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PubMed2004

iMOT: an interactive package for the selection of spatially interacting motifs.

Functional selection and three-dimensional structural constraints of proteins relate to the retention of significant sequence similarity between proteins of similar fold and function despite poor overall sequence identity and evolutionary pressures. We report the availability of 'iMOT' (interacting MOTif) server, an interactive package for the automatic identification of spatially interacting motifs among distantly related proteins sharing similar folds and possessing common ancestral lineage. Spatial interactions between conserved stretches of a protein are evaluated by calculations of pseudo-potentials that describe the strength of interactions. Such an evaluation permits the automatic identification of highly interacting conserved regions of a protein. Interacting motifs have been shown to be useful in searching for distant homologues and establishing remote homologies among the largely unassigned sequences in genome databases. Information on such motifs should also be of value in protein folding, modelling and engineering experiments. The iMOT server can be accessed from http://www.ncbs.res.in/~faculty/mini/imot/iMOTserver.html. Supplementary Material can be accessed from: http://www.ncbs.res.in/~faculty/mini/imot/supplementary.html.

Amino Acid Motifs↗
PubMed2001

Transplantation and gene therapy: combined approaches for repair of spinal cord injury.

Motor and sensory functions are lost after spinal cord injury because neurons die or atrophy and axons fail to regenerate. Until fairly recently, it was believed that damaged neurons could not be replaced and injured axons could not regenerate, and, therefore, functions dependent on injured neurons could not be recovered. We now know that damaged neurons can be rescued by providing therapeutic factors or replaced by grafting. In addition, the adult CNS contains a population of precursor cells with a potential to generate new neural cells, whose numbers and composition can be modified by extrinsic factors. The pioneering studies of Aguayo demonstrated that CNS axons could regenerate in the right environment. Subsequent studies have revealed the identity of some of the inhibitory molecules in myelin and scar tissue, and we now have a better understanding of how the CNS environment can be modified to become more permissive to regeneration. Axons that regenerate must find an appropriate target, but it may not be essential to reestablish the precise topography for some functions to be restored. There are now new and promising strategies for delivery of therapeutic genes to protect neurons and to stimulate regeneration. The ability to engineer cells by gene therapy combines the therapeutic values of cell transplantation and gene delivery. These remarkable developments from many disciplines have generated a new level of optimism in the search for a cure for CNS injury and in particular spinal cord injury. In this review, the authors summarize recent progress in these strategies and some of the challenges that remain in elucidating the most efficacious protocols for rescuing injured neurons, encouraging regeneration of their axons, and promoting recovery of function.

Adult↗
PubMed2004

Systematic Inventive Thinking: a new tool for the analysis of complex problems in medical management.

The complexity of medical problems is a well-recognized phenomenon. In the presence of economic and cultural restrictions, medical decision-making can be particularly challenging. This paper outlines a system of analysis and decision-making for solving such problems, and briefly describes a case study in which the method was used to analyze the case of antibiotic overprescribing in a large health maintenance organization. The purpose of the study was to determine if a technique for problem-solving in the field of engineering could be applied to the complex problems facing primary care. The method is designated Systematic Inventive Thinking and consists of a three-step procedure: problem reformulation, general search-strategy selection, and an application of idea-provoking techniques. The problem examined is the over-prescribing of antibiotics by general practitioners working in Maccabi Healthcare Services, an HMO serving one and a half million patients in Israel. The group of healthcare professionals involved in the discussions generated 117 ideas for improving antibiotic use. Six of these ideas were then implemented in a national campaign in the winter of 2000/1 and 2001/2. During this period, a significant reduction in per-visit antibiotic purchasing was observed for influenza visits (from 79.2 per 1,000 to 58.1 per 1,000, P < 0.0001), but not for other categories of visits. The SIT methodology is a useful technique for problem-solving and idea generation within the medical framework.

Anti-Bacterial Agents↗
PubMed1997

Gas residues of engine starting fluid in postmortem sample from an arsonist.

Diethyl ether was found in samples of the blood, urine, and lung from a fire victim. Because the lung also carried a number of low-boiling paraffins, it was inferred that the detected compounds came from engine starting fluid, which the victim apparently had been exposed to while be intentionally used it as an accelerant to start the fire. The reported death illustrates the value of searching post mortem samples for highly volatile residues of possible arson accelerants.

Adult↗
PubMed2005

Directed evolution strategies for improved enzymatic performance.

The engineering of enzymes with altered activity, specificity and stability, using directed evolution techniques that mimic evolution on a laboratory timescale, is now well established. However, the general acceptance of these methods as a route to new biocatalysts for organic synthesis requires further improvement of the methods for both ease-of-use and also for obtaining more significant changes in enzyme properties than is currently possible. Recent advances in library design, and methods of random mutagenesis, combined with new screening and selection tools, continue to push forward the potential of directed evolution. For example, protein engineers are now beginning to apply the vast body of knowledge and understanding of protein structure and function, to the design of focussed directed evolution libraries, with striking results compared to the previously favoured random mutagenesis and recombination of entire genes. Significant progress in computational design techniques which mimic the experimental process of library screening is also now enabling searches of much greater regions of sequence-space for those catalytic reactions that are broadly understood and, therefore, possible to model. Biocatalysis for organic synthesis frequently makes use of whole-cells, in addition to isolated enzymes, either for a single reaction or for transformations via entire metabolic pathways. As many new whole-cell biocatalysts are being developed by metabolic engineering, the potential of directed evolution to improve these initial designs is also beginning to be realised.

Journal Article↗
PubMed2003

In vivo bone engineering in a rabbit femur.

The repair of bone defects in reconstructive surgery has significant limitations. Donor site morbidity, limited supply of autograft, and risks and complications associated with allografting and synthetic bone substitutes are among the most significant. In an effort to address these problems, the search for an ideal bone replacement has led to the development of a new method of poly(lactide-co-glycolide) (PLGA) foam processing, enabling the production of a biodegradable scaffold with similar porosity to human trabecular bone. In this study, these scaffolds were evaluated for bone repair in vivo in a femoral critical-sized segmental defect in New Zealand White (NZW) rabbits. Three groups of nine animals were investigated. In the first group, the critical-sized defects were empty. Scaffolds alone were implanted in the second group, whereas autologous bone marrow cell-loaded scaffolds were implanted in the third group. Animals ambulated freely for 8 weeks after surgery, and bone formation throughout the defects was serially assessed radiographically and quantified using a bone formation index (BFI) measure. Postmortem radiography and histology were also undertaken to examine bone formation. There was a significant effect of applying this technology to the amount of bone formed in the defects as determined by the BFI (F = 3.41, P < 0.05). The mean BFI for the cell-loaded scaffolds was greater than for the control group at all measured time points (2-, 4-, 6-, and 8-week radiographs). This difference was significant for the 2- and 8-week radiographs (P < 0.05). Qualitative histological assessment confirmed these findings. We concluded from these findings that these PLGA scaffolds loaded with marrow-derived progenitor cells yield significant bone formation in a critical-sized rabbit femoral defect. This technology comprising a novel scaffold design and autologous cells may provide an alternative to current strategies for reconstruction of bony defects.

Absorbable Implants↗
PubMed1999

Novel approaches to the treatment of small-cell lung cancer.

Small-cell lung cancer (SCLC) is characterized by its initial responsiveness to chemotherapy and the appearance of early metastases. Although combination chemotherapy, in some instances together with radiation, has improved the prognosis of this disease, in most patients SCLC ultimately recurs in a drug-resistant form. Several new strategies for the eradication of SCLC are being explored at the preclinical level. The identification of selective target molecules on the surface of SCLC cells, together with the progress made in antibody engineering, have provided new generations of antibodies and immunoconjugates as well as growth factor antagonists and inhibitors. In addition, recent advances in understanding the biology of SCLC have stimulated new investigations searching to counter the molecular basis underlying the increased proliferation and the apoptosis deficiency of SCLC cells. This can be achieved using antisense oligodeoxynucleotides that repress the expression of growth factor receptors and anti-apoptosis genes, or by gene replacement to compensate for the loss or inactivation of tumor suppressor genes.

Antibodies, Neoplasm↗
PubMed1997

Gene targeting--homing in on alpha 2-adrenoceptor-subtype function.

The alpha-adrenoceptor was subdivided into three subtypes: alpha 2A-, alpha 2B- and alpha 2C-adrenoceptors almost ten years ago. Since then, the search has been on to discover and develop subtype-selective agonists and antagonists, but as yet no major breakthrough has been made. In the past year, several strains of genetically engineered mice have become available, either overexpressing, totally lacking or expressing heavily modified alpha 2-adrenoceptor subtypes. Ewen MacDonald, Brian Kobilka and Mika Scheinin describe how these mice may be utilized to elucidate the physiological functions of the receptor subtypes and the properties of future subtype-selective drugs.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

[The cloning and expression of the phospholipase D gene from Corynebacterium pseudotuberculosis].

In a number of consecutive gene engineering operations a DNA fragment having a size of about 2.8 kb was cloned in Escherichia coli by means of Blue-script II SK+ used as vector. The insert contained pld gene coding the synthesis of phospholipase D, one of the key factors of C. pseudotuberculosis virulence. The stable and active expression of this gene in E.coli was achieved. High phospholipase A activity was accumulated in the periplasmatic space. The molecular weight of the synthesized protein was 31 kD. The product obtained by gene engineering methods was found to possess the biological activity of the natural product: it induced the hemolysis of sheep red blood cells in the presence of equi factor of Rhinococcus equi and inhibited the hemolytic activity of Staphylococcus aureus beta-hemolysin (phospholipase C). The pld gene cloned in these experiments differed from that of another C.pseudotuberculosis strain. Further research is underway with a view of searching for the limits of pls gene.

Chromosomes, Bacterial↗
PubMed1994

Making a small enzyme smaller; removing the conserved loop structure of hen lysozyme.

Engineering a smaller lysozyme is a challenge for both random and site-directed mutagenesis. This paper illustrates the power of knowledge-based protein engineering in the design of a smaller lysozyme that folds correctly and has activity against bacterial cell walls. In this smaller lysozyme the conserved disulphide bridged loop is replaced by a short loop. The long loop was selected because it buries a predominantly hydrophilic surface. The short loop was discovered by searching for appropriate fragments in the protein databank. This approach is important in the design of small enzymes useful to the food industry.

Animals↗
PubMed2000

A string matching computer-assisted system for dolphin photoidentification.

This paper presents a syntactic/semantic string representation scheme as well as a string matching method as part of a computer-assisted system to identify dolphins from photographs of their dorsal fins. A low-level string representation is constructed from the curvature function of a dolphin's fin trailing edge, consisting of positive and negative curvature primitives. A high-level string representation is then built over the low-level string via merging appropriate groupings of primitives in order to have a less sensitive representation to curvature fluctuations or noise. A family of syntactic/semantic distance measures between two strings is introduced. A composite distance measure is then defined and used as a dissimilarity measure for database search, highlighting both the syntax (structure or sequence) and semantic (attribute or feature) differences. The syntax consists of an ordered sequence of significant protrusions and intrusions on the edge, while the semantics consist of seven attributes extracted from the edge and its curvature function. The matching results are reported for a database of 624 images corresponding to 164 individual dolphins. The identification results indicate that the developed string matching method performs better than the previous matching methods including dorsal ratio, curvature, and curve matching. The developed computer-assisted system can help marine mammalogists in their identification of dolphins, since it allows them to examine only a handful of candidate images instead of the currently used manual searching of the entire database.

Animal Identification Systems↗
PubMed2007

Identification of tunnels in proteins, nucleic acids, inorganic materials and molecular ensembles.

The knowledge of the access paths connecting interior of molecular systems with surrounding environment is important for the understanding of structurefunction relationships and engineering of molecules for biotechnological applications. CAVER is a computer program developed for calculations of tunnels, channels or pores in the biomolecules, inorganic materials and molecular ensembles. The algorithm performs a skeleton search based on a reciprocal distance function grid. The algorithm is implemented in the stand-alone version, web version and as plug-in for PyMol. CAVER is available from the website http://loschmidt.chemi.muni.cz/caver.

Algorithms↗
PubMed2001

Analysis of temporal gene expression profiles: clustering by simulated annealing and determining the optimal number of clusters.

MOTIVATION: Cluster analysis of genome-wide expression data from DNA microarray hybridization studies has proved to be a useful tool for identifying biologically relevant groupings of genes and samples. In the present paper, we focus on several important issues related to clustering algorithms that have not yet been fully studied. RESULTS: We describe a simple and robust algorithm for the clustering of temporal gene expression profiles that is based on the simulated annealing procedure. In general, this algorithm guarantees to eventually find the globally optimal distribution of genes over clusters. We introduce an iterative scheme that serves to evaluate quantitatively the optimal number of clusters for each specific data set. The scheme is based on standard approaches used in regular statistical tests. The basic idea is to organize the search of the optimal number of clusters simultaneously with the optimization of the distribution of genes over clusters. The efficiency of the proposed algorithm has been evaluated by means of a reverse engineering experiment, that is, a situation in which the correct distribution of genes over clusters is known a priori. The employment of this statistically rigorous test has shown that our algorithm places greater than 90% genes into correct clusters. Finally, the algorithm has been tested on real gene expression data (expression changes during yeast cell cycle) for which the fundamental patterns of gene expression and the assignment of genes to clusters are well understood from numerous previous studies.

Algorithms↗
PubMed2006

Costimulation couture: a designer approach to regulating autoimmunity.

Negative or inhibitory costimulatory pathways regulate T cell activation and play a role in peripheral tolerance. Targeting these pathways harnesses the physiologic mechanisms of regulating autoimmunity and could prove beneficial for the therapy of autoimmune diseases. However, attempts at targeting these pathways have been fraught with difficulties. In this issue of the JCI, Fife et al. describe a creative approach for targeting CTL-associated antigen 4 (CTLA-4) on activated T cells via genetically engineered B cells to prevent autoimmune diabetes in the NOD mouse (see the related article beginning on page 2252). Novel "designer" strategies targeting negative costimulatory pathways provide reasons for optimism in the search for a cure for devastating autoimmune diseases.

Antigens, CD↗
PubMed2000

Alfred P. Southwick, MDS, DDS: dental practitioner, educator and originator of electrical executions.

The search for a modern, humane method of criminal execution was triggered by a freak accident which occurred in Buffalo, New York in 1881. Dr. Alfred P. Southwick (a former steam-boat engineer, noted dentist and dental educator) happened to witness an intoxicated man die after he inadvertently touched a live generator terminal. Southwick's initial reaction was shock. Later, as he pondered this tragic event, he concluded that electrocution was, at least, a quick and seemingly painless way to depart from this earth. As his thoughts turned to common methods of capital punishment, Alfred concluded that death by electrocution could become a more humane alternative, as compared with the more grisly methods (e.g., hanging, beheading by guillotine, garroting, suffocation and flaying). Working through the governor of New York and the state legislature, Southwick originated and successfully promoted the passage of laws which mandated electrical executions in New York and in approximately 20 other states. During 1888-1889, Southwick served on the state's three-person Electrical Death Commission, a group who reported that electrical execution was superior to all other methods. On January 1, 1889, the world's first electrical execution law went into effect. On August 6, 1890, William Francis Kemmler, who had murdered his mistress, was the first person to die in the electric chair. However, this public event became an amateurish spectacle: the initial surge of current did not cause Kemmler's immediate death and a second jolt was needed. Those who witnessed this bungled execution were stunned. Graphic and detailed criticism from both the press and the general public ran high. However, Dr. Southwick vigorously continued to support and finally achieve his goal--to humanize capital punishment through the legal use of electrical execution.

Capital Punishment↗
PubMed1996

[Gene transfer in human hematopoietic stem cells isolated from peripheral blood].

To insert a new genetic information by gene transfer into haemopoietic stem cells would result in expression of the transgene in progenitors and progeny of cell blood lineages. If successfull, such an approach would open interesting prospectives in the field of experimental research and in the possibility to treat genetic defects affecting blood lineages such as immune deficiencies (ADA, SCID, AIDS) or enzymes defects. Moreover progenitors could be engineered to become more resistant to chemotherapy or oncogenic process. Many parameters and technical problems are still involved in this issue, including identification, isolation and selection of the most primitive progenitors, and search for the most efficient vectors to insert new genes into the target cells. So far retroviral vectors have been shown to be the most effective but search for better vectors are still underway. Peripheral blood stem cells isolated from patients stimulated by cytokines and/or chemotherapy appear interesting target cells for genetic manipulations aimed to correct an acquired or genetic defect.

Gene Transfer Techniques↗