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At least 199 records · Page 11Linked to original sources
PubMed2000

An optimization approach to design of generalized BSB neural associative memories.

This article is concerned with the synthesis of the optimally performing GBSB (generalized brain-state-in-a-box) neural associative memory given a set of desired binary patterns to be stored as asymptotically stable equilibrium points. Based on some known qualitative properties and newly observed fundamental properties of the GBSB model, the synthesis problem is formulated as a constrained optimization problem. Next, we convert this problem into a quasi-convex optimization problem called GEVP (generalized eigenvalue problem). This conversion is particularly useful in practice, because GEVPs can be efficiently solved by recently developed interior point methods. Design examples are given to illustrate the proposed approach and to compare with existing synthesis methods.

Association Learning↗
PubMed1996

Characterization of topoisomerase II-DNA interaction and identification of a DNA-binding domain by ultraviolet laser crosslinking.

We have used ultraviolet laser crosslinking to characterize the DNA-binding properties of highly purified yeast topoisomerase II in the absence of ATP. A single 5 ns, 20 mJ pulse of 266 nm light produced optimal crosslinking to a short DNA duplex, with an efficiency of 0.25%. An equilibrium binding constant (Keq) of 1.2 +/- 0.5 x 10(8) M(-1) was determined from kinetic analysis. Topoisomerase II showed highest affinity for supercoiled DNA. Limited proteolysis of crosslinked topoisomerase II-DNA complexes showed a site of crosslinking to be within a 29-kDa fragment with Leu-681 at its amino-terminal end. This region contains the active Tyr-783 and is homologous to the amino-terminal region of the DNA-binding bacterial gyrase GyrA subunit, suggesting a conserved DNA-binding mechanism.

Base Sequence↗
PubMed1988

Angiotensin II receptors in the fowl aorta.

In the domestic fowl, angiotensin II (ANG II) causes an in vivo depressor response and in vitro relaxation of aortic rings which appear to be a direct action of ANG II on the blood vessels. Thus, we determined whether binding sites specific to ANG II exist in the membrane fraction of the fowl aorta. The particulate fraction of aortas from adult female fowl, Gallus gallus, exhibits high specific binding to ANG II ligand. 125I-[Ile5]ANG II (0.5 nM) binding to the above fraction (30 micrograms protein) in 50 mM Tris (pH 7.2), 10 mM MgCl2, and 0.2% bovine serum albumin at 12 degrees (1) is rapid, saturable, and reversible; (2) increases as a function of ligand or membrane concentration, time, and temperature; and (3) optimally fits to a two-site (high and low affinity) model. The equilibrium dissociation constant (0.15 +/- 0.03 nM) and binding site concentration (28.7 +/- 8.1 fmol/mg protein) of the high affinity site as well as association (0.055 nM-1.min-1) and dissociation (0.0122 min-1) rate constants are similar to those of mammalian vascular ANG II receptors. Both 125I-[Ile5]ANG II and 125I-[Val5]ANG II are competitively displaced by unlabeled ANG II. These results suggest that specific ANG II receptors exist in the fowl aorta.

Angiotensin II↗
PubMed1982

The manpower situation in pathology: implications for the future.

With the exception of academic pathology and specific subspecialty areas, manpower in pathology is currently in a state of apparent equilibrium between supply and demand. Exogenous influences, and especially an influx of Americans who have attended foreign-chartered medical schools, could disturb this apparent equilibrium. Other key manpower issues with respect to pathology include mechanisms to determine optimal numbers of pathologists, the future productivity of pathologists, current and prospective needs in academic pathology and subspecialty areas, and the role of the federal government in the area of medical manpower. Recommendations to deal with these and related issues are presented.

Foreign Medical Graduates↗
PubMed1998

Length changes of the cat soleus muscle under frequency-modulated distributed stimulation of efferents in isotony.

The length changes of the cat soleus muscle have been examined in isotony within closed cycles of the stimulation rate change. Successive stimuli were applied in a cycle to five filaments of the preliminary dissected L7-S1 ventral roots (method of distributed stimulation), maximal rate did not exceed 80-90/s (16-18/s per single filament). At the beginning of a slow linear increase in the rate a muscle began shortening rather quickly, the rate changes without muscle reaction consisted of 5.91 +/- 0.28/s (mean +/- S.E.M.). A substantially linear movement was observed during increase of the input rate up to 40-50/s (i.e. 8-10/s per filament), a further rate increment could evoke a somewhat slowing of the shortening velocity with a distinctive infection of the rate-length curve. During a significant part of the rate decrease phase no movement was seen, the rate range with the absence of muscle lengthening was 29.93 +/- 1.57/s. After such a pronounced period of length fixation, a muscle began to elongate, the steady-state velocity at this part of the movement trajectory was invariably higher as compared with shortening velocity at the leading edge of the cycle. The striking feature of a powerful length clamping seen in active muscle at the phase of rate decrease preceded by previous rate increment allows us to suppose that this strongly non-linear behaviour of muscle might be a main reason for the existence of powerful dynamic components in efferent activity every time when muscle should shorten against external load in a ramp-and-hold fashion. We used the following experimental paradigm to check the assumption. Stimulation began with regular rate of 15/s; then, after transition from isometry to isotony and cessation of movement transients, the rate was raised linearly; after reaching a peak value of 50-90/s, it decreased linearly or exponentially, being afterwards fixed at several different levels between the maximal and initial values of the rate. It was demonstrated that such pattern of stimulation could be effective for a linear transition between two equilibrium lengths, provided that corresponding parameters in modulation signal were chosen in an optimal way. Duration and amplitude of the leading edge of the dynamic component seemed to completely define amplitude and velocity of the ramp phase of movement, parameters of decay to the final steady rate were, on the other hand, important for efficacy of the length clamping at hold phase. It was concluded that hysteresis effects of muscle contraction seemed to be an extremely important nonlinear property of muscle dynamics in producing any transition movements between two steady-states. Thus, oversimplified muscle models, like the spring model based on the isometric length-tension dependencies, seem to be incorrect. Possible mechanisms for the muscle hysteresis and its role in motor control are discussed.

Animals↗
PubMed1999

Efficient discrimination between different densities of target antigen by tetracycline-regulatable T bodies.

Engineered T cells expressing chimeric T cell receptors (chTCRs) are of interest for cancer gene therapy but many "cancer antigens" are thought to be unsuitable targets because they are expressed at low levels on normal tissues. We therefore sought to determine whether engineered T cells expressing variable surface densities of a high-affinity chTCR could discriminate different concentrations of the targeted antigen. We plotted the relationship between chTCR density and the concentration of target antigen using Jurkat T cells expressing a hapten-binding chTCR whose expression could be modulated by tetracycline. Our analysis reveals that there is a dynamic equilibrium between cell surface density of the chTCR and the antigen density that optimally triggers T cell activation. At a fixed density of target antigen, optimal T cell activation can be achieved only within a certain range of chTCR densities, while excessive TCR signaling triggers apoptosis of the engineered T cells. Our results show that T cells can be engineered to discriminate different antigen densities and that the T cell response to a fixed concentration of antigen can be optimized by tuning the cell surface density of TCRs.

Antigens, Neoplasm↗
PubMed1976

Creatine kinase in serum: 1. Determination of optimum reaction conditions.

To establish optimum conditions for creatine kinase (EC 2.7.3.2) activity measurement with the creatine phosphate in equilibrium creatine reaction, we re-examined all kinetics factors relevant to an optimal and standardized enzyme assay at 30 and 25 degrees C. We determined the pH optimum in vaious buffers, considering the effect of the type and concentration of the buffer, as well as the influence of various buffer anions on the activity. The relation between activity and substrate concentration was shown and the apparent Michaelis constants of creatine kinase for creatine phosphate and ADP were evaluated. We tested the effect on creatine kinase measurement of the concentration of substrates (glucose and NADP+) in the auxillary and indicator reactions, especially the influence of the added auxiliary (hexokinase) and indicator (glucose-6-phosphate dehydrogenase) enzymes on the lag phase, at different temperatures. The NADP+ concentration proved to be the factor limiting the duration of constant reaction rate. We studied the inhibition of creatine kinase and adenylate kinase by AMP and established a convenient AMP concentration. For reactivation of creatine kinase, N-acetyl cysteine as sulfhydryl compound was introduced. Finally, we examined the relationship between activity and temperature.

Blood Glucose↗
PubMed1992

Evolutionary optimization of the catalytic efficiency of enzymes.

1. The rate equation for a generalized Michaelian type of enzymic reaction mechanism has been analyzed in order to establish how the mechanism should be kinetically designed in order to optimize the catalytic efficiency of the enzyme for a given average magnitude of true and apparent first-order rate constants in the mechanism at given concentrations of enzyme, substrate and product. 2. As long as on-velocity constants for substrate and product binding to the enzyme have not reached the limiting value for a diffusion-controlled association process, the optimal state of enzyme operation will be characterized by forward (true and apparent) first-order rate constants of equal magnitude and reverse rate constants of equal magnitude. The drop in free energy driving the catalysed reaction will occur to an equal extent for each reaction step in the mechanism. All internal equilibrium constants will be of equal magnitude and reflect only the closeness of the catalysed reaction to equilibrium conditions. 3. When magnitudes of on-velocity constants for substrate and product binding have reached their upper limits, the optimal kinetic design of the reaction mechanism becomes more complex and has to be established by numerical methods. Numerical solutions, calculated for triosephosphate isomerase, indicate that this particular enzyme may or may not be considered to exhibit close to maximal efficiency, depending on what value is assigned to the upper limit for a ligand association rate constant. 4. Arguments are presented to show that no useful information on the evolutionary optimization of the catalytic efficiency of enzymes can be obtained by previously taken approaches that are based on the application of linear free-energy relationships for rate and equilibrium constants in the reaction mechanism.

Biological Evolution↗
PubMed1978

Experimental optimization of the detection limit of two-step solid-phase radioimmunoassay.

For two-step inhibition radioimmunoassay (sequential saturation or delayed addition of labeled antigen) generally a higher sensitivity than for one-step inhibition radioimmunoassay (equilibrium assay) is expected. The detection limit of a two-step solid phase inhibition radioimmunoassay for human serum immunoglobulin A was minimized by statistical methods of experimental optimization. Under optimal conditions the detection limit was 2.3 ng IgA. This is about 1.8 times lower than the minimal detection limit of the one-step assay under similar conditions of the qualitative variables such as the origin of the antibody. This increase in sensitivity was associated with a decrease in the precision of the assay. The results are discussed with respect to the comparison of the one-step and the two-step assay and the usefulness of a sensitive radioimmunoassay in practice.

Evaluation Studies as Topic↗
PubMed1999

A procedure to determine equilibrium postural configurations for arbitrary locations of the feet.

This research was directed toward predicting postural equilibrium configurations in normal humans for asymmetric locations of the feet. The objective of the study was to identify trends in the variation of the location of ground center of pressure (COP) with increasing levels of asymmetry in the foot placement. The procedure developed here minimized the muscular effort (active torques) in the lower extremities while maximizing postural stability margins for given foot locations. Minimizing muscular effort led to fully extended knees, and maximal stability margin led to the COP moving toward the rear foot in asymmetric stance. A combined analytical-numerical optimization scheme was used to avoid singularities that can arise due to the fact that at equilibrium postural configurations, the torso lies at or near the workspace boundary of the lower extremities. Experiments were conducted and the results obtained were in keeping with the model predictions. This basic understanding of asymmetric stance is important for studying asymmetric postural mechanics in the presence of external disturbances, and for extending the results from normal subjects to humans at both ends of the life span.

Algorithms↗
PubMed1987

Load sharing among spinal elements of a motion segment in extension and lateral bending.

A linear optimization model was formulated using a semi-experimental protocol to estimate the forces in the spinal elements of a lumbar motion segment subjected to an extension or lateral bending moment with and without a 120 N compressive preload. A morphometer was used to acquire the three-dimensional locations of the disk center, facet centers and ligament origin and insertion sites with the specimen in a "neutral" position. The relative motion of the superior vertebra, under the loading conditions tested, was monitored using a Selspot II system. These data allowed the formulation of the static equilibrium equations for the superior vertebra at each of the loading conditions mentioned above. A linear optimization technique was used, along with a suitable cost function, to find an optimum solution for the set of equations and imposed constraints. Results showed that for 6.9 Nm of extension moment, each facet carried a load of 52 N, with the disk carrying an axial tensile load of 104 N. At the 6.9 Nm extension moment coupled with 120 N preload, each facet carried a load of 77.2 N and the disk an axial tensile load of 37 N. In right lateral bending, with and without preload, the load was distributed among the right facet, the disk, the left ligamentum flavum and the left capsular ligament. At the 6.9 Nm load step without preload the right facet carried an axial load of 127.01 N with the disk carrying an axial compressive load of 7.8 N. Ligament forces for this step for the left ligamentum flavum and capsular ligament, respectively, were 61.03 N and 65.14 N. The addition of 120 N of preload reduced the load on the right facet to 83.5 N. The compressive load in the disk increased to 107.5 N. The corresponding ligament forces were 43.2 N (left ligamentum flavum) and 50.7 N (left capsular ligament).

Biomechanical Phenomena↗
PubMed2000

Physiologic and metabolic results of pancreatic cold storage with Histidine-Tryptophan-Ketoglutarate-HTK solution (Custodiol) in the porcine autotransplantation model.

UNLABELLED: Delayed graft function (DEGF) remains an obscure phenomenon in organ transplantation. For the optimal washing of the compounds of the different organ flush solutions, adequate temperature and equilibrium of electrolytes have to be provided. A total of 29 land-race pigs weighing 37.3-5.4 kg were included in this study. According to the model, the left hemipancreas was perfused with Histidine-Tryptophan-Ketoglutarate (HTK)-solution and autotransplanted after 24 h (G1, n = 13) and 48 h (G2, n = 4) of cold storage (CS). Results were compared with grafts perfused with UW-solution and autotransplanted after 24 h (G3, n = 8) and 48 h (G4, n = 4) CS respectively. Daily measurements of glycemia, glucosuria, amylase and lipase were carried out. HTK perfusion resulted in an increase in wet weight of the grafts after 24 h and 48 h CS (P = 0.031 vs UW). Postoperative glycemia levels in pancreases flushed with HTK-solution were higher after 48 h than after 24 h CS until the 6th postoperative day, when the glycemia returned to normal range (P = 0.02), suggesting a delayed endocrine graft function. The mean IVGTT values attained after full function were comparable in G1 and in G3 (-1.22 +/- 0.23 vs. -1.5 +/- 0.65). The rises in serum amylase and lipase levels were more pronounced after 48 h CS in both HTK and UW groups, (P = n.s.). Appearance of interstitial and intracellular edema after CS and reperfusion did not influence the function. CONCLUSION: HTK-solution is suitable for 24 h pancreatic preservation in vivo; the perfusion requires at least 4 min for electrolyte equilibration. Long preservation time (48 h) resulted in a transitory DEGF.

Animals↗
PubMed1990

Environmentally induced disorders of the musculoskeletal system.

The human suffering and economic cost attributable to musculoskeletal disorders cannot be overemphasized. Biomechanical principles have been introduced to explain the microtrauma and macrotrauma as mechanisms of injury. Stress-induced remodeling is a useful paradigm in the study of environmentally induced disorders. The concept of environment should include psychosocial and organizational factors with respect to musculoskeletal complaints and chronic pain. Low back pain, osteoarthritis, osteoporosis and its associated fractures, and cumulative trauma disorders are the most critical and common musculoskeletal disorders. The risk factors for low back pain have been identified, and preventive measures for reducing the chronicity of low back pain have been discussed. Preventive approaches to control or limit the fractures associated with osteoporosis and loss of bone mass are preferred to simple management of the fracture of osteoporotic patients. It can be concluded that too little or too much stress can disturb the homeostatic or the equilibrium state of health and that much remains to be researched to quantify the optimal stress levels.

Back Pain↗
PubMed1995

Backbone dynamics of chymotrypsin inhibitor 2: effect of breaking the active site bond and its implications for the mechanism of inhibition of serine proteases.

The backbone dynamics of uniformly 15N-labeled chymotrypsin inhibitor 2 (CI2) and of the complex formed by the association of two fragments consisting of residues 20-59 and 60-83 have been studied. A data set consisting of 15N longitudinal (T1) and transverse (T1 rho) relaxation times and (1H)-15N NOE enhancements has been measured for all backbone NH groups in both proteins. Information on internal motions has been extracted from these data using the model-free approach to determine order parameters (S2) and effective internal correlation times (tau e). The data indicate that most of the backbone of CI2 is highly constrained (S2 approximately 0.9) with the exception of residues in the binding loop (residues 54-64), which have slightly lower order parameters. Most of the residues in the CI2(20-59).(60-83) complex are also highly constrained (S2 approximately 0.9). However, the loss of the covalent bond between Met59 and Glu60 leads to a large increase in the mobility of residues in the loop region. The residues in the first half of the loop region have significantly lower order parameters than those in the second half of the loop. This observation suggests that the NH2 group that is released on cleavage of the scissile bond remains anchored in its original position, inhibiting the attack of water on the acyl-enzyme that is formed between the protease and the cleaved inhibitor. More importantly, the NH2 group is optimally placed for reversing the formation of the acyl-enzyme so that the equilibrium between the cleaved and uncleaved inhibitor, bound to the protease, greatly favors the uncleaved complex.

Amino Acid Sequence↗
PubMed1976

Lysine-sensitive aspartokinase of Escherichia coli K12. Synergy and autosynergy in an allosteric V system.

The interactions of the lysine-sensitive aspartokinase of E. coli K12 with lysine and leucine, as evidenced in the inhibition and binding curves, are well explained by the equations of an allosteric V model. Mathematical treatments of such a model lead to new linearized plots. These representations are applied to our experimental results and allow the direct determination of some parameters of the model (equilibrium constant L' and leucine dissociation constants). The other parameters are obtained by an optimization method. The theoretical curves drawn according to this model account well for the synergistic inhibition between lysine and leucine and for the role of the two nonequivalent lysine binding sites ("autosynergy").

Allosteric Regulation↗
PubMed1992

Reversible steps in the bacteriorhodopsin photocycle.

The absorbance changes that accompany the light-driven proton-pumping cycle of bacteriorhodopsin measured over a broad range of times, wavelengths, temperatures, and pH values have been globally fitted to the kinetic model K in equilibrium with L in equilibrium with X in equilibrium with M in equilibrium with N in equilibrium with O----bR. A remarkably good fit to the data was obtained by optimizing the rate constants at 20 degrees C and the corresponding activation energies at each pH value, together with the extinction coefficients for each intermediate, which were assumed to be independent of both pH and temperature. Back-reactions are included for all but the last step of the cycle and are found to be essential for fitting the data. The rates of these reactions are large, and the analogous irreversible model produced significantly worse fits to the data. Small systematic differences between the fit and the experimental data associated with the X, M, and O intermediates, together with the inability of the model to produce spectra for the X and M intermediates consistent with their assignment as molecular species, indicate that this model must be an incomplete description of the photocycle. We suggest that these problems arise from the presence of additional occupied states that are difficult to distinguish on the basis of their visible absorption spectra alone.

Bacteriorhodopsins↗
PubMed1991

Differential ontogeny of in vitro vascular responses to three categories of calcium channel antagonists in rats.

We examined the ontogeny of relaxation responses to three categories of calcium channel antagonists, represented by verapamil, diltiazem, and nifedipine, for both potential-operated (KCl-mediated) and receptor-operated channels [norepinephrine (NE)-mediated] in rat thoracic aorta. Aortic rings from 2- to 3-d, 1-wk, and 12-wk-old Sprague Dawley rats were mounted in an organ bath, bathed in Krebs' solution, and connected to a force-displacement transducer to measure isometric tension. Endothelium intact vessels at optimal passive force were exposed to a single ED50 of isotonic KCl or NE, equilibrium contraction was measured, then vessels were washed and exposed for 30 min to 1 microM verapamil, 1 microM diltiazem, or 0.1 microM nifedipine, followed by another dose of KCl or NE. Verapamil and diltiazem demonstrated significant (p less than 0.05) age-related increases in effectiveness for blocking KCl-mediated contraction [(% reduction of control contraction +/- SEM) (Verapamil: 2-3 d, 67.7 +/- 4.2; 1 wk, 72.5 +/- 1.8; 12 wk, 89.5 +/- 1.0. Diltiazem: 2-3 d, 64.6 +/- 2.9; 1 wk, 73.5 +/- 3.0; 12 wk, 83.1 +/- 1.8]. Nifedipine was equally effective at all ages: 2-3 d, 85.6 +/- 1.3; 1 wk, 90.0 +/- 1.6; and 12 wk, 91.3 +/- 1.4. Verapamil and diltiazem also showed significant age-related increases in effectiveness for blocking NE-mediated contraction (Verapamil: 2-3 d, 6.2 +/- 3.9; 1 wk, 28.0 +/- 4.8; 12 wk, 44.1 +/- 6.0. Diltiazem: 2-3 d, 8.0 +/- 3.1; 1 wk, 20.5 +/- 3.9; 12 wk, 46.5 +/- 4.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗