Staden: using patterns to analyze protein sequences.
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Amino Acid Sequence↗
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Combinatorial Heterogeneous Catalysis-A New Path in an Old Field.
Combinatorial catalysis is the systematic preparation, processing, and testing of large diversities of chemically and physically different materials libraries in a high-throughput fashion. It also embodies microfabrication, robotics, automation, instrumentation, computational chemistry, and large-scale information management (informatics), and as such carries the promise of a renaissance in catalytic reaction engineering. Significant progress has already been made in demonstrating the speed and economic advantage of combinatorial approaches by the discovery of superior catalytic materials in a matter of hours and days, as opposed to the months and years required using traditional methods. Combinatorial methods can also significantly contribute to our understanding of catalytic function by increasing our chances of discovering totally new and unexpected catalytic materials, and by expediting the recognition of trends and patterns of structure-activity relations, from which new catalytic materials can be designed more efficiently. Combinatorial catalysis undoubtedly will be the new paradigm of catalysis research as the industry faces increasing global competition and pressure for the development of environmentally friendly processes at a time when resources for research are diminishing.
Journal Article↗
The formation of learning sets by the chinchilla in an auditory discrimination task.
The performance of 9 chinchillas (Chinchilla lanigera) in a completely computer-automated sound-discrimination experiment was observed using stimulus pairs from a library of 180 complex sounds. Each sound of a pair was 0.2-2.08 sec in duration, separated by an interval of 250 +/- 125 msec. A modified "go/no go" paradigm was used. Licking behavior at a water-delivery tube was occasioned by keeping Ss at about 85% of ad-lib weight by water deprivation. After habituation and blank-trials training stages, sound discrimination was required: If the sounds of a pair were identical, no response was required; if they were different, a fleeing response (crossing a mid-cage barrier) was required. Each problem set utilized a different sound pair, for a total of 90 problems. Therefore, Ss learned to perform general auditory discriminations, not sound-specific discriminations. The chinchillas quickly learned to respond, but not at a rate consistently higher than 75 %-correct. The results were compared to those of other studies of sensory discrimination in monkey and chinchilla. Suggestions were made for minor improvement of the paradigm for use in future sound-discrimination tasks.
Animals↗
Molecular surveillance of European quinolone-resistant clinical isolates of Pseudomonas aeruginosa and Acinetobacter spp. using automated ribotyping.
Nosocomial isolates of Pseudomonas aeruginosa and Acinetobacter spp. exhibit high rates of resistance to antibiotics and are often multidrug resistant. In a previous study (D. Milatovic, A. Fluit, S. Brisse, J. Verhoef, and F. J. Schmitz, Antimicrob. Agents Chemother. 44:1102-1107, 2000), isolates of these species that were resistant to sitafloxacin, a new advanced-generation fluoroquinolone with a high potency and a broad spectrum of antimicrobial activity, were found in high proportion in 23 European hospitals. Here, we investigate the clonal diversity of the 155 P. aeruginosa and 145 Acinetobacter spp. sitafloxacin-resistant isolates from that study by automated ribotyping. Numerous ribogroups (sets of isolates with indistinguishable ribotypes) were found among isolates of P. aeruginosa (n = 34) and Acinetobacter spp. (n = 16), but the majority of the isolates belonged to a limited number of major ribogroups. Sitafloxacin-resistant isolates (MICs > 2 mg/liter, used as a provisional breakpoint) showed increased concomitant resistance to piperacillin, piperacillin-tazobactam, ceftriaxone, ceftazidime, amikacin, gentamicin, and imipenem. The major ribogroups were repeatedly found in isolates from several European hospitals; these isolates showed higher levels of resistance to gentamicin and imipenem, and some of them appeared to correspond to previously described multidrug-resistant international clones of P. aeruginosa (serotype O:12) and Acinetobacter baumannii (clones I and II). Automated ribotyping, when used in combination with more discriminatory typing methods, may be a convenient library typing system for monitoring future epidemiological dynamics of geographically widespread multidrug-resistant bacterial clones.
4-Quinolones↗
A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases.
The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of organic synthesis and biochemical screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compounds in the thousands. With automated synthesis, the number of compounds to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chemical libraries are made wisely. The objective of this work is to provide both quantitative and qualitative characterization of known drugs which will help to generate "drug-like" libraries. In this work we analyzed the Comprehensive Medicinal Chemistry (CMC) database and seven different subsets belonging to different classes of drug molecules. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quantitative characterization based on computed physicochemical property profiles such as log P, molar refractivity, molecular weight, and number of atoms as well as a qualitative characterization based on the occurrence of functional groups and important substructures are developed here. For the CMC database, the qualifying range (covering more than 80% of the compounds) of the calculated log P is between -0.4 and 5.6, with an average value of 2.52. For molecular weight, the qualifying range is between 160 and 480, with an average value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an average value of 97. For the total number of atoms, the qualifying range is between 20 and 70, with an average value of 48. Benzene is by far the most abundant substructure in this drug database, slightly more abundant than all the heterocyclic rings combined. Nonaromatic heterocyclic rings are twice as abundant as the aromatic heterocycles. Tertiary aliphatic amines, alcoholic OH and carboxamides are the most abundant functional groups in the drug database. The effective range of physicochemical properties presented here can be used in the design of drug-like combinatorial libraries as well as in developing a more efficient corporate medicinal chemistry library.
Algorithms↗
High throughput analysis and purification in support of automated parallel synthesis.
Rapid reverse-phase analytical and preparative HPLC methods have been developed for application to parallel synthesis libraries. Gradient methods, short columns, and high flow rates allow analysis of over 300 compounds per day on a single system, or purification of up to 200 compounds per day on a single preparative system. Hardware and software modifications allow continuous unattended use for maximum efficiency and throughput.
Automation↗
Integration of image analysis and robotics into a fully automated colony picking and plate handling system.
We describe here the integration of image analysis and robotics to produce a fully automated colony picking/plate handling system. Biological tests were performed to verify its performance in terms of sterilisation and accuracy of picking. The machine was then used by a single operative to pick a 36,000 clone cDNA library in approximately 42 hrs over 5 days.
Automation↗
Automated metabolic profiling analysis of urinary steroids by a gas chromatography mass spectrometry data system.
A computer system (MSSMET), using methylene unit retention indices for an off-line reverse library search analysis of selected ion chromatograms from gas-liquid chromatographic mass spectrometric data, has been applied for the qualitative and quantitative determination of daily variations in the excreted levels of urinary steroids of two individuals, using capillary column gas-liquid chromatography. Aliquots of 24 h urine collections and morning spot urine samples were examined. The daily excretion pattern of most of the major steroid metabolites was fairly consistent from day to day (i.e. 3 alpha-hydroxy-5 alpha-androstane-17-one, androsterone; 3 alpha-hydroxy-5 beta-androstane-17-one, etiocheolanolone; 3 alpha, 17 alpha, 21-trihydroxy-5 beta-pregnane-11,20-dione, THE; 3 alpha, 11 beta, 17 alpha, 21-tetrahydroxy-5 beta-pregnane-20-one, THF; 3 alpha, 11 beta, 17 alpha, 21-tetrahydroxy-5 alpha-pregnane-20-one; allo-THF; 3 alpha, 17 alpha, 20 alpha, 21-tetrahydroxy-5 beta-pregnane-11-one, cortolone; 3 alpha, 17 alpha, 20 beta, 21-tetrahydroxy-5 beta-pregnane-11-one, beta-cortolone; 5 beta-pregnane-3 alpha, 11 beta,17 alpha,20 alpha,21-pentol, cortol; 5 beta-pregnane-3 alpha, 11 beta, 17 alpha, 20 beta, 21-pentol, beta-cortol), while certain other steroid metabolites had a less consistent excretion pattern (3 beta-hydroxy-5-androstene-17-one, for example). Advantages and disadvantages of using capillary columns for the automated metabolic profile analysis of urinary steroids by reverse library search of selected mass chromatograms.
Adult↗
Combinatorial chemistry, automation and molecular diversity: new trends in the pharmaceutical industry.
Combinatorial chemistry has emerged as a set of novel strategies for the synthesis of large sets of compounds (combinatorial libraries) for biological evaluation. Within a few years combinatorial chemistry has undergone a series of changes in trends, which are closely related to two important factors in libraries: numbers and quality. While the number of compounds in a library may be easily expressed, it is a lot more difficult to indicate the degree of quality of a library. This degree of quality can be split into two aspects: purity and diversity. The changing trends in combinatorial chemistry with respect to the strategies, the technologies, the libraries themselves (numbers and purity aspects) and the molecular diversity are outlined in this paper.
Automation↗
Direct-injection NMR (DI-NMR): a flow NMR technique for the analysis of combinatorial chemistry libraries.
A new tool for analyzing compound libraries by NMR has been developed. Aliquots of solution-state samples (between 120 and 350 microL) are directly injected, using a standard liquids handler, into an NMR (LC-NMR) flow probe. Automated NMR software tracks--and suppresses--intense signals arising from the nondeuterated solvents used (if any) and acquires high-sensitivity one-dimensional 1H NMR spectra. An 88-member combinatorial library, dissolved in DMSO and stored in a 96-well microtiter plate, has been analyzed a number of ways using this technique. This nondestructive technique, which we call direct-injection NMR (DI-NMR) and which is embodied in our versatile automated sample changer (VAST) hardware, has proven to be both routine and robust. Our success in automatically acquiring the NMR data for entire plates of library compounds (within 4-8 h) has caused us to develop new ways to display and analyze the resulting NMR data, as will be shown here.
Chemistry, Organic↗
Compound library management.
The increasing size of the collections used for drug-discovery purposes has demanded both hardware and software automation of compound management in order to cope with the increasing demands of HTS. Splitting the collection into a number of copies in different formats is a desirable approach to keep a balance between rapid response to the demands and best storage conditions. Flexibility to different assay configurations can be provided with the appropriate selection of liquid handlers, and the informatic management systems should be accessible to keep track of the samples and link them to a variety of information that can help interpret HTS data. In this respect, QC data on the compounds and quality checks of the equipment used are highly desirable. It is also prudent for a large organization with different research sites to have a unified database and compatible plate format and concentration in order to be able to exchange samples and share screening results. The accomplishment of all the previous requirements is the only way to ensure an efficient and effective compound library management.
Computational Biology↗
Single cell assay with an automated capillary microinjection system.
An automated capillary microinjection system with computer-controlled positioning of the cells and of the capillary, and its applications and advantages, is described. The system is easy in handling and manipulation. About 1500 injections are possible in 1 h, with high reproducibility. In cytoplasmic and nuclear injections more than 90 and 85% of the cells are successfully injected. Using FITC-dextran at a concentration of 0.5% as a fluorescently labeled coinjection marker, 99% of the cells can be retrieved in culture medium even 48 h after injection. The coordinates of the cells are stored in the computer and accuracy in statistical evaluation of experiments is improved in comparison to the manual techniques. Methods for preparation and handling of glass capillaries were developed resulting in reproducible form and significantly reduced clogging rate. The improved characteristics offered by this system are demonstrated in studies leading to the confirmation of existence of an mRNA inhibiting DNA synthesis in cells. Functional screening by cell injections of cDNA libraries and of size-fractionated mRNA molecules can be performed efficiently with the automated microinjection system.
Autoradiography↗
Identification of clinical isolates of gram-negative nonfermentative bacteria by an automated cellular fatty acid identification system.
An automated cellular fatty acid (CFA) bacterial identification system, Microbial Identification System (MIS; Microbial ID, Newark, Del.), was compared with a conventional system for the identification of 573 strains of gram-negative nonfermentative bacteria. MIS identifications were based exclusively on the CFA composition following 22 to 26 h of growth at 28 degrees C on Trypticase soy agar. MIS identifications were listed with a confidence measurement (similarity index [SI]) on a scale of 0 to 1.0. A value of greater than or equal to 0.5 was considered a good match. The MIS correctly listed as the first choice 478 of 532 (90%) strains contained in the data base. However, only 314 (59%) had SI values of greater than or equal to 0.5. Of the 54 strains in which there was not agreement, 37 belonged to the genera Acinetobacter, Moraxella, or Alcaligenes or were Pseudomonas pickettii. Reproducibility studies suggest that SI variation is most likely a function of a difference in culture age at the time of analysis, which is due to the relatively low temperature and time of incubation. Other discrepancies were attributable to insufficiently characterized library entries or an inability to differentiate chemotaxonomically closely related species. The MIS, as the first automated CFA identification system, is an accurate, efficient, and relatively rapid method for the identification of gram-negative nonfermentative bacteria. The development of a CFA library with the media and incubation conditions routinely used for the isolation of clinical pathogens could further decrease the identification time and provide an increase in accuracy.
Bacteriological Techniques↗
Amino terminal sequence of the mitochondrial protein mtDBP-C: similarity with nonhistone chromosomal proteins HMG 1 and 2.
We have previously reported the characterization of a DNA-binding protein isolated from Xenopus laevis mitochondria (mtDBP-C). The amino terminal sequence of this protein (26 residues) has been determined by automated Edman degradation and used to search for sequence similarity with the NBRF library. A segment of 17 amino acids displays 47.1% of identity with proteins HMG-1 and 2 of various vertebrate species.
Amino Acid Sequence↗
Structural and comparative analysis of the mouse gene for pigment epithelium-derived factor (PEDF).
PURPOSE: Pigment epithelium-derived factor (PEDF), a neurotrophic protein, is a member of the serine protease inhibitor supergene family. PEDF promotes both neuronal phenotype in cultured Y79 cells and neuronal survival in cultured cerebellar granulocytes. The purpose of this study was to clone the mouse PEDF gene and to determine its structure and levels of expression in different tissues. METHODS: The mouse PEDF cDNA was cloned from a mouse liver cDNA library using human PEDF cDNA as a probe. The mouse PEDF gene was cloned from a mouse ES genomic P1 library. DNA sequencing was performed using a PE-Applied Biosystems model 373 automated fluorescent sequencer. RESULTS: The mouse PEDF cDNA is 1461 bp in length and contains an open reading frame of 417 amino acids. The mouse PEDF gene spans approximately 13 kb and, like the human, it is fragmented into 8 exons. The splice sites follow the AG/GT consensus rule. Southern blot analysis indicates that the mouse genome contains only one gene for PEDF. Northern blot analysis shows the presence of the PEDF transcript in a broad range of adult mouse tissues with liver showing the highest level of expression. CONCLUSIONS: The mouse and human PEDF promoters share overall 27% similarity but are nearly identical between mouse +86 to -166 and human +102 to -96. The present study will allow us to move from in vitro experiments to in vivo studies through the development of a "knock-out" mouse model.
Animals↗
Evaluation of human-readable annotation in biomolecular sequence databases with biological rule libraries.
MOTIVATION: Computer-based selection of entries from sequence databases with respect to a related functional description, e.g. with respect to a common cellular localization or contributing to the same phenotypic function, is a difficult task. Automatic semantic analysis of annotations is not only hampered by incomplete functional assignments. A major problem is that annotations are written in a rich, non-formalized language and are meant for reading by a human expert. This person can extract from the text considerably more information than is immediately apparent due to his extended biological background knowledge and logical reasoning. APPROACH: A technique of automated annotation evaluation based on a combination of lexical analysis and the usage of biological rule libraries has been developed. The proposed algorithm generates new functional descriptors from the annotation of a given entry using the semantic units of the annotation as prepositions for implications executed in accordance with the rule library. RESULTS: The prototype of a software system, the Meta_A(nnotator) program, is described and the results of its application to sequence attribute assignment and sequence selection problems, such as cellular localization and sequence domain annotation of SWISS-PROT entries, are presented. The current software version assigns useful subcellular localization qualifiers to approximately 88% of all SWISS-PROT entries. As shown by demonstrative examples, the combination of sequence and annotation analysis is a powerful approach for the detection of mutual annotation/sequence inconsistencies. AVAILABILITY: Results for the cellular localization assignment can be viewed at the URL http://www.bork. embl-heidelberg.de/CELL_LOC/CELL_LOC.html.
Algorithms↗
Spreadsheets for automated data collection, analysis, and report generation for diagnostic medical physics: publicly available on the world wide web.
A library of spreadsheets has been developed to facilitate the practice of diagnostic physics quality assurance. Each spreadsheet follows a standard template and uses the highest ranking controlling authority (within the United States) for pass/fail criteria and testing procedures. Sheets are now available for CT (computed tomography), MR (magnetic resonance), US (ultrasound), screen-film mammography, stereotactic breast, radiographic, fluoroscopic, computed radiography, film digitizer, and display quality control. Use is made of spreadsheet "workbooks" so that each testing event is a single sheet in the workbook. Thus, results over the lifetime of the device are gathered in a single file, and historical control charts are gathered on the first sheet. The spreadsheets are available at http://radweb.mcis.washington.edu/~sglanger, and are released under the Gnu (a recursive acronym. Gnu's Not Unix) public license. It is expected that others will add improvements, and they are expected and requested to submit them back to the author to be shared with the diagnostic physicist community at large.
Diagnostic Imaging↗
Technology at Washington University School of Medicine Library: BACS, PHILSOM, and OCTANET.
A brief overview of the Bibliographic Access and Control System developed by the Washington University School of Medicine Library is presented. Because the system has been described in two previous reports, this paper focuses on its relationship to other automated programs (i.e., PHILSOM and OCTANET), education of users, evaluation of the system, and outreach to the medical center. In operation for more than two years, BACS represents the computerization of much of the managerial and operational functions of the library, and marks the completion of stage 1 of the three stages of library evolution described in the AAMC report Academic Information in the Academic Health Sciences Center: Roles for the Library in Information Management.
Computers↗