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At least 1,657 records · Page 92Linked to original sources
PubMed2003

Detection of suppressor T lymphocytes and estimation of their frequency in limiting dilution assays by generalized linear regression modeling.

The estimate of the frequency of suppressor T lymphocytes in unfractionated cell populations remains challenging, mainly because these regulatory cells do not display specific immunophenotypic markers. In this paper, we describe a novel theoretical approach for quantifying the frequency of suppressor cells. This method is based on limiting dilution data modeling, and allows the simultaneous estimation of the frequencies of both proliferating and suppressor cells. We used previously published biological data, characterizing the inhibiting activity of suppressor T cell clones. Starting from these data, we propose a mathematical model describing the interaction between suppressor and proliferating T cells, and applied to a Poisson process. Limiting dilution data corresponding to this non-single-hit, suppressor two-target Poisson model were artificially generated, then modeled according to a generalized linear regression procedure. Deviation from the single-hit Poisson model was revealed by a statistical slope test, and a stepwise analysis of the regression appeared to be an efficient method that strongly argued in favor of the presence of suppressor cells. By using the frequency of proliferating T cells calculated in the first step of the regression, we demonstrated the possibility to provide a reasonable estimate of the frequency of suppressor T cells. Based on these findings, a practical decision-making procedure is given to perform standard analyses of limiting dilution data.

Animals↗
PubMed1999

Identification of residues essential for a two-step reaction by malonyl-CoA synthetase from Rhizobium trifolii.

Malonyl-CoA synthetase (MCS) catalyses the formation of malonyl-CoA in a two-step reaction consisting of the adenylation of malonate with ATP followed by malonyl transfer from malonyl-AMP to CoA. In order to identify amino acid residues essential for each step of the enzyme, catalysis based on chemical modification and database analysis, Arg-168, Lys-170, and His-206 were selected for site-directed mutagenesis. Glutathione-S-transferase-fused enzyme (GST-MCS) was constructed and mutagenized to make R168G, K170M, R168G/K170M and H206L mutants, respectively. The MCS activity of soluble form GST-MCS was the same as that of wild-type MCS. Circular dichroism spectra for the four mutant enzymes were nearly identical to that for the GST-MCS, indicating that Arg-168, Lys-170 and His-206 are not important for conformation but presumably for substrate binding and/or catalysis. HPLC analysis of products revealed that the intermediate malonyl-AMP is not accumulated during MCS catalysis and that none of the mutant enzymes accumulated it either. Kinetic analysis of the mutants revealed that Lys-170 and His-206 play a critical role for ATP binding and the formation of malonyl-AMP, whereas Arg-168 is critical for formation of malonyl-CoA and specificity for malonyl-AMP. Molecular modelling based on the crystal structures of luciferase and gramicidin S synthetase 1 provided MCS structure which could fully explain all these biochemical data even though the MCS model was generated by comparative modelling.

Adenosine Triphosphate↗
PubMedDate not supplied

[Completely implantable venous access systems. A study of the morbidity and benefits of a model third-generation device, the PAS Port with Cath-Finder].

Venous access for chemotherapy in oncological patients, has experienced continuous modifications in recent years, both with regard to the types of devices used as with regard to the venous access itself. We present a prospective study of two groups of 25 patients, in which the patients in the first group were given a Port-A-Cath PAS Port venous access system with a Cath-Finder catheter locating system, and those in the second group were given a conventional Implantofix and Hickman venous access system. The device placed in the first group belongs to a third generation venous access system, involving a simple and safe placing technique which neither requires an operating room nor radiology. The incidence of complications in the first group was similar to that seen in conventional systems. To prevent early or late phlebitis in the cephalic or basilar vein, we recommended the prophylactic use of low molecular weight heparin during the procedure and maintaining this during the next three to five days, as well as during each new chemotherapy session and at any time this complication may arise. The economic benefits of this device are much greater than those of conventional systems.

Catheterization, Peripheral↗
PubMed1998

Calculation of HyHel10-lysozyme binding free energy changes: effect of ten point mutations.

The change in free energy of binding of hen egg white lysozyme (HEL) to the antibody HyHel-10 arising from ten point mutations in HEL (D101K, D101G, K96M, K97D, K97G, K97G, R21E, R21K, W62Y, and W63Y) was calculated using a combination of the finite difference Poisson-Boltzmann method for the electrostatic contribution, a solvent accessible surface area term for the non-polar contribution, and rotamer counting for the sidechain entropy contribution. Comparison of experimental and calculated results indicate that because of pKa shifts in some of the mutated residues, primarily those involving Aspartate or Glutamate, proton uptake or release occurs in binding. When this effect was incorporated into the binding free energy calculations, the agreement with experiment improved significantly, and resulted in a mean error of about 1.9 kcal/mole. Thus these calculations predict that there should be a significant pH dependence to the change in binding caused by these mutations. The other major contributions to binding energy changes comes from solvation and charge charge interactions, which tend to oppose each other. Smaller contributions come from nonpolar interactions and sidechain entropy changes. The structures of the HyHel-10-HEL complexes with mutant HEL were obtained by modeling, and the effect of the modeled structure on the calculations was also examined. "Knowledge based" modeling and automatic generation of models using molecular mechanics produced comparable results.

Animals↗
PubMed1988

A personal computer-based arrhythmia generator based on mathematical models of cardiac arrhythmia.

A personal computer-based arrhythmia generator has been developed based upon mathematical models of modulated parasystole and the related equations. A system of nonlinear difference equations is used to generate the time series of RR intervals of ECG that contain normal as well as ectopic QRS waves. The ECG waveform is synthesized according to the computed RR interval and the type of QRS wave and output via DA converter in a real-time base. Various types of ECGs with ventricular ectopic beats and those with very long periods were generated by selecting values for a small number of model parameters. This method requires neither large RAM nor external memory for storing a library of arrhythmic ECGs. The theory, hardware design, software implementation on a personal computer, and experimental reconstruction of clinical ECGs based on the model are discussed.

Arrhythmias, Cardiac↗
PubMed1999

Models of respiratory rhythm generation in the pre-Bötzinger complex. I. Bursting pacemaker neurons.

A network of oscillatory bursting neurons with excitatory coupling is hypothesized to define the primary kernel for respiratory rhythm generation in the pre-Bötzinger complex (pre-BötC) in mammals. Two minimal models of these neurons are proposed. In model 1, bursting arises via fast activation and slow inactivation of a persistent Na+ current INaP-h. In model 2, bursting arises via a fast-activating persistent Na+ current INaP and slow activation of a K+ current IKS. In both models, action potentials are generated via fast Na+ and K+ currents. The two models have few differences in parameters to facilitate a rigorous comparison of the two different burst-generating mechanisms. Both models are consistent with many of the dynamic features of electrophysiological recordings from pre-BötC oscillatory bursting neurons in vitro, including voltage-dependent activity modes (silence, bursting, and beating), a voltage-dependent burst frequency that can vary from 0.05 to >1 Hz, and a decaying spike frequency during bursting. These results are robust and persist across a wide range of parameter values for both models. However, the dynamics of model 1 are more consistent with experimental data in that the burst duration decreases as the baseline membrane potential is depolarized and the model has a relatively flat membrane potential trajectory during the interburst interval. We propose several experimental tests to demonstrate the validity of either model and to differentiate between the two mechanisms.

Animals↗
PubMed2003

Comparison of wound-healing characteristics with feedback circuit electrosurgical generators in a porcine model.

The type of incisional instrument used to create a surgical wound can influence the rate of wound healing and overall wound strength. The purpose of this study was to evaluate several facets of wound healing within incisions created in the small intestine, uterus, and skin in a porcine model by using feedback circuit electrosurgical generators and a standard steel scalpel blade in a porcine model. Eighteen pigs were evaluated by creating surgical incisions in the skin, uterus, and small intestine utilizing 2 computerized electrosurgical generators (FX, ValleyLab, Boulder, CO, and PEGASYS, Ethicon Endo-Surgery, Inc., Cincinnati, OH) and a scalpel blade. All incisions were reapproximated with absorbable suture. Incision sites were evaluated histologically at 3, 7, or 14 days postincision according to randomization. The skin and small intestine samples were tested for wound tensile strength at 7 and 14 days. There were no statistically significant differences demonstrated with tensile strength testing comparing the electrosurgical devices to the scalpel-blade incisions for skin or small intestine at all time points. The only significant difference detected with respect to wound tensile strength was when different organ types were compared, regardless of device used (i.e., skin, 19.5 N/cm2 vs. small intestine, 5.78 N/cm2). Histologic evaluation demonstrated that the wounds created by the electrosurgical generators displayed decreased overall wound healing at 3, 7, and 14 days compared to the scalpel group. These findings indicate that the electrosurgical devices tested delay wound healing at the surgical site, but fail to demonstrate any significant difference in overall wound tensile strength. Wound healing may occur at a more rapid rate when a traditional scalpel blade is used to create the surgical incision, but no difference in global wound dynamics could be detected.

Animals↗
PubMed2001

A model for phase noise generation in amplifiers.

In this paper, a model is presented for predicting the phase modulation (PM) and amplitude modulation (AM) noise in bipolar junction transistor (BJT) amplifiers. The model correctly predicts the dependence of phase noise on the signal frequency (at a particular carrier offset frequency), explains the noise shaping of the phase noise about the signal frequency, and shows the functional dependence on the transistor parameters and the circuit parameters. Experimental studies on common emitter (CE) amplifiers have been used to validate the PM noise model at carrier frequencies between 10 and 100 MHz.

Journal Article↗
PubMed2002

Conditional mouse models of sporadic cancer.

First-generation mouse tumour models, which used transgenic mice or conventional knockouts, are now being superseded by models that are based on conditional knockouts and mice that carry regulatable oncogenes. In these mice, somatic mutations can be induced in a tissue-specific and time-controlled fashion, which more faithfully mimics sporadic tumour formation. These second-generation models provide exciting new opportunities to gain insight into the contribution of known and unknown genes in the initiation, progression and treatment of cancer, and mimic human cancer better than ever before.

Alleles↗
PubMed2003

Discrete restraint-based protein modeling and the Calpha-trace problem.

We present a novel de novo method to generate protein models from sparse, discretized restraints on the conformation of the main chain and side chain atoms. We focus on Calpha-trace generation, the problem of constructing an accurate and complete model from approximate knowledge of the positions of the Calpha atoms and, in some cases, the side chain centroids. Spatial restraints on the Calpha atoms and side chain centroids are supplemented by constraints on main chain geometry, phi/xi angles, rotameric side chain conformations, and inter-atomic separations derived from analyses of known protein structures. A novel conformational search algorithm, combining features of tree-search and genetic algorithms, generates models consistent with these restraints by propensity-weighted dihedral angle sampling. Models with ideal geometry, good phi/xi angles, and no inter-atomic overlaps are produced with 0.8 A main chain and, with side chain centroid restraints, 1.0 A all-atom root-mean-square deviation (RMSD) from the crystal structure over a diverse set of target proteins. The mean model derived from 50 independently generated models is closer to the crystal structure than any individual model, with 0.5 A main chain RMSD under only Calpha restraints and 0.7 A all-atom RMSD under both Calpha and centroid restraints. The method is insensitive to randomly distributed errors of up to 4 A in the Calpha restraints. The conformational search algorithm is efficient, with computational cost increasing linearly with protein size. Issues relating to decoy set generation, experimental structure determination, efficiency of conformational sampling, and homology modeling are discussed.

Algorithms↗
PubMed1993

Synthetic model peptides for apolipoproteins. II. Characterization of the discoidal complexes generated between phospholipids and synthetic model peptides for apolipoproteins.

The structure, composition and physico-chemical properties of complexes generated between phospholipids and synthetic model peptides for the amphipathic helices of the plasma apolipoproteins were studied. The sequences of the peptides were derived from that of the 18A peptide and designed to either enhance or decrease ionic interactions between pairs of peptides, as described in the accompanying paper. Complexes were prepared with dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or with DPPC and cholesterol, and isolated on a Superose 6HR column. Association kinetics for the DMPC-peptides complexes were followed by measuring the turbidity as a function of the temperature. The diameters of the DPPC-peptide complexes, measured by gradient gel electrophoresis (GGE), were about 120 A. Fluorescence polarization measurements after labeling with diphenyl hexatriene (DPH) yielded transition temperatures of, respectively, 40.6, 41.5 and 41.8 degrees C for the DPPC/18AM1-, DPPC/18AM4- and DPPC/18A-peptide complexes. These values were confirmed by differential scanning calorimetry. Circular dichroism and infrared spectroscopy revealed that the peptides adopt an alpha-helical structure in solution and this percentage increased from 30-40% in the free peptides up to 50-60% in the complexes. Attenuated total reflection (ATR) infrared measurements of the complexes indicated that the peptides are oriented parallel to the acyl chains of the phospholipid bilayer. Denaturation of the peptides and of the peptide-lipid complexes was monitored by Trp fluorescence under addition of increasing amounts of GdmCl. The mid-points of the denaturation curves lie at, respectively, 0.05, 0.25 and 0.35 M GdmCl for the 18AM4, 18A and 18AM1 peptide and are shifted towards higher GdmCl concentrations after peptide-lipid binding. GdmCl denaturation decreased the alpha-helical content of the peptides and of the complexes, as monitored by circular dichroism measurement. The helix to random coil structure transition occurred at, respectively, 2.1, 2.2, and 2.0 M GdmCl for 18A, 18AM1 and 18AM4, compared to 5.1, 5.0, and 5.3 M in the corresponding complexes. These data suggest altogether that the structural properties, the mode of lipid-protein association and the stability of the phospholipid-peptide complexes are similar to those of native plasma apolipoproteins. The 18A and 18AM4 peptides which contain charged residues along the edge of the helix, leading to salt bridge formation between peptides were shown to mimic the amphipathic helices of the plasma apolipoproteins.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2006

3D finite element mesh generation of complicated tooth model based on CT slices.

An interactive three-dimensional finite element generation method is presented for modelling a multi-connected teeth and mandible structure. The tetrahedron is chosen as the basic element type due to its rigorous adaptability to structures with geometric complexities. The mesh generation is implemented by allocating two quadrangles in adjacent CT image slices to form a set of tetrahedrons. By examining all the possible allocations and their degradations, an algorithm is developed for interactive mesh generation, resulting in a series of tetrahedrons consistent with all the others without overlapping and spacing. The developed system was applied to a tooth-mandibular structure, generating a complicated 3D FEM model consisting of 4762 nodes and 18,534 tetrahedral elements with nine different materials. This 3D model was successfully used to evaluate different tooth restoration strategies, which proved the viability and effectiveness of the proposed method.

Finite Element Analysis↗
PubMed1991

Linearized model for the initiation of factor Va, and thrombin generation.

A simple model of the initiation of thrombin formation in plasma as a response to factor Xa generation was constructed. In this model factor Xa is considered as an input with a constant concentration. Substrate depletion and inactivation by activated protein C are neglected. The resulting linear model allows a closed form solution by standard methods. With values of the reaction rate constants, as determined in purified systems, this model predicts a highly explosive and complete activation of factor V and prothrombin as a response to any given (steady state) factor Xa concentration even in situations where prothrombinase and(/or) thrombin are rapidly inactivated. However, the time delay to rapid thrombin production becomes longer at lower factor Xa concentrations. Analysis of this time delay as a function of the factor Xa concentration indicates that the gain of the feedback loop of factor V activation by thrombin is so high that the contribution of factor V activation by factor Xa is relatively unimportant for factor Xa concentrations in the nanomolar range. It appears that the time lag is mainly determined by the gain of this feedback loop: similar proportional reductions of each of these reaction rates causes a similar effect. The effects of moderately enhanced inhibition rates of thrombin and prothrombinase on the time delay depend strongly on factor Xa concentration. Only a minor prolongation of the delay is predicted for factor Xa concentrations in the nanomolar range, but for factor Xa concentrations in the 1-10 pM range, the enhanced decay will cause considerable delays. Simultaneous reduction of the turnover rate of prothrombinase results in much larger delays for the entire range of factor Xa concentrations.

Computer Simulation↗