Structure-directed combinatorial library design

In recent years pharmaceutical companies have utilized structure-based drug design and combinatorial library design techniques to speed up their drug discovery efforts. Both approaches are routinely used in the lead discovery and lead optimization stages of the drug discovery process. Fragment-based drug design, a new power tool in the drug design toolbox, is also gaining acceptance across the pharmaceutical industry. This review will focus on the interplay between these three design techniques and recent developments in computational methodologies that enhance their integration. Examples of successful synergistic applications of these three techniques will be highlighted. Opinion regarding possible future directions of the field will be given.     

DNA微阵列技术在阿尔茨海默病及其防治药物研究中的应用

在生物技术飞速发展的今天,DNA微阵列已成为功能基因组时代大规模、高通量乃至全基因组表达和功能研究的有力工具。阿尔茨海默病,因其发病机制复杂,迄今尚无定论,因此在临床上也缺乏有效的防治药物。简要综述DNA微阵列技术应用于阿尔茨海默病发病机制、早期诊断及防治药物等方面的研究进展。     

Why and how terrestrial plants exchange gases with air

This work is intended as a review of gas exchange processes between the atmosphere and the terrestrial vegetation, which have been known for more than two centuries since the discovery of photosynthesis. The physical and biological mechanisms of exchange of carbon dioxide, water vapour, volatile organic compounds emitted by plants and air pollutants taken up by them, is critically reviewed. The role of stomatal physiology is emphasised, as it controls most of these processes. The techniques used for measurement of gas exchange fluxes between the atmosphere and vegetation are outlined.     

The early history of the polarizing region: from classical embryology to molecular biology

The polarizing region of the developing limb bud is one of the best known examples of a cell-cell signalling centre that mediates patterning in vertebrate embryos. This article traces some highlights in the history of the polarizing region from its discovery by John Saunders and early work that defined polarizing activity through a period in which modelling was pre-eminent, right up to the discovery of defined molecules with polarizing activity. There is a particular focus on the discovery that retinoic acid could mimic signalling of the polarizing activity and this finding is then set in the context of more recent work which implicates Shh and BMPs in mediating polarizing activity.     

Finding complex biological relationships in recent PubMed articles using Bio-LDA

The overwhelming amount of available scholarly literature in the life sciences poses significant challenges to scientists wishing to keep up with important developments related to their research, but also provides a useful resource for the discovery of recent information concerning genes, diseases, compounds and the interactions between them. In this paper, we describe an algorithm called Bio-LDA that uses extracted biological terminology to automatically identify latent topics, and provides a variety of measures to uncover putative relations among topics and bio-terms. Relationships identified using those approaches are combined with existing data in life science datasets to provide additional insight. Three case studies demonstrate the utility of the Bio-LDA model, including association predication, association search and connectivity map generation. This combined approach offers new opportunities for knowledge discovery in many areas of biology including target identification, lead hopping and drug repurposing.     

How Owen ‘stole’ the Dodo: academic rivalry and disputed rights to a newly-discovered subfossil deposit in nineteenth century Mauritius

The discovery of the first fossil Dodo remains in the Mare aux Songes marsh, Mauritius, in 1865 resulted in a race to publish on the Dodo's post-cranial anatomy. George Clark, probable discoverer of the fossil site, sent consignments of bones initially to Richard Owen (British Museum), and subsequently to Alfred Newton, Cambridge, via Alfred's brother Edward, who was stationed on Mauritius. After receiving the first consignment, Owen intercepted material intended for Alfred, and abused his position to forestall any complaints from Alfred. Owen published on the Dodo first, while Clark was financially rewarded, but Clark's ensuing arguments over the site discovery with railway engineer, Harry Higginson, and attempt to cover up the abundance of Dodo bones, thus keeping prices high, concluded in a bitter rivalry that was never resolved between Owen and the Newton brothers.     

Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent,TR beta subtype-selective thyromimetics

In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.     

Metagenomics-based drug discovery and marine microbial diversity

As the global threat of drug-resistant pathogens continues to rise, new strategies and resources are required to accelerate and advance the drug discovery process. We believe that rapid progress in metagenomics has opened up a new era in the study of marine microbial diversity that enables direct access to the genomes of numerous uncultivable microorganisms. This review outlines recent developments and future trends in metagenomics-based drug discovery in marine microbial communities and their associated chemical prosperity.     

Simulating multiplexed SNP discovery rates using base-specific cleavage and mass spectrometry

MOTIVATION: Single Nucleotide Polymorphisms (SNPs) are believed to contribute strongly to the genetic variability in living beings, and SNP and mutation discovery are of great interest in today's Life Sciences. A comparatively new method to discover such polymorphisms is based on base-specific cleavage, where resulting cleavage products are analyzed by mass spectrometry (MS). One particular advantage of this method is the possibility of multiplexing the biochemical reactions, i.e. examining multiple genomic regions in parallel. Simulations can help estimating the performance of a method for polymorphism discovery, and allow us to evaluate the influence of method parameters on the discovery rate, and also to investigate whether the method is well suited for a certain genomic region. RESULTS: We show how to efficiently conduct such simulations for polymorphism discovery using base-specific cleavage and MS. Simulating multiplexed polymorphism discovery leads us to the problem of uniformly drawing a multiplex. Given a multiset of natural numbers we want to uniformly draw a subset of fixed cardinality so that the elements sum up to some fixed total length. We show how to enumerate multiplex layouts using dynamic programming, which allows us to uniformly draw a multiplex.     

Testing Methods: The Evaluation of Discovery Operations in Evolutionary Biology

Scientific discovery requires both abstract, theoretically defined concepts and discovery operations formed by sets of rules that permit the empirical detection of instances of those concepts. In this paper, I examine the ontological status of discovery operations and the tests employed to evaluate them in evolutionary biology. Attention is drawn to the distinction between nomothetic (universal, predictive) and ideographic (historical, retrodictive) discovery operations, and between complementary and exclusive discovery operations. Three types of tests of discovery operations are commonly employed in evolutionary biology. Theoretical tests aim to show that a discovery operation is inconsistent with accepted, well-corroborated, empirical theories. Empirical tests evaluate the performance of competing discovery operations in terms of their results when applied to the same empirical data sets. Philosophical tests aim to show that an operation is inconsistent with logical and epistemological principles. Appropriately designed theoretical and philosophical tests of ideographic discovery operations may be scientifically valid. Empirical tests, however, are incapable of evaluating the scientific merits of competing discovery operations. Nonetheless, empirical comparisons (not tests ) of competing discovery operations may provide insight into the ways discovery operations may be misleading and therefore may play an important role in stimulating critical debate and eventually establishing a scientifically optimal operation. In practice, theoretical and philosophical tests are often combined to test competing discovery operations as rigorously as possible.     

What is the story telling? Examining discovery with the storytelling method (TSM) and testing with a control group.

This research tested the storytelling method of dream interpretation (TSM), which expands on previously established methods of interpretation by adding an additional step that involves creating a story after word association is completed. Two studies tested the method, the efficacy of the method, and assessed dreamer discovery. Study 1 revealed a significant relationship between word association and discovery and between the story that was created and discovery. Furthermore, word association significantly predicted discovery in Block 1, but the story added to the prediction of discovery, above word association alone, in Block 2. When testing with a control group, there was a significant difference between the group who interpreted a dream with TSM and those who used the method with association alone. Results reveal a significant difference between the groups, indicating that discovery, insight, and bridging to waking-day circumstances was more likely with TSM when participants used their own dream rather than a dream that was not their own. These findings extend previous research and show that TSM is a brief, effective dream technique that shows therapeutic promise. Limitations and future research are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discovery and Validation of Clinical Biomarkers of Cancer: A Review Combining Metabolomics and Proteomics

Early detection and diagnosis of cancer can allow timely medical intervention, which greatly improves chances of survival and enhances quality of life. Biomarkers play an important role in assisting clinicians and health care providers in cancer diagnosis and treatment follow‐up. In spite of years of research and the discovery of thousands of candidate cancer biomarkers, only a few have transitioned to routine usage in the clinic. This review highlights advances in proteomics technologies that have enabled high rates of discovery of candidate cancer biomarkers and evaluates integration with other omics technologies to improve their progress through to validation and clinical translation. Furthermore, it gauges the role of metabolomics technology in cancer biomarker research and assesses it as a complementary tool in aiding cancer biomarker discovery and validation.     

Using NMR for ligand discovery and optimization

Several recent technology-driven advances in the area of NMR have rekindled an interest in the application of the technology to problems in drug discovery and development. A unique aspect of NMR is that it has applicability in broadly different areas of the drug discovery and optimization processes. NMR techniques for screening aimed at the discovery of novel ligands or low molecular weight structures for fragment-based build up procedures are being applied commonly in the industry. Application of NMR in structure-guided drug design and metabonomics are also becoming routine. We present an overview of some of the most recent NMR developments in these areas.     

Structure-based design of COX-2 selectivity into flurbiprofen

Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-1 and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1.     

Optimal analysis of complex protein mass spectra

Due to physical and chemical phenomena, a simple sample can give rise to a complex mass spectrum with many more peaks than the number of molecular species present in the sample. We link peaks within and between different spectra, and come up with an advanced analysis approach to produce reliable estimates of the molecule masses and abundances. By linking peaks, we can locate multiple‐charge peaks at the correct position in the spectrum, we can deconvolute complex regions with many overlapping peaks by including information from related regions with lower complexity and higher resolution, and we reduce the total number of observed peaks in a spectrum to a much smaller number of underlying molecular species. In this paper we properly model 29 952 peaks in 64 spectra, using only 39 location parameters and one shape parameter. This major reduction from many different molecules to a limited set of molecular species reduces the statistical test multiplicity for biomarker discovery and therefore we imply that the reduction should eventually increase the biomarker discovery power significantly, too.     

A new diet for yeast to improve biofuel production

In 2010, our group announced the discovery of two cellodextrin transporter families from the cellulolytic fungus, Neurospora crassa. Furthermore, we demonstrated the utility of these transporters in the production of lignocellulosic biofuels. This discovery was made possible by a decision to systematically study cell wall degradation by N. crassa. The identified transport pathway has opened up a new way of thinking about microbial fermentation of hexoses as well as pentoses derived from plant cell walls.?Integrating this pathway with the endogenous metabolism and signaling networks of S. cerevisiae is now a major goal of our group.     

The knowledge-integrated network biomarkers discovery for major adverse cardiac events

The mass spectrometry (MS) technology in clinical proteomics is very promising for discovery of new biomarkers for diseases management. To overcome the obstacles of data noises in MS analysis, we proposed a new approach of knowledge-integrated biomarker discovery using data from Major Adverse Cardiac Events (MACE) patients. We first built up a cardiovascular-related network based on protein information coming from protein annotations in Uniprot, protein-protein interaction (PPI), and signal transduction database. Distinct from the previous machine learning methods in MS data processing, we then used statistical methods to discover biomarkers in cardiovascular-related network. Through the tradeoff between known protein information and data noises in mass spectrometry data, we finally could firmly identify those high-confident biomarkers. Most importantly, aided by protein-protein interaction network, that is, cardiovascular-related network, we proposed a new type of biomarkers, that is, network biomarkers, composed of a set of proteins and the interactions among them. The candidate network biomarkers can classify the two groups of patients more accurately than current single ones without consideration of biological molecular interaction.