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PubMed1996

Infective endocarditis: ten-year review of medical and surgical therapy.

BACKGROUND: Infective endocarditis is a complex disease process. Optimal outcome often requires both medical and surgical expertise. The need for and timing of surgical intervention is controversial and continues to evolve in parallel to advancements in diagnosis and treatment. Our experience with the treatment of infective endocarditis is reviewed herein. METHODS: A retrospective review was compiled of 140 consecutive patients who fulfilled the modified von Reyn criteria for the diagnosis of endocarditis between January 1982 and April 1992. RESULTS: Patient characteristics, symptoms, and risk factors are described. Follow-up averaged 3.5 +/- 0.8 years and totaled 491 patient-years. New York Heart Association functional class at presentation had a significant influence on survival (p < 0.0001). Long-term survival was significantly greater (p = 0.036) in patients treated medically/surgically than those treated with medical therapy alone (75% versus 54% at 5 years). Medical treatment of aortic and prosthetic endocarditis was associated with higher mortality (58% and 67%, respectively) when compared with combined medical/surgical treatment (28% and 38%, respectively). Among the survivors, New York Heart Association class at follow-up was better (p < 0.0001) in the medical/surgical group (1.05 +/- 0.04) versus the medical treatment group (1.70 +/- 0.14). CONCLUSIONS: Combined medical/surgical treatment for infective endocarditis is associated with improved survival. Patients with aortic or prosthetic endocarditis are identified as subgroups that benefit most from surgical intervention. Valvular dysfunction incited by the infective process is an important factor that should be weighed carefully in the therapeutic decision.

Adolescent↗

PubMed1996

Implications of 3-dimensional target shape and motion in aperture design.

To determine the shape of a radiation beam aperture a margin is typically applied to the clinical target volume (CTV) to yield the planning target volume (PTV), and the aperture is then determined from the projection of the PTV onto the aperture plane. This margin accounts for setup variability and organ motion originating from respiration or other physiologic processes. The use of either a uniform margin, or alternatively one which takes into account only the expected magnitude and direction of target motion, fails to account for the three-dimensional nature of the target; such a method neglects the volumetric effect of target shape on the fractional target volume irradiated when the target shifts partially out of the aperture. A mathematical framework is developed to analyze and illustrate the consequences of irradiating an irregular target shape in the presence of target motion. The effect of target shape on volume coverage is demonstrated for selected cases involving conventional BEV aperture design techniques. The volumetric implications of target shape are considered from two complementary points of view. The first involves transformation into a "displacement space," which isolates the volumetric effect of the shape of the target allowing it to be studied independently of the probability distribution of target motion. The second point of view combines the effects of the 3D target shape and the probability distribution of motion in a manner independent of beam direction to yield a 3D "target distribution." The two points of view represent distinct starting points for computation of the expected value of fractional target volume coverage in the presence of target motion. In certain cases it may be beneficial to (1) employ "target distributions" for the target and normal tissues in place of the conventional static PTV and, (2) include the aperture shape, on equal footing with parameters such as beam weights and energies, into a quantitative optimization process explicitly accounting for uncertainties in the position of the target volume and critical structures.

Equipment Design↗

PubMed1998

Influence of physical exercise on aging rats. III. Life-long exercise modifies the aging changes of the mechanical properties of limb muscle tendons.

We have previously shown that long-term regular physical exercise has a systemic influence on the rat by slowing the aging of its connective tissues, measured as thermal stability and biomechanical properties of tail tendons. This paper analyses whether the properties of limb muscle tendons are influenced not only by the aging process and the systemic effects of exercise but also from direct mechanical stimuli from long-term physical exercise. Male Sprague-Dawley rats were trained in a treadmill from the age of 5 to 23 months. The effects of training on muscle tendons were analyzed with respect to biomechanical properties. Also, the viscoelastic activation energies for interactions between collagen and the proteoglycan gel as well as between collagen fibrils were measured. Finally the asymptotes from the creep curves were calculated in order to estimate the magnitude of the viscoelastic creep. The effects of aging were analyzed with respect to the same parameters by comparing the group of 23-month-old sedentary rats with a 5-month-old baseline group. The biomechanical parameters did not change significantly with physical exercise. Neither did the activation energies change, but the asymptotes of the creep curves decreased, showing that there was less viscoelastic creep. Aging rendered the tendons significantly stronger and stiffer, increased the energy-absorbing capacity and decreased the strain values. The activation energies did not change with aging, but the high creep curve asymptote for the flexor tendons decreased. We conclude that aging rendered both types of tendons stiffer, and decreased their strain values at breaking point. Aging also increased the stress value, the energy absorption and the dry weight for the flexor tendon. Further, while physical exercise has a systemic delaying effect on age changes in connective tissues, in tendons subjected to substantial mechanical loads this effect as measured with biomechanical methods is counteracted by the optimization process elicited by the same physical exercise.

Aging↗

PubMed1996

Structure optimization of an artificial neural filter detecting membrane-spanning amino acid sequences.

An artificial neural network has been developed for the recognition and prediction of transmembrane regions in the amino acid sequences of human integral membrane proteins. It provides an additional prediction method besides the common hydrophobicity analysis by statistical means. Membrane/nonmembrane transition regions are predicted with 92% accuracy in both training and independent test data. The method used for the development of the neural filter is the algorithm of structure evolution. It subjects both the architecture and parameters of the system to a systematical optimization process and carries out local search in the respective structure and parameter spaces. The training technique of incomplete induction as part of the structure evolution provides for a comparatively general solution of the problem that is described by input-output relations only. Seven physiochemical side-chain properties were used to encode the amino acid sequences. It was found that geometric parameters like side-chain volume, bulkiness, or surface area are of minor importance. The properties polarity, refractivity, and hydrophobicity, however, turned out to support feature extraction. It is concluded that membrane transition regions in proteins are encoded in sequences as a characteristic feature based on the respective side-chain properties. The method of structure evolution is described in detail for this particular application and suggestions for further development of amino acid sequence filters are made.

Algorithms↗

PubMed1999

The Design of Leadlike Combinatorial Libraries.

The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence of affinity enhancement. Hits with affinity at µM levels discovered by screening leadlike libraries allow scope for this optimization process, as shown schematically by the distributions of M(r) for a leadlike library (1), oral drugs (2), and a typical combinatorial chemistry library (3). y=percentage with a particular molecular weight.

Journal Article↗

PubMed2000

Green fluorescent protein in Saccharomyces cerevisiae: real-time studies of the GAL1 promoter.

Green fluorescent protein (GFP) was used to study the regulation of the galactose-inducible GAL1 promoter in yeast Saccharomyces cerevisiae strains. GFP was cloned into the pGAL110 vector and transformed into the yeast strains. Time course studies comparing culture fluorescence intensity and GFP concentration were conducted along with on-line monitoring of GFP expression. Our results demonstrated that GFP fluorescence could be used as a quantifiable on-line reporter gene in yeast strains. The effect of an integrated GAL10p-GAL4 transcription cassette was investigated. Induction time studies showed that there was no significant difference in GFP expression level by adding galactose at different culture times. A wide range of galactose concentrations was used to study the initial galactose concentration effect on GFP expression kinetics. A minimum of 0.05 g/L galactose doubled the GFP fluorescence signal as compared to the control, whereas 0.1 g/L gave the highest specific GFP yield. A simple analytical model was proposed to describe GFP expression kinetics based on the experimental results. In addition, this GFP-based approach was shown to have potential use for high-throughput studies. The use of GFP as a generic tool provided important insights to the GAL expression system and has great potential for further process optimization applications.

Blotting, Western↗

PubMed2001

An evaluation of the detection limits possible for competitive capillary electrophoretic immunoassays.

Using a high-affinity antibody for estradiol, thermodynamic and experimental limitations on detection limits for competitive capillary electrophoretic immunoassays were examined. Theoretical modeling of the dose-response curves for such assays allowed for optimization of experimental conditions. Through the examination of experimental and theoretical results generalizations could be made as to the ability of capillary electrophoretic immunoassays to achieve low detection limits. An experimental detection limit of 310 pM, corresponding to 2100 molecules, was achieved. A minimum theoretical detection limit for the antibody of interest was approximated to be 125-525 pM depending on the standard deviation. An overview of the optimization process is given as well as commentary on theoretical predictions.

Antibodies↗

PubMed2026

Engineering the Vero Cell Lineage: Toward a Programmable Vaccine Manufacturing Platform.

Vero cells remain an indispensable continuous substrate for human viral vaccine manufacturing. Despite decades of empirical process optimization, intrinsic genomic instability, including segmental aneuploidy and dynamic chromatin rearrangements, continues to limit the durability of engineered phenotypes under sustained viral burden and bioreactor stress. Here, we review the expanding engineering toolkit for the Vero lineage across a three-layered functional framework: the membrane interface, cytoplasmic foundry, and nuclear blueprint, evaluating translational prospects at each level. Receptor transplantation and morphological reprogramming have broadened viral entry range and enabled suspension-adapted culture formats, while metabolic flux management and temporally controlled apoptosis modulation have addressed intracellular production bottlenecks, albeit often with trade-offs between productivity, biosafety, and long-term population stability. At the genomic level, targeted perturbations of transcriptional regulators and emerging epigenetic interventions offer more durable gains, yet expression drift, clonal heterogeneity, and karyotypic instability during extended passaging highlight the need for locus-level precision rather than constitutive trait installation. Looking forward, infection-responsive dynamic logic circuits and the systematic identification of Vero-specific genomic safe harbors could shift the paradigm toward a conditionally responsive manufacturing architecture. Collectively, these advances suggest a pathway for transitioning the Vero lineage from a passive, empirically optimized biological substrate into a conditionally responsive, genomically stable, and programmable platform for modern vaccine preparedness.

Vero cells↗

PubMed1987

Promoter recognition and promoter strength in the Escherichia coli system.

The strength of Escherichia coli promoters in vivo as well as the rates of association between RNA polymerase and promoter sequences differ by more than an order of magnitude. Since efficient promoter recognition and rapid binding of the enzyme might be a prerequisite for exceptional promoter strength we have determined the forward rate constants kon (as well as koff) for nine promoters including PL, PA1, and PN25 from phages lambda, T7, and T5, respectively as well as Pbla and PlacUV5 from E. coli. The second order forward rate constants span a 30-fold range from 1 X 10(7) M-1 s-1 for Pbla and PL up to 2.9 X 10(8) M-1 S-1 for PN25. Little correlation between 'promoter recognition' as defined by the rate of complex formation of a promoter sequence with RNA polymerase and its strength in vivo as defined by the rate of RNA synthesis has been found. This adds to the evidence that the complex functional pathway encoded in a promoter sequence can be limited at various levels and that promoter strength in vivo is the result of an optimization process involving more than just one functional parameter.

Bacteriophage lambda↗

PubMed1990

The effects of a biosurfactant on oxygen transfer in a cyclone column reactor.

A laboratory-scale cyclone column reactor was tested to determine how its oxygen transfer characteristics were affected by surfactants in the liquid medium. The volumetric oxygen transfer coefficient was greatly decreased by small quantities of the synthetic surfactants dodecyltrimethylammonium bromide and sodium dodecylsulfate, and the biosurfactant surfactin produced by Bacillus subtilis (ATCC 21332). Since the gas holdup fraction was generally increased due to foaming, the effectiveness of the surfactants was probably due to an increase in the interfacial film resistance. B. subtilis was grown in the cyclone column to 0.6 g dm-3 with a significant level of surfactin produced while maintaining at least 75% oxygen saturation in the broth. Process optimization and scale-up of surfactin production will have to consider oxygen transfer as a key parameter.

Bacillus subtilis↗

PubMed1998

Optimal design of gradient coils in MR imaging: optimizing coil performance versus minimizing cost functions.

The "forward" method of an optimal gradient coil design provides a coil that has the minimal cost function value. It is shown in this study that the solution obtained by minimizing the cost function is directly dependent on the specified cost function and generally results in a deviation from the most desirable coil design. In this paper, a gradient coil design approach for obtaining the best achievable coil performance for pre-determined imaging applications is presented. Through this approach, all intermediate coil performance values calculated during an optimization process, using a simulated annealing algorithm, are stored and presented in a three-dimensional data set. Using this three-dimensional data set, a coil designer is able to make a balance between different coil performance parameters and to select a coil that is the most desirable for the pre-determined imaging applications.

Algorithms↗

PubMedDate not supplied

Quantitative magnetic resonance spectroscopy by optimized numerical curve fitting.

A technique is reported for generating the quantitative area under selected peaks within a 31P NMR spectrum. A numerical iterative method generates the fitted curve so as to minimize the RMS deviation between the fit and the experimental data. The curve is constructed from elemental grains of spectral density ('spexels'), each of which represents an elemental Lorentzian distribution, where the centre frequency and line width of the spexel may be varied within predetermined limits. This provides a fit that in principle is not restricted to a Lorentzian model. The method allows peak areas to be estimated, including the case of overlapping peaks. The method has been tested using simulated spectra containing six overlapping spectral lines each of known amplitude (ranging from 367 to 661 mV) and area; together with additional Gaussian noise with a standard deviation ranging from 30 to 646 mV. The results of fitting both unfiltered and filtered spectra were compared. The variation of quality of fit with spectral noise and filtering has been evaluated. In all cases, the method fitted the peak amplitudes to within 1% of the simulated value. The optimization processes provide an excellent non-linear spectrum filtering algorithm. Provided the noise in the spectra did not exceed ca 400 mV, prefiltered data could be adequately fitted.

Computer Simulation↗

PubMed2003

Generation of bioreagents for protein chips.

Protein microarrays have the potential to dramatically increase the throughput of proteomic analysis. Protein expression profiling chips with distinct spots of immobilized protein capture agents will allow the simultaneous measurement of hundreds to thousands of proteins from one sample. In contrast to DNA chips, for which the capture probes are easily designed and synthesized, the development of content for protein biochips is a long and laborious process. Careful consideration must be given to the specificities desired, the format of the assay, and the requirements of the capture agents, as well as to process optimization to minimize development time and cost. Monoclonal antibodies have been the prime choice as protein capture agents for the majority of protein chips developed to date. New technologies for the production of protein capture agents are more amenable to automation than traditional monoclonal antibody production and therefore carry the promise for industrialization.

Affinity Labels↗

PubMed1996

Cryopreservation of an attenuated vaccine strain of the protozoan parasite Toxoplasma gondii.

Toxoplasma gondii is a protozoan parasite that infects birds and mammals, including humans. T. gondii T-263 is an attenuated mutant strain that is being developed as a live vaccine to protect cats from shedding oocysts. A cryopreservation procedure for T. gondii T-263 bradyzoites has been developed to meet the requirement for product stability. A Me2SO-based procedure for the cryopreservation of tachyzoites was used as a basis for process optimization. A modified cell culture plaque assay was used to determine the effects of selected cryobiological parameters on bradyzoite viability. The major parameters evaluated were: (i) cooling rates; (ii) intermediate plunge temperature; and (iii) thawing and dilution rates and temperatures. The optimized cryopreservation protocol comprised incubation in 12.5% Me2SO and 4% BSA for 30 min at room temperature, cooling at 1 degree C min-1 to -40 degrees C, followed by direct transfer into liquid nitrogen. Rapid thawing (approximately 120 degrees C min-1) followed by slow dilution of cryoprotectant over 15 min resulted in the highest survival. The optimized procedure increased survival 10,000-fold over that obtained using an established tachyzoite protocol. This procedure is to be adapted for the large-scale cryopreservation of T. gondii T-263 bradyzoites in individual vaccine doses.

Animals↗

PubMed1996

Fitness spectrum among random mutants on Mt. Fuji-type fitness landscape.

Statistical properties of a Mt. Fuji-type fitness landscape on a multi-valued sequence space were analysed. We constructed the model landscape based on additivity of the free energy contributed by each residue on a biopolymer, introducing "tolerance functions" that describe tolerance to residue substitution at each site. The fitness spectrum among a random mutant population around a wild-type sequence was theoretically obtained as the probability density distribution function of fitness. As the Hamming distance from the wild-type to the mutants increases, the mean fitness of the mutant population gradually decreases, and the variance of the fitness increases. These features are originated from the anisotropy of the landscape. On the assumption that the free energy is statistically additive around a wild-type in a sequence space of a real biopolymer, one can estimate the Hamming distance from the wild-type to the optimal biopolymer and the fitness of the optimum. Two sets of experimental data were analysed: (1) a promoter strength spectrum of a mutant population produced by the random mutagenesis of a wild-type lac promoter; (2) four stepwise optimization processes of different peptide mixtures evaluated with ligand binding affinity. Analysis of both experiments showed the compatibility with the hypothesis that local fitness landscapes around contemporary biopolymers are near Mt. Fuji-type. The mean slope of each of the four affinity landscapes for (2) was estimated as delta In K(d)/delta d = 1.3 approximately 2.3, where d denotes the Hamming distance from the optimum and K(d) represents the mean dissociation constant of sequences located at the Hamming distance of d. Mt. Fuji-type landscape can be regarded as a zero-th order approximation to the real local landscape just like an "ideal gas". We showed a method to gauge statistically the shape of a near Mt. Fuji-type landscape by measuring mutant fitness spectra.

Animals↗

PubMed2001

Recycling probability and dynamical properties of germinal center reactions.

We introduce a new model for the dynamics of centroblasts and centrocytes in a germinal center. The model reduces the germinal center reaction to the elements considered as essential and embeds proliferation of centroblasts, point mutations of the corresponding antibody types represented in a shape space, differentiation to centrocytes, selection with respect to initial antigens, differentiation of positively selected centrocytes to plasma or memory cells and recycling of centrocytes to centroblasts. We use exclusively parameters with a direct biological interpretation such that, once determined by experimental data, the model gains predictive power. Based on the experiment of Han et al. (1995b) we predict that a high rate of recycling of centrocytes to centroblasts is necessary for the germinal center reaction to work reliably. Furthermore, we find a delayed start of the production of plasma and memory cells with respect to the start of point mutations, which turns out to be necessary for the optimization process during the germinal center reaction. The dependence of the germinal center reaction on the recycling probability is analysed.

Animals↗

PubMed2001

Evolutionary engineering of industrially important microbial phenotypes.

The tremendous complexity of dynamic interactions in cellular systems often impedes practical applications of metabolic engineering that are largely based on available molecular or functional knowledge. In contrast, evolutionary engineering follows nature's 'engineering' principle by variation and selection. Thus, it is a complementary strategy that offers compelling scientific and applied advantages for strain development and process optimization, provided a desired phenotype is amenable to direct or indirect selection. In addition to simple empirical strain development by random mutation and direct selection on plates, evolutionary engineering also encompasses recombination and continuous evolution of large populations over many generations. Two distinct evolutionary engineering applications are likely to gain more relevance in the future: first, as an integral component in metabolic engineering of strains with improved phenotypes, and second, to elucidate the molecular basis of desired phenotypes for subsequent transfer to other hosts. The latter will profit from the broader availability of recently developed methodologies for global response analysis at the genetic and metabolic level. These methodologies facilitate identification of the molecular basis of evolved phenotypes. It is anticipated that, together with novel analytical techniques, bioinformatics, and computer modeling of cellular functions and activities, evolutionary engineering is likely to find its place in the metabolic engineer's toolbox for research and strain development. This review presents evolutionary engineering of whole cells as an emerging methodology that draws on the latest advances from a wide range of scientific and technical disciplines.

Biological Evolution↗

PubMed1986

A multicomponent, random walk model of transport and metabolism inside a neuron.

A model of multicomponent transport, consumption, and production of metabolites inside a neuron containing discrete mitochondria and glycolytic enzymes is developed using a random walk model of molecular transport. The ratio of anaerobic to aerobic metabolism which maximizes ATP production under normal, ischemic, and anoxic conditions is calculated. The ratio of the number of mitochondria to glycolytic enzymes which maximizes ATP under normal conditions is also calculated. Because the volume of the neuron is fixed, the sum of the number of mitochondria and glycolytic enzymes is fixed. This constraint is incorporated in the optimization process as an interior penalty function. Some of the advantages of employing the random walk technique are simple stoichiometry can be used to model consumption and production of metabolites, the geometry of the enzyme system and their active sites can be easily included in the model, and saturation of enzymes can be more easily modeled.

Animals↗