Relieving the first bottleneck in the drug discovery pipeline:using array technologies to rationalize membrane protein production

The slow down in the drug discovery pipeline is, in part, owing to a lack of structural and functional information available for new drug targets. Membrane proteins, the targets of well over 50% of marketed pharmaceuticals, present a particular challenge. As they are not naturally abundant, they must be produced recombinantly for the structural biology that is a prerequisite to structure-based drug design. Unfortunately, however, obtaining high yields of functional, recombinant membrane proteins remains a major bottleneck in contemporary bioscience. While repeated rounds of trial-and-error optimization have not (and cannot) reveal mechanistic details of the biology of recombinant protein production, examination of the host response has provided new insights. To this end, we published an early transcriptome analysis that identified genes implicated in high-yielding yeast cell factories, which has enabled the engineering of improved production strains. These advances offer hope that the bottleneck of membrane protein production can be relieved rationally.

A soft-computing-based method for the automatic discovery of fuzzy rules in databases:uses for academic research and management support in marketing

The study here highlights the potential that analytical methods based on Knowledge Discovery in Databases (KDD) methodologies have to aid both the resolution of unstructured marketing/business problems and the process of scholarly knowledge discovery. The authors present and discuss the application of KDD in these situations prior to the presentation of an analytical method based on fuzzy logic and evolutionary algorithms, developed to analyze marketing databases and uncover relationships among variables. A detailed implementation on a pre-existing data set illustrates the method. © 2012 Published by Elsevier Inc.

Communities and emerging semantics in semantic link network:discovery and learning

The World Wide Web provides plentiful contents for Web-based learning, but its hyperlink-based architecture connects Web resources for browsing freely rather than for effective learning. To support effective learning, an e-learning system should be able to discover and make use of the semantic communities and the emerging semantic relations in a dynamic complex network of learning resources. Previous graph-based community discovery approaches are limited in ability to discover semantic communities. This paper first suggests the Semantic Link Network (SLN), a loosely coupled semantic data model that can semantically link resources and derive out implicit semantic links according to a set of relational reasoning rules. By studying the intrinsic relationship between semantic communities and the semantic space of SLN, approaches to discovering reasoning-constraint, rule-constraint, and classification-constraint semantic communities are proposed. Further, the approaches, principles, and strategies for discovering emerging semantics in dynamic SLNs are studied. The basic laws of the semantic link network motion are revealed for the first time. An e-learning environment incorporating the proposed approaches, principles, and strategies to support effective discovery and learning is suggested.

Application of genomics, proteomics and metabolomics in drug discovery, development and clinic

Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug-discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries.

Genetic algorithms for discovery of matrix multiplication methods

We present a parallel genetic algorithm for nding matrix multiplication algo-rithms. For 3 x 3 matrices our genetic algorithm successfully discovered algo-rithms requiring 23 multiplications, which are equivalent to the currently best known human-developed algorithms. We also studied the cases with less mul-tiplications and evaluated the suitability of the methods discovered. Although our evolutionary method did not reach the theoretical lower bound it led to an approximate solution for 22 multiplications.

Relation discovery from web data for competency management

In current organizations, valuable enterprise knowledge is often buried under rapidly expanding huge amount of unstructured information in the form of web pages, blogs, and other forms of human text communications. We present a novel unsupervised machine learning method called CORDER (COmmunity Relation Discovery by named Entity Recognition) to turn these unstructured data into structured information for knowledge management in these organizations. CORDER exploits named entity recognition and co-occurrence data to associate individuals in an organization with their expertise and associates. We discuss the problems associated with evaluating unsupervised learners and report our initial evaluation experiments in an expert evaluation, a quantitative benchmarking, and an application of CORDER in a social networking tool called BuddyFinder.

Community relation discovery by named entities

Discovering who works with whom, on which projects and with which customers is a key task in knowledge management. Although most organizations keep models of organizational structures, these models do not necessarily accurately reflect the reality on the ground. In this paper we present a text mining method called CORDER which first recognizes named entities (NEs) of various types from Web pages, and then discovers relations from a target NE to other NEs which co-occur with it. We evaluated the method on our departmental Website. We used the CORDER method to first find related NEs of four types (organizations, people, projects, and research areas) from Web pages on the Website and then rank them according to their co-occurrence with each of the people in our department. 20 representative people were selected and each of them was presented with ranked lists of each type of NE. Each person specified whether these NEs were related to him/her and changed or confirmed their rankings. Our results indicate that the method can find the NEs with which these people are closely related and provide accurate rankings.

LRD : Latent Relation Discovery for vector space expansion and information retrieval

In this paper, we propose a text mining method called LRD (latent relation discovery), which extends the traditional vector space model of document representation in order to improve information retrieval (IR) on documents and document clustering. Our LRD method extracts terms and entities, such as person, organization, or project names, and discovers relationships between them by taking into account their co-occurrence in textual corpora. Given a target entity, LRD discovers other entities closely related to the target effectively and efficiently. With respect to such relatedness, a measure of relation strength between entities is defined. LRD uses relation strength to enhance the vector space model, and uses the enhanced vector space model for query based IR on documents and clustering documents in order to discover complex relationships among terms and entities. Our experiments on a standard dataset for query based IR shows that our LRD method performed significantly better than traditional vector space model and other five standard statistical methods for vector expansion.

The effect of universal futures on opening and closing stock market price discovery

Purpose – On 29 January 2001, Euronext LIFFE introduced single security futures contracts on a range of global companies. The purpose of this paper is to examine the impact that the introduction of these futures contracts had on the behaviour of opening and closing UK equity returns. Design/methodology/approach – The paper models the price discovery process using the Amihud and Mendelson partial adjustment model which can be estimated using a Kalman filter. Findings – Empirical results show that during the pre-futures period both opening and closing returns under-react to new information. After the introduction of futures contracts opening returns over-react. A rise in the partial adjustment coefficient also takes place for closing returns but this is not large enough to cause over-reaction. Originality/value – This is the first study to examine the impact of a single security futures contract on the speed of spot market price discovery.

Price discovery for Chinese shares cross-listed in multiple markets

In this article we study the relationship between security returns cross-listed on the A share market of China and the H share market at the Stock Exchange of Hong Kong (SEHK). Most of these securities are also cross-listed on other markets. An important feature of this article is that we focus on the multilateral relationships between all cross-listed markets rather than concentrating only on the bi-lateral relationship between A and Hong Kong H shares. Using the impulse response functions and the variance decompositions from a Vector Autoregressive (VAR) process we show that the returns to the A share market are almost exclusively determined by domestic factors. In contrast, we find that the H share market is influenced by both the A share market within China and foreign stock markets elsewhere in the world. Impulse response functions suggest that innovations to the A share market and the Hong Kong H share market are partly transmitted to each other and to stock markets outside China. We show that liquidity has an important role to play in determining the impact that the home market has on cross-listed variance decompositions. © 2012 Copyright Taylor and Francis Group, LLC.

Application of genomics, proteomics and metabolomics in drug discovery, development and clinic

Genomics, proteomics and metabolomics are three areas that are routinely applied throughout the drug-development process as well as after a product enters the market. This review discusses all three 'omics, reporting on the key applications, techniques, recent advances and expectations of each. Genomics, mainly through the use of novel and next-generation sequencing techniques, has advanced areas of drug discovery and development through the comparative assessment of normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and the identification of biomarkers. Proteomics, through techniques including isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems is utilized in multiple areas through the drug development pipeline including target and lead identification, compound optimization, throughout the clinical trials process and after market analysis. Metabolomics, although the most recent and least developed of the three 'omics considered in this review, provides a significant contribution to drug development through systems biology approaches. Already implemented to some degree in the drug-discovery industry and used in applications spanning target identification through to toxicological analysis, metabolic network understanding is essential in generating future discoveries.

Some historical extracts relevant to the discovery and application of the diffraction of X-rays by crystals to contribute to the centennial celebration and the International Year of Crystallography

Illustrative extracts from the writings of Paul P. Ewald and of Max von Laue are presented. The latter in turn contains extensive text contributions from William Lawrence Bragg. These selections we have chosen so as to indicate the nature of the discovery of X-ray diffraction from crystals (experiments undertaken by Friedrich, Knipping and von Laue) and its early and prompt application in crystal structure analyses (by William Henry Bragg and William Lawrence Bragg). The platform for these discoveries was provided by a macroscopic physics problem dealt with by Ewald in his doctoral thesis with Arnold Sommerfeld in the Munich Physics Department, which is also where von Laue was based. W.L. Bragg was a student in Cambridge who used Trinity College Cambridge as his address on his early papers; experimental work was done by him in the Cavendish Laboratory, Cambridge, and also with his father, W.H. Bragg, in the Leeds University Physics Department. Of further historical interest is the award of an Honorary DSc (Doctor of Science) degree in 1936 to Max von Laue by the University of Manchester, UK, while William Lawrence Bragg was Langworthy Professor of Physics there. © 2012 Copyright Taylor and Francis Group, LLC.

Applications of Nonclassical Logic Methods for Purposes of Knowledge Discovery and Data Mining

* The work is partially supported by Grant no. NIP917 of the Ministry of Science and Education – Republic of Bulgaria.

Automatic Discovery of Word Semantic Relations

In this paper, we propose an unsupervised methodology to automatically discover pairs of semantically related words by highlighting their local environment and evaluating their semantic similarity in local and global semantic spaces. This proposal di®ers from previous research as it tries to take the best of two different methodologies i.e. semantic space models and information extraction models. It can be applied to extract close semantic relations, it limits the search space and it is unsupervised.