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A searching and reporting system for relational databases using a graph-based metadata representation.

Relational databases are the current standard for storing and retrieving data in the pharmaceutical and biotech industries. However, retrieving data from a relational database requires specialized knowledge of the database schema and of the SQL query language. At Anadys, we have developed an easy-to-use system for searching and reporting data in a relational database to support our drug discovery project teams. This system is fast and flexible and allows users to access all data without having to write SQL queries. This paper presents the hierarchical, graph-based metadata representation and SQL-construction methods that, together, are the basis of this system's capabilities.

Computer Simulation↗

HostDesigner: a program for the de novo structure-based design of molecular receptors with binding sites that complement metal ion guests.

This paper describes a novel approach to the discovery of host structures with binding sites that complement targeted metal ion guests. This approach uses a de novo structure-based design strategy that couples molecular building algorithms with scoring functions to prioritize candidate structures. The algorithms described herein have been implemented in a program called HostDesigner, the first structure-based design software specifically created for the discovery of metal ion receptors. HostDesigner generates and evaluates millions of candidate structures within minutes, rapidly identifying three-dimensional architectures that position binding sites to provide an optimal interaction with the metal ion.

Algorithms↗

Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III.

Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.

Acetaminophen↗

Search for improved host architectures: application of de novo structure-based design and high-throughput screening methods to identify optimal building blocks for multidentate ethers.

This paper presents a computational approach to the deliberate design of improved host architectures. The approach, which involves the use of computer-aided design software, is illustrated by application to cation hosts containing multiple aliphatic ether oxygen binding sites. De novo molecule building software, HostDesigner, is interfaced with molecular mechanics software, GMMX, providing a tool for generating and screening millions of potential bidentate building block structures. Enhanced cation binding affinity can be achieved when highly organized building blocks are used to construct macrocyclic hosts.

Journal Article↗

Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships.

Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed.

DNA-Binding Proteins↗

Probing spin accumulation in Ni/Au/Ni single-electron transistors with efficient spin injection and detection electrodes.

We have investigated spin accumulation in Ni/Au/Ni single-electron transistors assembled by atomic force microscopy. The fabrication technique is unique in that unconventional hybrid devices can be realized with unprecedented control, including real-time tunable tunnel resistances. A grid of Au disks, 30 nm in diameter and 30 nm thick, is prepared on a SiO2 surface by conventional e-beam writing. Subsequently, 30 nm thick ferromagnetic Ni source, drain, and side-gate electrodes are formed in similar process steps. The width and length of the source and drain electrodes were different to exhibit different coercive switching fields. Tunnel barriers of NiO are realized by sequential Ar and O2 plasma treatment. By use of an atomic force microscope with specially designed software, a single nonmagnetic Au nanodisk is positioned into the 25 nm gap between the source and drain electrodes. The resistance of the device is monitored in real time while the Au disk is manipulated step-by-step with angstrom-level precision. Transport measurements in magnetic field at 1.7 K reveal no clear spin accumulation in the device, which can be attributed to fast spin relaxation in the Au disk. From numerical simulations using the rate-equation approach of orthodox Coulomb blockade theory, we can put an upper bound of a few nanoseconds on the spin-relaxation time for electrons in the Au disk. To confirm the magnetic switching characteristics and spin injection efficiency of the Ni electrodes, we fabricated a test structure consisting of a Ni/NiO/Ni magnetic tunnel junction with asymmetric dimensions of the electrodes similar to those of the single-electron transistors. Magnetoresistance measurements on the test device exhibited clear signs of magnetic reversal and a maximum tunneling magnetoresistance of 10%, from which we deduced a spin polarization of about 22% in the Ni electrodes.

Electrodes↗

DBParser: web-based software for shotgun proteomic data analyses.

We describe a web-based program called 'DBParser' for rapidly culling, merging, and comparing sequence search engine results from multiple LC-MS/MS peptide analyses. DBParser employs the principle of parsimony to consolidate redundant protein assignments and derive the most concise set of proteins consistent with all of the assigned peptide sequences observed in an experiment or series of experiments. The resulting reports summarize peptide and protein identifications from multidimensional experiments that may contain a single data set or combine data from a group of data sets, all related to a single analytical sample. Additionally, the results of multiple experiments, each of which may contain several data sets, can be compared in reports that identify features that are common or different. DBParser actively links to the primary mass spectral data and to public online databases such as NCBI, GO, and Swiss-Prot in order to structure contextually specific reports for biologists and biochemists.

Amino Acid Sequence↗

Homology model directed alignment selection for comparative molecular field analysis: application to photosystem II inhibitors.

The use of a computational docking protocol in conjunction with a protein homology model to derive molecular alignments for Comparative Molecular Field Analysis (CoMFA) was examined. In particular, the DOCK program and a model of the herbicidal target site, photosystem II (PSII), was used to derive alignments for two PSII inhibitor training sets, a set of benzo- and napthoquinones and a set of butenanilides. The protein design software in the QUANTA molecular modeling package was used to develop a homology model of spinach PSII based on the reported amino acid sequence and the X-ray crystal structure of the purple bacterium reaction center. The model is very similar to other reported PSII protein homology models. DOCK was then used to derive alignments for CoMFA modeling by docking the inhibitors in the PSII binding pocket. The molecular alignments produced from docking yielded highly predictive CoMFA models. As a comparison, the more traditional atom-atom alignments of the same two training sets failed to produce predictive CoMFA models. The general utilities of this application for homology model refinement and as an alternative scoring method are discussed.

Amino Acid Sequence↗

The dream of consensus: finding common ground in a bioethical context.

Consensus is the holy grail of bioethics, the lynch pin of the assumption that well informed, well intentioned people may reach generally acceptable positions on ethically contentious issues. It has been especially important in bioethics, where advancing technology has assured an increasing field of complex medical dilemmas. This paper results on the use of a multicriterion decision making system (MCDM) analyzing group process in an attempt to better define hospital policy. In a pilot program at The Hospital for Sick Children, Toronto, a series of small scale focus groups was constituted to examine criteria defining organ transplant eligibility. Criteria were organized hierarchically using the Analytic Hierarchy Process, an MCDM approach, and the resulting data was analyzed using Expert Choice 9.0, software designed to facilitate AHP analysis. Qualitative and quantitative analysis map barriers to practical consensus in a way not previously possible.

Child↗

Electrical activity from colon overlaps with normal gastric electrical activity in cutaneous recordings.

The stability of EGG recordings is affected by a variety of artifacts. The aim of this study was to investigate possible overlapping of dominant frequencies in recorded cutaneous electrical activity arising simultaneously from the stomach and/or colon. Ten normal volunteers, eight posttotal colectomy patients, and four patients posttotal gastrectomy were studied. Fasting cutaneous recordings were obtained using four pediatric ECG electrodes attached to the abdominal surface. Electrical activity was recorded and digitally analyzed using custom-designed software. Spectral analysis after gastrectomy and colectomy showed persistence of power peaks in the gastric electrical activity range of frequency (2.5-3.75 cpm). In conclusion, noninvasively obtained colonic frequencies overlap EGG. This hypothesis is supported by the persistence of power peaks in the EGG range of frequency after gastrectomy and colectomy. Therefore, we conclude that contribution of electrical activity arising from the colon could substantially affect EGG recordings.

Aged↗

A continuing education programme for general practitioners. Status report after 5 years of function.

In 1992, following newly issued university regulations, the board of the School of Dental Medicine of the University of Geneva decided to establish a structured continuing education course programme for practising dentists in an effort to better meet the school's continuing education mandate. The programme started in January 1994 and was structured so that regular courses would be offered in each discipline of dentistry. The course contents were aimed at satisfying the demands of practising dentists, but it was also established that basic science issues and theoretical concepts should be included. Possible course formats were "conference", "hands-on", "clinical" and "seminar". The courses were meant as a form of knowledge transfer from the school to the practising community, but also as a means to generate revenue for research and teaching programmes. Operative aspects were supervised by a small staff which was assisted by computer software designed to handle all procedural steps of course administration, participant registration, accounting, communication. The dentists' responses were rewarding in that attendance was very satisfactory. Closer scrutiny of our data, however, indicates that our impact is still low since at best only 20% of the course-hours required by the Swiss dental association are actually taken. Both course and programme evaluations were satisfactory and are discussed using the Harden and Laidlaw CRISIS criteria.

Adult↗

Effect of type of practice in a computer-aided design environment in visualizing three-dimensional objects from two-dimensional orthographic projections.

The purpose of this study was to determine the effect of practice in manipulating 2- and 3-dimensional (D) wireframe images on a learner's ability to visualize 3-D objects. Practice, either rotational or not, consisted of visualizing 2- and 3-D objects generated by personal computer (PC)-based computer-assisted design software. Results indicated that participants in the rotation treatment group performed significantly better than those in either the nonrotation or control group on measures of spatial ability and 3-D visualization ability. Both treatment groups performed significantly better than the control group on measures of metacognition, effort, and worry. These results support a conclusion that spatial ability can be improved through practice that allows the learner to see the relationship between the 2-D and 3-D features of objects.

Adult↗

Evolutionary computation.

Evolution does not require DNA, or even living organisms. In computer science, the field known as 'evolutionary computation' uses evolution as an algorithmic tool, implementing random variation, reproduction and selection by altering and moving data within a computer. This harnesses the power of evolution as an alternative to the more traditional ways to design software or hardware. Research into evolutionary computation should be of interest to geneticists, as evolved programs often reveal properties - such as robustness and non-expressed DNA - that are analogous to many biological phenomena.

Algorithms↗

Digital imaging of umbelliferone clearance: a method for repeated measurements of cerebral cortical blood flow with high temporal and spatial resolution.

We have developed a procedure for digital imaging of the exposed cerebral cortex during elution of a fluorescent dye. This avoids disturbing the cortex and has provided a method for the repeated estimation of regional CBF (rCBF) with a high topographical resolution. Under varying conditions of MABP and arterial blood gases, grey-level images of the exposed cortex irradiated with ultraviolet light (340 or 370 nm) were digitised (8 bits) at 15-s intervals after the injection of 1-2 ml of saturated umbelliferone solution into the lingual or external carotid artery of anaesthetised cats and rabbits. Specifically designed software allowed (a) regions of interest (ROIs) in the exposed cortex to be defined that were automatically applied to the sequence of images in a selected clearance and (b) solution of the initial slope equation for rCBF from the decay in grey-level fluorescence by exponential regression. Separate software that solved the equation at the level of a single pixel allowed a pseudocolour map of cortical rCBF to be generated. The factors affecting the resolution of this technique have been identified and quantified. Thus consistent and reproducible results were obtained provided that the fluorescence enhancement exceeded 20 grey levels and the r2 coefficient for regression was 90% or above. Mean rCBF values of 99.5 [95% confidence interval (CI), 89.4-110] ml 100 g-1 min-1 were obtained for rabbits (N = 12; mean MABP = 75.2; mean PaCO2 = 32.9; PaO2 = 111.8; pH 7.38) and 65.1 (95% CI, 55.1-75.1) ml 100 g-1 min-1 for cats (N = 8; mean MABP = 92.8; PaCO2 = 31.5; PaO2 = 114.6, pH 7.40).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Preliminary results from the use of the novel Interactive binocular treatment (I-BiT) system, in the treatment of strabismic and anisometropic amblyopia.

BACKGROUND: We have developed a novel application of adapted virtual reality (VR) technology, for the binocular treatment of amblyopia. We describe the use of the system in six children. METHODS: Subjects consisted of three conventional treatment 'failures' and three conventional treatment 'refusers', with a mean age of 6.25 years (5.42-7.75 years). Treatment consisted of watching video clips and playing interactive games with specifically designed software to allow streamed binocular image presentation. RESULTS: Initial vision in the amblyopic eye ranged from 6/12 to 6/120 and post-treatment 6/7.5 to 6/24-1. Total treatment time was a mean of 4.4 h. Five out of six children have shown an improvement in their vision (average increase of 10 letters), including those who had previously failed to comply with conventional occlusion. CONCLUSIONS: Improvements in vision were demonstrable within a short period of time, in some children after 1 h of treatment. This system is an exciting and promising application of VR technology as a new treatment for amblyopia.

Amblyopia↗

A novel system for collecting longitudinal self-reported dietary consumption information: the internet data logger (iDL).

As diet has been considered as the major exposure pathway for toxic chemicals, such as heavy metals and pesticides, we have developed a web-based questionnaire system, the internet data logger (iDL), in order to facilitate the collection of detailed self-recording of standardized daily dietary consumption. An iDL prototype optimized for hand-held devices was tested in the on-going Children's Pesticide Exposure Study (CPES) in Atlanta, GA in which 15 consecutive days of dietary consumption information were recorded by 11 children or their parents and transmitted to a server via broadband wireless internet connection. Participants spent an average of 6.2 min in day 1 to enter a meal into iDL and approximately 4 min per meal for the remaining 14 study days. Approximately 75% of 446 total meals were entered into iDL on the date of consumption. A within-person comparison revealed that many food items recorded on paper diary were later classified as "unknown" according to iDL standards due to the lack of detailed information provided by the participants. The development of iDL represents a novel and pioneering tool, which integrates dietary data collection, transmission, and management in a real-time and automated manner. iDL provides the needed flexibility and mobility for research focused on collecting not only dietary consumption data but also other time-sensitive behavior data. This study has demonstrated that iDL can be deployed to collect long-term dietary consumption information in a population-based study, though future modifications/enhancements will undoubtedly improve its usability and application.

Child↗

Large-scale gene expression analysis in molecular target discovery.

The evolution of simple arrays consisting of a few genes to ones composed of thousands of genes and/or ESTs has allowed investigators unprecedented views of the molecular mechanisms within cells. Due to the enormous quantities of information derived from microarray analysis, new types of problems have surfaced, such as where to store all of the data. The ability to solve database or statistical problems has required the bench biologist to collaborate with database developers, software designers and statisticians to determine solutions for storage, analysis and interpretation of microarray data. The collaborative effort between these extremely diverse disciplines has led to the development of creative database query and gene expression analysis tools, producing significant reductions in the time required by researchers to filter through the datasets and discover the key processes perturbed by the diseases of interest. Both unsupervised and supervised analysis methods have been applied to gene expression data leading to the discovery of novel therapeutic targets and diagnostic markers. Furthermore, tumor classification based on their respective molecular fingerprints has led to the classification of cancer subtypes and the discovery of novel molecular taxonomies that may eventually lead to improved patient stratification and superior therapeutic strategies.

Databases, Factual↗