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At least 523 records · Page 29Linked to original sources

PubMed2006

Predictive value of the original content of CD34(+) cells for enrichment of hematopoietic progenitor cells from bone marrow harvests by the apheresis procedure.

We retrospectively investigated the feasibility of the apheresis procedure for red blood cell (RBC) reduction with a closed-bag system. We also sought to determine the optimal processing volume for the maximal recovery of hematopoietic progenitor cells (HPC). Twelve bone marrow (BM) harvests were processed for major ABO-incompatible allogeneic transplantation and one BM harvest was processed for autologous transplantation. The processing was performed through seven apheresis cycles with a two-bag system using COBE Spectra Version 6.1. The mean recovery rates were compared in the products after four cycles and seven cycles of BM processing. Mean cell recovery rates were 79.2% (67.6-97.5%) and 87.3% (68.9-111.9%) for the mononuclear cells (MNC) and 84.5% (69.4-109.5%) and 92.0% (79.0-107.7%) for the CD34(+) cells after four and seven cycles, respectively. A mean of 96.3% (93.0-98.1%) of the RBCs were finally removed. The yield of CD34(+) cells after seven cycles of processing (median: 10.35 x 10(7) cells) was 7.9% greater than that after four cycles of processing (median: 9.65 x 10(7) cells), exhibiting a less-than-significant enhancement in yield. The CD34(+) cell contents recovered in the concentrates up to four cycles (r = 0.989) and up to seven cycles (r = 0.993) were strongly correlated with the original content of the CD34(+) cells. Engraftment was obtained in all patients except one patient infused with purified CD34(+) cells. This latter result confirmed the hematopoietic potential of the cell populations recovered. Granulocyte recovery (defined as an absolute neutrophil cell count > or = 500/microL for a period of three consecutive days) ranged from 8 to 25 days (median: 16 days) post-transplantation. No hemolytic reaction was observed in any of the patients. Our results confirmed the efficacy of BM processing cycles with the COBE Spectra device. However, we could not conclude that the large-volume apheresis for BM processing significantly enhanced the yields of HPC. The final recovery of CD34(+) cells after processing could be predicted from the CD34(+) cell content of the original collected marrow.

ABO Blood-Group System↗

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↗

PubMed2004

TOPS-MODE approach for the prediction of blood-brain barrier permeation.

The blood-brain barrier permeation has been investigated by using a topological substructural molecular design approach (TOPS-MODE). A linear regression model was developed to predict the in vivo blood-brain partitioning coefficient on a data set of 119 compounds, treated as the logarithm of the blood-brain concentration ratio. The final model explained the 70% of the variance and it was validated through the use of an external validation set (33 compounds of the 119, MAE = 0.33), a leave-one-out crossvalidation (q(2) = 0.65, S(press) = 0.43), fivefold full crossvalidation (removing 28 compounds in each cycle, MAE = 33, RMSE = 0.43) and the prediction of +/- values for an external test set (85.7% of good prediction). This methodology evidenced that the hydrophobicity increase the blood-brain barrier permeation, while the polar surface and its interaction with the atomic mass of compounds decrease it; suggesting the capacity of the TOPS-MODE descriptors to estimate brain penetration potential of new drug candidates. Finally, by the present approach, positive and negative substructural contributions to the brain permeation were identified, and their possibilities in the lead generation and optimization processes were evaluated.

Blood-Brain Barrier↗

PubMed2006

A topological substructural approach for the prediction of P-glycoprotein substrates.

A topological substructural molecular design approach (TOPS-MODE) has been used to predict whether a given compound is a P-glycoprotein (P-gp) substrate or not. A linear discriminant model was developed to classify a data set of 163 compounds as substrates or nonsubstrates (91 substrates and 72 nonsubstrates). The final model fit the data with sensitivity of 82.42% and specificity of 79.17%, for a final accuracy of 80.98%. The model was validated through the use of an external validation set (40 compounds, 22 substrates and 18 nonsubstrates) with a 77.50% of prediction accuracy; fivefold full cross-validation (removing 40 compounds in each cycle, 80.50% of good prediction) and the prediction of an external test set of marketed drugs (35 compounds, 71.43% of good prediction). This methodology evidenced that the standard bond distance, the polarizability and the Gasteiger-Marsilli atomic charge affect the interaction with the P-gp; suggesting the capacity of the TOPS-MODE descriptors to estimate the P-gp substrates for new drug candidates. The potentiality of the TOPS-MODE approach was assessed with a family of compounds not covered by the original training set (6-fluoroquinolones), and the final prediction had a 77.7% of accuracy. Finally, the positive and negative substructural contributions to the classification of 6-fluoroquinolones, as P-gp substrates, were identified; evidencing the possibilities of the present approach in the lead generation and optimization processes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Chemical extraction and direct adsorptive purification of recombinant human antigen Ro52.

The antigenic protein Ro52 was expressed in the E. coli system harboring a 6 x His tag in the form of insoluble inclusion bodies. Direct chemical extraction of the product using 6-8 M urea proved to be effective. Furthermore, the tagged protein was recovered by direct adsorption on Ni2+-loaded commercial adsorbents derivatized with iminodiacetic acid. Screening experiments in small packed columns revealed that selective binding and elution were possible using a denaturing buffer at pH 4.5. The hydrodynamic evaluation of scaled-up fluidized systems showed values for the phi (dynamic zone) parameter in the range 0.95-1.00 for fluidization in buffer and in the range 0.70-0.85 for the biomass-containing feedstock. Removal of macromolecular DNA released by the disrupted biomass was mandatory. Under optimized process conditions good recovery (60-70%) was achieved and a highly purified (95%) product obtained. The purified Ro52 retained its immunoreactivity against sera of patients with systemic lupus erythematosus (SLE) and Sjogren's syndrome-related disorders. The production and application of new recombinant antigens may contribute to increasing the sensitivity and specificity of the detection of anti-Ro antibodies in these autoimmune diseases.

Adsorption↗

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↗

PubMed2005

Optimizing brain tissue contrast with EPI: a simulated annealing approach.

A new magnetization preparation and image acquisition scheme was developed to obtain high-resolution brain images with optimal tissue contrast. The pulse sequence was derived from an optimization process using simulated annealing, without prior assumptions with regard to the number of radiofrequency (RF) pulses and flip angles. The resulting scheme combined two inversion pulses with the acquisition of three images with varying contrast. The combination of the three images allowed separation of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) based on T1, contrast. It also enabled the correction of small errors in the initial T1 estimates in postprocessing. The use of three-dimensional (3D) sensitivity-encoded (SENSE) echo-planar imaging (EPI) for image acquisition made it possible to achieve a 1.15(3) mm3 isotropic resolution within a scan time of 10 min 21 s. The cortical GM signal-to-noise ratio (SNR) in the calculated GM-only image varied between 30 and 100. The novel technique was evaluated in combination with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) on human subjects, and provided for excellent coregistration of anatomical and functional data.

Brain Mapping↗

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↗

PubMed1989

Parameter optimization model of learning in stepping motion.

In this study we combine the representation of motion by a finite number of hardwired functions with parameter optimization to model learning during a stepping motion. Representation of experimental kinematic data by a finite number of predetermined functions and undetermined coefficients was analyzed. Least squares approximation was used to represent experimental data of stepping motions over obstacles of different heights. Functional relationships between coefficients and obstacles heights were also obtained. Learning of stepping over an obstacle was then formulated as a finite dimensional optimization problem. The pattern of foot path, and joint angles trajectories obtained by this learning model, were then compared to the experimental data. The results of the data fitting analysis and of the optimization process as a model for motion learning, indicate that motion can be adequately represented by a set of hardwired functions, and a finite number of task dependent coefficients.

Humans↗

PubMed1987

On visual orientation of dot patterns.

Two-dimensional normally distributed random dot patterns were used in two experiments on visual orientation estimation. In the first experiment the patterns differed in their sample correlation and in dot number. In the second one the number of dots was maintained constant but the patterns were generated as a superposition of two normally distributed orthogonal sets composed of different number of dots. In both experiments the estimated orientation depended on stimuli correlation - with increasing correlation the estimated orientation gets closer to the orientation of the least square distance axis of the pattern. Even at very low unsignificant correlations there still remained a hint about stimulus orientation which was not estimated at random. Equalizing consecutively the number of dots in the two orthogonal dot patterns during the second experiment did not result in chance performance either. The bimodal angular distributions of the obtained responses permitted to approach the problem of orientation ambiguity. The results are discussed in terms of optimization processes taking place in the visual system.

Cybernetics↗

PubMed1980

Pathology of skeletal muscle: principles of reaction patterns and histochemistry and experience with 195 biopsies.

Technique and interpretation of muscle biopsies require the coordinated team work between referring clinician, surgeon, and pathologist so that optimal management of a patient with neuromuscular disease may be attained. Investigation of muscle diseases has advanced so much with an interdisciplinary approach that not only can accurate diagnosis be offered for the benefit of the patient in certain instances, but also genetic counselling provided and pre-natal diagnosis established. The principal reaction patterns and pathogenetic mechanisms of skeletal muscle as a contractile and metabolically active tissue are described; the diagnostic usefulness of enzyme histochemistry and the basic principles of the motor unit are discussed and illustrated. For the practicing pathologist, adequate tissue preparation of a muscle biopsy specimen requires interest and a willingness to dedicate time, effort and funds. While the paraffin-embedded section is still very valuable, enzyme histochemistry provides certain highly diagnostic information not otherwise obtainable. Likewise, there must be an interest in electron microscopy and appreciation for its value in depicting ultrastructural abnormalities when certain reaction patterns are apparent on light microscopic sections, enzyme histochemical stains, or Epon-embedded "thick" sections. Finally, concurrent sural nerve biopsy also requires optimal processing and interpretation.

Biopsy↗

PubMed1981

Scintillation autoradiography at the light microscopic level: a review.

This article reviews the reported attempts to expose autoradiographs, intended for examination by light microscopy, in the presence of scintillation fluid in order to increase efficiency and thus shorten exposure times. The scintillation process is reviewed, together with the use of comparable techniques in the autoradiography of chromatograms and electrophoresis gels. The conflicting reports on the usefulness of scintillation autoradiography in light microscopy are then discussed, and explanations sought for the wide diversity of claims made for the technique. Many of the more optimistic claims can be explained on the basis that the 'normal' autoradiographs used for comparison had unduly low efficiencies caused by inadequate drying of the emulsion and consequent latent image fading. The techniques used are unlikely to have produced any increase in efficiency through the scintillation process. Optimal conditions for obtaining such increases are derived from theoretical considerations.

Animals↗