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PubMed2001

Formation of unusual sugars: mechanistic studies and biosynthetic applications.

Carbohydrates are highly abundant biomolecules found extensively in nature. Besides playing important roles in energy storage and supply, they often serve as essential biosynthetic precursors or structural elements needed to sustain all forms of life. A number of unusual sugars that have certain hydroxyl groups replaced by a hydrogen, an amino group, or an alkyl side chain play crucial roles in determining the biological activity of the parent natural products in bacterial lipopolysaccharides or secondary metabolite antibiotics. Recent investigation of the biosynthesis of these monosaccharides has led to the identification of the gene clusters whose protein products facilitate the unusual sugar formation from the ubiquitous NDP-glucose precursors. This review summarizes the mechanistic studies of a few enzymes crucial to the biosynthesis of C-2, C-3, C-4, and C-6 deoxysugars, the characterization and mutagenesis of nucleotidyl transferases that can recognize and couple structural analogs of their natural substrates and the identification of glycosyltransferases with promiscuous substrate specificity. Information gleaned from these studies has allowed pathway engineering, resulting in the creation of new macrolides with unnatural deoxysugar moieties for biological activity screening. This represents a significant progress toward our goal of searching for more potent agents against infectious diseases and malignant tumors.

Anti-Bacterial Agents↗
PubMed1998

Active sites in complement component C3 mapped by mutations at indels.

Engineered mutants of human complement component C3 were used to test the idea that sites of length polymorphisms in protein families (indels) can guide a search for protein:protein interaction sites. Sequence changes were introduced at each of the 27 indels in the C3/4/5 protein family, and mutants at 26 indels were expressed by transiently transfected COS cells. Expressed proteins were assayed 1) for concentration, by ELISA and by autoradiography of radiolabeled protein; 2) for classical pathway hemolytic activity; 3) for susceptibility to proteolytic activation by the alternative pathway and cobra venom factor C3 convertases; and 4) for susceptibility to complement factor I in the presence of factor H. Most of the mutations did not appreciably alter expression or activity relative to wild-type C3, consistent with the idea that most indels occur at the protein surface. Mutations at four indels severely damaged C3 functional activity, but did not affect the stability or structure of the protein, as assessed by their effects on expression by COS cells and on susceptibility to cleavage by C3 convertases and factor I. These indels are therefore near functionally important amino acid residues; they represent good candidates for sites of protein:protein interactions. Mutation of the sequence at a fifth indel altered the equilibrium between the latent and reacted C3 conformations, and mutations at 4 other indels substantially decreased both protein activity and expression. The mutants provided an overview of the structural and functional roles played by different parts of C3.

Amino Acid Sequence↗
PubMed2005

Engineered antibodies act as targeted therapies in cancer treatment.

Over the last two decades cancer cure rates have not gone up as expected, and the effectiveness of chemotherapy has reached a plateau. This has prompted a search for targeted therapies with higher efficacy and lesser toxicities. Monoclonal antibodies against cancer cells offer targeted therapies with little or no toxicities against normal tissues. In this review we will discuss the concepts behind the development of monoclonal antibodies in cancer and their present status in the clinic. Specifically, we will discuss the clinical use of Rituximab (RituxanO), Trastuzumab (HerceptinO) and Bevacizumab (AvastinO) in various cancers and the key clinical trials that have led to their incorporation in cancer therapeutics.

Angiogenesis Inhibitors↗
PubMed1994

Searching protein structure databases has come of age.

The number of protein structures known in atomic detail has increased from one in 1960 (Kendrew, J.C., Strandberg, B.E., Hart, R.G., Davies, D.R., Phillips, D.C., Shore, V.C. Nature (London) 185:422-427, 1960) to more than 1000 in 1994. The rate at which new structures are being published exceeds one a day as a result of recent advances in protein engineering, crystallography, and spectroscopy. More and more frequently, a newly determined structure is similar in fold to a known one, even when no sequence similarity is detectable. A new generation of computer algorithms has now been developed that allows routine comparison of a protein structure with the database of all known structures. Such structure database searches are already used daily and they are beginning to rival sequence database searches as a tool for discovering biologically interesting relationships.

Algorithms↗
PubMed2003

The application of a Pareto optimisation method in the design of an integrated bioprocess.

A rapid method for designing integrated bioprocesses, using a combination of a windows of operation and a Pareto optimisation approach, is described in this paper. Within bioprocesses, multiple objectives are common, and achieving a satisfactory trade-off amongst the design objectives is crucial. Conventional optimisation results in the identification of the best operating policy for a given desired performance but gives little insight into how the process performance changes in the vicinity of the solution. In this paper, we explore the use of a Pareto optimisation technique to locate the optimal conditions for an integrated bioprocessing sequence and the benefits of first reducing the feasible space by the development of a series of windows of operation to provide a smaller search area for the optimisation. The final results are then presented in performance trade-off graphs and look-up tables, which give the design engineer an easily manageable solution set to work with. In this way, the decision-making procedure for design is made faster and more transparent. Two case studies illustrate the results from this integrated design methodology, some of which are counter-intuitive compared with the general design experience.

Journal Article↗
PubMed2004

Critical nucleation size in the folding of small apparently two-state proteins.

For apparently two-state proteins, we found that the size (number of folded residues) of a transition state is mostly encoded by the topology, defined by total contact distance (TCD) of the native state, and correlates with its folding rate. This is demonstrated by using a simple procedure to reduce the native structures of the 41 two-state proteins with native TCD as a constraint, and is further supported by analyzing the results of eight proteins from protein engineering studies. These results support the hypothesis that the major rate-limiting process in the folding of small apparently two-state proteins is the search for a critical number of residues with the topology close to that of the native state.

Kinetics↗
PubMed2006

Advances in the management of leg ulcers--the potential role of growth factors.

Venous ulcers are a major health problem because of the increased costs of the treatment and the refractory nature of the ulcers. The treatment cost is estimated to be around 1 billion dollars per year in the United States (US), and the average cost for one patient over a lifetime exceeds dollars 400,000. There has been an increasing trend in the use of growth factors in their management. Genetic engineering has revolutionised the research of wound healing, as the majority of recombinant growth factors are now available for in vitro and in vivo studies. Online searches of Medline, Pub Medical and Embase were carried out using the terms venous ulcers, leg ulcers, growth factors and growth hormone. The literature regarding the potential role of growth factors in the management of leg ulcers is reviewed. The important clinical studies are critically analysed with a view to appreciate the emerging therapies and the further research possibilities in the management of venous leg ulcers. Clinical results with the use of growth factors in non-healing wounds are encouraging. However, small sample sizes and inconsistent end points in different clinical studies have been the main hurdle in reaching a definite conclusion. Further research is needed to provide the definite evidence. Future developments may include different delivery methods for the growth factors, use of different combinations of growth factors administered simultaneously or, sequentially, bioengineered skin grafts and chemical induction of angiogenesis with the use of gene transfer techniques.

Growth Substances↗
PubMed2006

DWARF--a data warehouse system for analyzing protein families.

BACKGROUND: The emerging field of integrative bioinformatics provides the tools to organize and systematically analyze vast amounts of highly diverse biological data and thus allows to gain a novel understanding of complex biological systems. The data warehouse DWARF applies integrative bioinformatics approaches to the analysis of large protein families. DESCRIPTION: The data warehouse system DWARF integrates data on sequence, structure, and functional annotation for protein fold families. The underlying relational data model consists of three major sections representing entities related to the protein (biochemical function, source organism, classification to homologous families and superfamilies), the protein sequence (position-specific annotation, mutant information), and the protein structure (secondary structure information, superimposed tertiary structure). Tools for extracting, transforming and loading data from public available resources (ExPDB, GenBank, DSSP) are provided to populate the database. The data can be accessed by an interface for searching and browsing, and by analysis tools that operate on annotation, sequence, or structure. We applied DWARF to the family of alpha/beta-hydrolases to host the Lipase Engineering database. Release 2.3 contains 6138 sequences and 167 experimentally determined protein structures, which are assigned to 37 superfamilies 103 homologous families. CONCLUSION: DWARF has been designed for constructing databases of large structurally related protein families and for evaluating their sequence-structure-function relationships by a systematic analysis of sequence, structure and functional annotation. It has been applied to predict biochemical properties from sequence, and serves as a valuable tool for protein engineering.

Amino Acid Sequence↗
PubMedDate not supplied

Particulate air pollution: possible relevance in asthma.

The relative importance of air pollution in the pathogenesis of bronchial asthma has been of interest for several decades. Numerous studies on the role of gaseous air pollution containing ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide have been published. Very little attention has been focused on the role of respirable particles in the causation of asthma. In this article we summarize some of our ongoing investigations into the sources and composition of airborne particles in the Los Angeles and Pasadena atmosphere, including the search for biologically active particles that may induce asthma attacks. If is found that the urban atmosphere contains not only combustion-derived particles from diesel engine exhaust and gasoline-powered motor vehicle exhaust, but also particles formed from biological starting materials including plant debris, cigarette smoke, wood smoke, and meat smoke as well as tire debris containing some natural rubber and paved road dust. Paved road dust is a very complex mixture of particles including garden soil, tire dust, plant fragments, redeposited atmospheric particles of all types, and pollen fragments presumably ground up by passing traffic. We have shown previously that latex allergen can be extracted from tire dust, from roadside dust, and from respirable air samples taken at Los Angeles and Long Beach. At present, work is underway to identify the larger range of allergens that may be contributed by the entrainment of paved road dust into the atmosphere. The possible importance of pollen fragments present in paved road dust in very small particle sizes is discussed as well as their potential relevance in asthma.

Air Pollutants↗
PubMed2007

Recent progress in engineering alpha/beta hydrolase-fold family members.

The members of the alpha/beta hydrolase-fold family represent a functionally versatile group of enzymes with many important applications in biocatalysis. Given the technical significance of alpha/beta hydrolases in processes ranging from the kinetic resolution of enantiomeric precursors for pharmaceutical compounds to bulk products such as laundry detergent, optimizing and tailoring enzymes for these applications presents an ongoing challenge to chemists, biochemists, and engineers alike. A review of the recent literature on alpha/beta hydrolase engineering suggests that the early successes of "random processes" such as directed evolution are now being slowly replaced by more hypothesis-driven, focused library approaches. These developments reflect a better understanding of the enzymes' structure-function relationship and improved computational resources, which allow for more sophisticated search and prediction algorithms, as well as, in a very practical sense, the realization that bigger is not always better.

Epoxide Hydrolases↗
PubMed2001

Electronic teaching files: seven-year experience using a commercial picture archiving and communication system.

With the advent of electronic imaging and the internet, the ability to create, search, access, and archive digital imaging teaching files has dramatically improved. Despite the fact that a picture archival and communication system (PACS) has the potential to greatly simplify the creation of, archival, and access to a department or multifacility teaching file, this potential has not yet been satisfactorily realized in our own and most other PACS installations. Several limitations of the teaching file tools within our PACS have become apparent over time. These have, at our facility, resulted in a substantially reduced role of the teaching file tools for conferences, daily teaching, and research purposes. With the PACS at our institution, academic folders can only be created by the systems engineer, which often serves as an impediment to the teaching process. Once these folders are created, multiple steps are required to identify the appropriate folders, and subsequently save images. Difficulties exist for those attempting to search for the teaching file images. Without pre-existing knowledge of the folder name and contents, it is difficult to query the system for specific images. This is due to the fact that there is currently no fully satisfactory mechanism for categorizing, indexing, and searching cases using the PACS. There is currently no easy mechanism to save teaching, research, or clinical files onto a CD or other removable media or to automatically strip demographic or other patient information from the images. PACS vendors should provide much more sophisticated tools to create and annotate teaching file images in an easy to use but standard format (possibly Radiological Society of North America's Medical Image Resource Center [MIRC] format) that could be exchanged with other sites and other vendors' PAC systems. The privilege to create teaching or conference files should be given to the individual radiologists, technologists, and other users, and an audit should be kept of who has created these files, as well as keep track of who has accessed the files. Vendors should maintain a local PACS library of image quality phantoms, normal variants, and interesting cases and should have the capability of accessing central image repositories such as the RSNA's MIRC images. Commercial PAC systems should utilize a standard lexicon to facilitate the creation and categorization of images, as well as to facilitate sharing of images and related text with other sites. This should be combined with a very easy to use mechanism to write images and related text when appropriate onto removable media (while maintaining a high level of security and confidentiality) to make it easier to share images for teaching, research, or clinical purposes.

Computer-Assisted Instruction↗
PubMed2000

Side-chain flexibility in proteins upon ligand binding.

Ligand binding may involve a wide range of structural changes in the receptor protein, from hinge movement of entire domains to small side-chain rearrangements in the binding pocket residues. The analysis of side chain flexibility gives insights valuable to improve docking algorithms and can provide an index of amino-acid side-chain flexibility potentially useful in molecular biology and protein engineering studies. In this study we analyzed side-chain rearrangements upon ligand binding. We constructed two non-redundant databases (980 and 353 entries) of "paired" protein structures in complexed (holo-protein) and uncomplexed (apo-protein) forms from the PDB macromolecular structural database. The number and identity of binding pocket residues that undergo side-chain conformational changes were determined. We show that, in general, only a small number of residues in the pocket undergo such changes (e.g., approximately 85% of cases show changes in three residues or less). The flexibility scale has the following order: Lys > Arg, Gln, Met > Glu, Ile, Leu > Asn, Thr, Val, Tyr, Ser, His, Asp > Cys, Trp, Phe; thus, Lys side chains in binding pockets flex 25 times more often then do the Phe side chains. Normalizing for the number of flexible dihedral bonds in each amino acid attenuates the scale somewhat, however, the clear trend of large, polar amino acids being more flexible in the pocket than aromatic ones remains. We found no correlation between backbone movement of a residue upon ligand binding and the flexibility of its side chain. These results are relevant to 1. Reduction of search space in docking algorithms by inclusion of side-chain flexibility for a limited number of binding pocket residues; and 2. Utilization of the amino acid flexibility scale in protein engineering studies to alter the flexibility of binding pockets.

Amino Acids↗
PubMed1992

Endocrine strategies for the control of ectoparasites and insect pests.

The increasing knowledge about endocrine mechanisms in arthropods facilitates the biorational search for drugs against insect pests and parasites that interfere with arthropod hormone action. Juvenile hormone mimics have been successfully applied for about 20 years; however, resistance to juvenile hormone analogues has developed. The introduction of moulting hormone agonists, which compete for binding to the ecdysteroid receptor, is expected in the near future. Despite the considerable progress that has been achieved in peptide hormone research during the last few years, no successful insecticide is currently available, although comparisons of drugs for medical use demonstrate that in principle, successful interference with peptide hormone action is possible. The search for new drugs has been facilitated by advances in cell-culture techniques, which improve the development of suitable screening systems, and by progress in genetic engineering, which could be an important tool in the creation of new strategies for insect pest control.

Animals↗
PubMed2005

A positive correlation between occlusal trauma and peri-implant bone loss: literature support.

The relationship between occlusal overload and peri-implant bone loss remains a controversial topic in implant dentistry. A causal relationship between the incidence of marginal bone loss next to an implant and occlusal overload implies a treatment plan and occlusal scheme would benefit from a force management approach. A MEDLINE-assisted and hand search of peer-reviewed English literature and relative textbooks were used for a selective review of articles addressing biomechanical stress and bone loss in cellular biomechanics, engineering principles, mechanical properties of bone, animal studies, clinical reports, bone physiology, and implant design biomechanics. These papers demonstrate occlusal overload on implants may increase the incidence of marginal bone loss.

Alveolar Bone Loss↗