and how her familiarity with these discourses was incorporated into her imaginative work. Her focus for these two related themes is the naturalist Roger Hamley, whose character and exploits are meant to parallel those of the young Charles Darwin. Roger's direct involvement in the historical Geoffroy–Cuvier debate allows Gaskell to offer a sophisticated examination of how discussions about evolutionary biology (about which she learned from personal acquaintances and printed sources) contributed to political and social change in the era of the first Reform Bill. Roger's subsequent journey to Abyssinia to gather specimens allows Gaskell to form a link between science and imperial exploration, which demonstrates how, when carried to its conclusion, the development of classificatory knowledge systems was never innocent; rather, it facilitated colonial exploitation and intervention, which allowed for the ‘opening up of Africa’. Gaskell's pronouncements about science in the novel are far more explicit than her brief references to empire; the article ponders why this should be so, and offers some suggestions about how her reliance on imaginative and discursive constructs concerning the ‘Dark Continent’ may be interpreted as tacit complicity with the imperial project, or at least an interest in its more imaginative aspects.

Novel genomic methods for drug discovery and mechanism-based toxicological assessment

Genomics encompasses a range of powerful technologies that can be applied at all levels of gene expression, from transcription to mRNA translation. Collectively, these technologies have great potential for improving drug discovery, both target and molecule recognition, and development. In this article we review the current and potential future status of established and novel genomic methods within drug discovery.

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M-1) Antagonist In Vitro and In Vivo Probe

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.

Discovery and evolving history of two genetically related but phenotypically different viruses, porcine circoviruses 1 and 2

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.