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PubMed1994

Design and application of PDBlib, a C++ macromolecular class library.

PDBlib is an extensible object-oriented class library written in C++ for representing the three-dimensional structure of biological macromolecules. The software design strategy, features of many of the 129 classes currently distributed with the library, and two sample applications which use the library are described. Version 1.0 of the library represents the structural features of proteins, DNA, RNA and complexes thereof, at a level of detail on a par with that which can be parsed from a Protein Data Bank (PDB) entry. However, the memory-resident representation of the macromolecule is independent of the PDB entry and can be obtained from other sources, e.g. relational and object-oriented databases. PDBlib classes are organized into four categories: (i) classes that model the macromolecule; (ii) classes that enhance the extensibility of the library; (iii) classes that provide navigation facilities of the object-oriented macromolecular structure representation; and (iv) a class that loads a PDB file into the memory-resident object-oriented representation. A number of general-purpose procedures that return features of this representation and that are relevant to all biological disciplines are included in (i). The library has been used to develop PDBtool, a prototype structure verification tool, and PDBview, a structure rendering tool that requires no specialized graphics hardware and software. Current work centers on making the macromolecular structures represented by PDBlib persistent using a commercial object-oriented database and providing an additional class library, MMQLlib, to query those structures.

Databases, Factual↗
PubMed2006

LitMiner: integration of library services within a bio-informatics application.

BACKGROUND: This paper examines how the adoption of a subject-specific library service has changed the way in which its users interact with a digital library. The LitMiner text-analysis application was developed to enable biologists to explore gene relationships in the published literature. The application features a suite of interfaces that enable users to search PubMed as well as local databases, to view document abstracts, to filter terms, to select gene name aliases, and to visualize the co-occurrences of genes in the literature. At each of these stages, LitMiner offers the functionality of a digital library. Documents that are accessible online are identified by an icon. Users can also order documents from their institution's library collection from within the application. In so doing, LitMiner aims to integrate digital library services into the research process of its users. METHODS: Case study RESULTS: This integration of digital library services into the research process of biologists results in increased access to the published literature. CONCLUSION: In order to make better use of their collections, digital libraries should customize their services to suit the research needs of their patrons.

Journal Article↗
PubMed2004

Designing combinatorial libraries optimized on multiple objectives.

The recent emphasis in combinatorial library design has shifted from the design of very large diverse libraries to the design of smaller more focused libraries. Typically the aim is to incorporate as much knowledge into the design as possible. This knowledge may relate to the target protein itself or may be derived from known active and inactive compounds. Other factors should also be taken into account, such as the cost of the library and the physicochemical properties of the compounds that are contained within the library. Thus, library design is a multi objective optimization problem. Most approaches to optimizing multiple objectives are based on aggregation methods whereby the objectives are assigned relative weights and are combined into a single fitness function. A more recent approach involves the use of a Multiobjective Genetic Algorithm in which the individual objectives are handled independently without the need to assign weights. The result is a family of solutions each of which represents a different compromise in the objectives. Thus, the library designer is able to make an informed choice on an appropriate compromise solution.

Combinatorial Chemistry Techniques↗
PubMed2002

Testing non-additivity of biological activity in a combinatorial library.

Combinatorial chemistry offers new opportunities to generate and analyze QSAR data. Traditional QSAR attempts to correlate activity with structure. With combinatorial chemistry, it is possible to correlate activity directly with the reagents used in a combinatorial library. If one can determine which reagents lead to the compounds of highest activities, it may then be possible to predict active compounds in virtual libraries of 10(6) to 10(10) compounds. This would greatly facilitate library design and provide confidence that the best compounds are being considered for synthesis. An important question is whether the activity of a product molecule can be considered as a sum of its components. This is referred to as additivity between reagents. If there is non-additivity, it is necessary to identify and include the non-additive terms in the model in order to improve QSAR models. Presented here are methods for developing QSAR models relating compound activity to reagents and a method for detecting the second effects of side-chain non-additivity. If the reagents in a library are shown to be additive in their contribution to activity, simple QSAR based on additive models can be applied confidently to reagents. Testing non-additivity can also guide the synthesis of the library. If the contributions are shown to be additive then the strategy for library synthesis may be shifted to include many reagents of a given type but not to make all combinations. The result is more efficient use of resources. In the analysis of percent inhibition data of a combinatorial library an additive model using reagents as descriptors yields a R(2) of 0.43. Application of this method is probably appropriate for HTS single point data while methods employing topological or pharmacophore based descriptors would be necessary to adequately model IC50 data.

Combinatorial Chemistry Techniques↗
PubMed2002

Scalable methods for the construction and analysis of virtual combinatorial libraries.

One can distinguish between two kinds of virtual combinatorial libraries: viable and accessible . Viable libraries are relatively small in size, are assembled from readily available reagents that have been filtered by the medicinal chemist, and often have a physical counterpart. Conversely, accessible libraries can encompass millions or billions of structures, typically include all possible reagents that are in principle compatible with a particular reaction scheme, and they can never be physically synthesized in their entirety. Although the analysis of viable virtual libraries is relatively straightforward, the handling of large accessible libraries requires methods that scale well with respect to library size. In this work, we present novel, efficient and scalable techniques for the construction, analysis, and in silico screening of massive virtual combinatorial libraries.

Combinatorial Chemistry Techniques↗
PubMed2004

Current progress in natural product-like libraries for discovery screening.

Natural product-like libraries represent an effort to combine the attractive features of natural products and combinatorial libraries for high-throughput screening. Three approaches to natural product-like library design are discussed: (1) Libraries based on core scaffolds from individual natural products, (2) libraries of diverse structures with general structural characteristics of natural products, and (3) libraries of diverse structures based on specific structural motifs from classes of natural products. Examples of successful applications in discovery screening are described for each category. These studies highlight the exciting potential of natural product-like libraries in both chemical biology and drug discovery.

Biological Factors↗
PubMed2006

Recent developments in focused library design: targeting gene-families.

For many years, the most frequently optimized qualities of a screening library, or corporate compound collection, were size and diversity. Maximizing the number of diverse hits is the fundamental goal of such strategies. The ostensible justification that "bigger is better" is based on the large, estimated size of small-molecule space and the hypothesis that the notoriously low hit rates from high-throughput screening (HTS) could be overcome by brute force: i.e. by screening more compounds. Published, detailed studies about the success (or failure) of the brute-force strategy are rare, but it is well-known that it did not fulfill expectations. As a result, published reports in recent years have increasingly described methods for designing, selecting or synthesizing gene family-focused or -biased libraries. Moreover, many of the larger compound suppliers now sell such libraries, reflecting the growing interest in them from both the pharmaceutical and biotechnology markets. The trend towards gene family-focused libraries marks the emergence of a different hypothesis about how to increase HTS hit rates and also reflects an increasingly pragmatic focus on the management of screening libraries. An important, underlying assumption in this trend is that a high-quality, general-purpose screening library of manageable size is neither realizable nor desirable. Whether a biasing strategy based on a specific gene family will do a better job of meeting both the scientific and business needs of the drug discovery enterprise still remains to be seen, but it is certainly an active area of current research. This review focuses on the "who, what, why, when, and how" of the design of gene family-focused libraries. Particular attention is given to reports that discuss not only the techniques used, but also any results obtained.

Chemistry, Pharmaceutical↗
PubMed1999

Construction of Early Human Embryo cDNA Libraries and Screening Objective Genes.

The construction, evaluation, and application of cDNA libraries from 3-, 4-, and 5-week-old human embryos are described. Total RNAs were extracted from whole embryos using a modified single-step method. mRNA purified by two passes through oligo (dT) columns was reverse-transcripted into single-stranded cDNA. Alkaline agarose electrophoresis showed that the double-strand cDNA fragments ranged from 0.4 9.0 kb and most of them were in the range of 1.0 2.0 kb. After separation on SizeSep 400 Spun columns to eliminate excess adaptors and small cDNA fragments(less than 400 bp), the cDNAs were ligated into pSPORT1 plasmid and lambdaZipLox phage. The plasmid libraries have complexities of 2.6x10(5), 1.7x10(5) and 2.1x10(5) clones and the phage cDNA libraries have complexities of 3.4x10(6), 3.7x10(6) and 2.3x10(6) clones, respectively. Three whole length cDNAs encoding human CD59, MCP and DAF were amplified by PCR using 3-week-old phage library as templates, and human tPA gene with whole length cDNA was screened from 4-week-old plasmid library by hybridization. It was shown that these libraries are of high quality and are suitable to screen rarely expressed genes. The libraries are a valuable source for the study of novel gene expression during human development.

Journal Article↗
PubMed2003

Phenotypic library-based microbial source tracking methods: efficacy in the California collaborative study.

As part of a larger microbial source tracking (MST) study, several laboratories used library-based, phenotypic subtyping techniques to analyse fecal samples from known sources (human, sewage, cattle, dogs and gulls) and blinded water samples that were contaminated with the fecal sources. The methods used included antibiotic resistance analysis (ARA) of fecal streptococci, enterococci, fecal coliforms and E. coli; multiple antibiotic resistance (MAR) and Kirby-Bauer antibiotic susceptibility testing of E. coli; and carbon source utilization for fecal streptococci and E. coli. Libraries comprising phenotypic patterns of indicator bacteria isolated from known fecal sources were used to predict the sources of isolates from water samples that had been seeded with fecal material from the same sources as those used to create the libraries. The accuracy of fecal source identification in the water samples was assessed both with and without a cut-off termed the minimum detectable percentage (MDP). The libraries (approximately 300 isolates) were not large enough to avoid the artefact of source-independent grouping, but some important conclusions could still be drawn. Use of a MDP decreased the percentage of false-positive source identifications, and had little effect on the high percentage of true-positives in the most accurate libraries. In general, the methods were more prone to false-positive than to false-negative errors. The most accurate method, with a true-positive rate of 100% and a false-positive rate of 39% when analysed with a MDP, was ARA of fecal streptococci. The internal accuracy of the libraries did not correlate with the accuracy of source prediction in water samples, showing that one should not rely solely on parameters such as the average rate of correct classification of a library to indicate its predictive capabilities.

Animals↗
PubMed1972

Extending library services by using a new technology.

The University of Kentucky Medical Library Extension Service is an experimental program attempting to stimulate medical library use among medical professionals by offering medical information to all health practitioners. The purpose of the program, sponsored by the Ohio Valley Regional Medical Program, is to encourage the establishment of medical libraries in community hospitals and to develop cooperative relationships among those institutions capable of providing medical library services.The University of Kentucky program, through cooperation with other sections of the OVRMP, is endeavoring to make the medical library the center for a variety of clinically oriented information services.Through a WATS line, this Extension Service offers medical library services, drug information, and bibliographic support to OVRMP.It is anticipated that a substantial number of health professionals will become accustomed to medical library services and that health services provided to the citizens of the region will thereby be improved.

Journal Article↗
PubMed1967

Library statistics of schools in the health sciences. II.

This report is a continuation of "Library Statistics of Health Science Libraries: Part I," published in the July 1966 issue of the Bulletin. Interlibrary loan transactions, space assigned to library functions, historical collections, pharmacy libraries, new library construction, and automation are covered in this paper. Questions are raised concerning the adaptation of a general university library questionnaire to the subset of health science libraries.

Canada↗
PubMedDate not supplied

Linear presentation of variable side-chain spacing in a highly diverse combinatorial library.

A synthetic library that presents potential pharmacophores in a linear fashion with variable spacing was designed (alpha, beta, gamma-library). To prove the concept, we synthesized a number of individual compounds as well as a model library. Diamino acids connected by amide bonds via their alpha- or side-chain amino groups were used to form the backbone (scaffold) of this library. The remaining amino group of the diamino acids were acylated by a variety of carboxylic acids, generating an appreciable diversity of compounds in this library. The compositions of compounds in the library were identified by reading a peptide tag synthesized concurrently with the library structures. This code contained the information regarding the carboxylic acid coupled, and the diamino acid and amino group to which the acid was coupled.

Amino Acid Sequence↗
PubMed2001

Construction of high-complexity combinatorial phage display peptide libraries.

Random peptide libraries displayed on the surface of filamentous bacteriophage are widely used as tools for the discovery of ligands for biologically relevant macromolecules, including antibodies, enzymes, and cell surface receptors. Phage display results in linkage of an affinity-selectable function (the displayed peptide) to the DNA encoding that function, allowing selection of individual binding clones by iterative cycles of in vitro panning and in vivo amplification. Critical to the success of a panning experiment is the complexity of the library: the greater the diversity of clones within the library, the more likely the library contains sequences that will bind a given target with useful affinity. A method for construction of high-complexity (> or = 10(9) independent clones) random peptide libraries is presented. The key steps are highly efficient binary ligation under conditions where the vector is relatively dilute, with only a modest molar excess of insert, followed by efficient electrotransformation into Escherichia coli. Library design strategies and a protocol for rapid sequence characterization are also presented.

Amino Acid Sequence↗
PubMed1991

Children in hospital: I. Survey of library and book provision.

Between 1989 and 1991 two related research projects were undertaken by the authors at the Department of Information and Library Studies, Aberystwyth, into services for children in hospital. This article summarizes the findings of the first of the projects, a survey of book and library services to children in hospital, giving a national profile of provision. It demonstrates a substantial provision of reading and other materials available to children in hospital but a small number of library services, as such. Nurses, teachers and hospital play staff generally exploited these materials for pleasure, educational and therapeutic purposes. The survey was based on questionnaires sent to all hospitals in the UK which treated children and was addressed, where possible, to hospital librarians, otherwise to the senior paediatric nurse. A shorter questionnaire was also addressed to all local authority Young People's and Schools Library services for a public library or school library perspective. Where there was evidence of the use of reading therapy, a further questionnaire was sent to explore its practice. A second article will discuss the results of the second project, which was devoted to a further exploration of reading therapy with children in hospital.

Bibliotherapy↗
PubMed1996

The 'market' for medical and health information in transition: the case of the Hong Kong Hospital Authority libraries.

The last few years have been a period of transition not only for hospitals and their governance but also for post-graduate medical education in Hong Kong. Both trends have a direct impact on the information market place. This article starts by studying the provision of medical and health-related information in Hong Kong. The two university medical and dental libraries, together with the hospital and health sciences libraries in government hospitals and the Department of Health, house the major collections on medicine and health care. The demand for medical and health care information is increasingly felt with the takeover of 39 hospitals by the statutory Hong Kong Hospital Authority in 1991. The major problems and issues in planning for library information services are the historically uneven development of libraries, discrepancies in funding, the changes in organizational and management structure, and the competition with higher development priorities within the organization. In view of current technology and the availability of rich external resources, the adopted strategies tend towards the formation of 10 library service networks, development of integrated library information systems on the Health Authority-wide area network, and the devolution of management responsibilities. The future challenges in store for the information professional are examined.

Community Networks↗
PubMed1999

Selection of human elastase inhibitors from a conformationally constrained combinatorial peptide library.

A resin-bound cyclic peptide library was constructed based on the sequence of the reactive-site loop of Bowman-Birk inhibitor, a proteinase inhibitor protein. The constrained loop sequence, which incorporates the minimal proteinase-binding motif, was retained throughout the library, but selected residues known to be important for inhibitor specificity were randomised. The approach was used to create a 'one bead, one peptide' library with 8000 variants resulting from randomization at three target locations in the sequence (P4, P1 and P2'). This library allows us to examine the degree to which variations in this proteinase-binding motif can redirect activity, as well as providing information about the binding specificity of a proteinase target. Screening this library for binding to human leucocyte elastase identified sequences with a strong consensus, and on resynthesis all were found to act as inhibitors, with Ki values as low as 65 nM. Human leucocyte elastase is known to have a substrate preference for small alkyl chains at the P1 locus, with valine being preferred. However, alanine and not the expected valine was found in 21 out of 23 identified sequences. The remaining two sequences had threonine at P1, a finding that would be hard to predict based on substrate specificity alone. Further analysis of resynthesized peptides demonstrated that valine substitution results in an analogue that is hydrolysed far more rapidly than ones having library-selected P1 residues. Testing of the human leucocyte elastase-selected sequences as inhibitors of porcine pancreatic elastase demonstrates a significant difference in the specificity of the P4 locus between these two proteinases.

Animals↗
PubMed2001

In vitro selection and characterization of Bcl-X(L)-binding proteins from a mix of tissue-specific mRNA display libraries.

The covalent coupling of an mRNA to the protein that it encodes (mRNA display) provides a powerful tool for analysis of protein function in the post-genomic era. This coupling allows the selective enrichment of individual members from libraries of displayed proteins and the subsequent regeneration of an enriched library using the RNA moiety. Tissue-specific libraries from poly(A)(+) mRNA were prepared by priming first and second strand cDNA synthesis with oligonucleotides containing nine random 3' nucleotides, the fixed regions of which encoded the requisite sequences for formation of mRNA display constructs and a library-specific sequence tag. Starting with a pool of uniquely tagged libraries from different tissues, an iterative selection was performed for binding partners of the anti-apoptotic protein Bcl-X(L). After four rounds of selection, the pool was deconvoluted by polymerase chain reaction amplification with library-specific primers. Subsequent clonal sequence analysis revealed the selection of three members of the Bcl-2 family known to bind to Bcl-X(L). In addition, several proteins not previously demonstrated to interact with Bcl-X(L) were identified. The relative binding affinities of individual selected peptides were determined, as was their susceptibility to competition with a BH3 domain peptide. Based on these data, a putative BH3 domain was identified in most peptides.

Amino Acid Sequence↗
PubMed1993

Unique pancreatic carcinoma cDNA found via subtracted libraries with limited normal tissue and tumor from the same patient.

We have approached the problem of isolating clones unique to specific malignancies such as T-cell acute lymphoblastic leukemia (ALL) and pancreatic adenocarcinoma by using subtractive hybridization techniques. Our initial studies involved using normal donor tissue (i.e., normal blood donors for ALL and cadaver renal transplant donors for normal pancreatic tissue) and cultured malignant cell lines. It occurred to us that normal pancreatic tissue from the same patient source as that of the malignant tissue might subtract out normal sequences more readily and enrich clones unique to pancreatic adenocarcinoma because of patient/donor identity. Using such a method meant that the amounts of tissue for overcoming this obstacle. We constructed independent UNI-ZAP-XR cDNA libraries (normal and malignant) and used them to amplify either the normal or malignant cDNA prior to subtractive hybridization. We then obtained rescued single stranded cDNA from the malignant ZAP library. The RNA which was not hybridized was isolated. The process was repeated and a double subtraction was effected. The residual non-hybridized RNA was used as a template for first and second strand synthesis. After the EcoRI adaptors were ligated to the double stranded cDNA it was cloned into Lambda ZAP II arms to form a double subtracted malignant cDNA library. A subtracted probe was prepared from the double subtracted cDNA library. Single stranded cDNA was rescued, double stranded plasmid was made, the plasmid DNA was digested with EcoRI, the digested DNA was run on a 1% SeaPlaque gel, and the insert cDNA was recovered using Ultra-Free MC and Ultra-Free Probind filters. The subtracted malignant cDNA library was probed with the subtracted probe and with normal cDNA (obtained from the normal ZAP library) and those plaques which were positive per the subtracted probe and negative per the normal cDNA were isolated; their cDNA inserts are being further characterized.

Actins↗