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PubMed2003

Directed evolution of an extremely fast phosphotriesterase by in vitro compartmentalization.

We describe the selection of a phosphotriesterase with a very fast k(cat) (over 10(5) s(-1)), 63 times higher than the already very efficient wild-type enzyme. The enzyme was selected from a library of 3.4 x 10(7) mutated phosphotriesterase genes using a novel strategy based on linking genotype and phenotype by in vitro compartmentalization (IVC) using water-in-oil emulsions. First, microbeads, each displaying a single gene and multiple copies of the encoded protein, are formed by compartmentalized in vitro translation. These microbeads can then be selected for catalysis or binding. To select for catalysis the microbeads are re-emulsified in a reaction buffer of choice with a soluble substrate. The product and any unreacted substrate are coupled to the beads when the reaction is finished. Product-coated beads, displaying active enzymes and the genes that encode them, are detected with anti-product antibodies and selected using flow cytometry. This completely in vitro process selects for all enzymatic features simultaneously (substrate recognition, product formation, rate acceleration and turnover) and single enzyme molecules can be detected.

Amino Acid Sequence↗
PubMed2000

Body weight-specific zinc compartmental masses in girls significantly exceed those reported in adults: a stable isotope study using a kinetic model.

Maintaining optimal zinc status is important for normal growth and development in children, but minimal data are available regarding zinc metabolism in this age group. Our objectives were to utilize stable isotope-based compartmental modeling techniques to investigate zinc metabolism in healthy children; to expand a current stable isotope-based model to include red blood cell data; and to compare kinetic parameters in children with those previously reported in adults. Seven healthy girls, age 9.94 +/- 0.79 y, received 1.1 mg of a (67)zinc-enriched tracer orally and 0.5 mg of a (70)zinc-enriched tracer intravenously. Blood, urine and fecal samples were collected for 6 d. Stable isotope enrichments were measured by thermal ionization magnetic sector mass spectrometry. A six-compartment model based on a model previously reported in adults was used; the model excluded red blood cell data. Body weight-corrected masses of the body zinc compartments derived using this model were significantly greater in children than those reported in adults. Modification of the model to include a red blood cell compartment increased the total identifiable zinc mass of the nongastrointestinal compartments by approximately 2.5%. We conclude that compartmental modeling can be used to describe zinc kinetics in children, and that the body weight-corrected zinc pool masses are significantly greater in children than in adults.

Adult↗
PubMed2004

In vitro selection of restriction endonucleases by in vitro compartmentalization.

Restriction endonucleases are widely used in laboratory applications from recombinant DNA technology to diagnostics, but engineering of restriction enzymes by structure-guided design and in vivo directed evolution is at an early stage. Here, we report the use of an in vitro compartmentalization system for completely in vitro selection of restriction enzymes. Compartmentalization of a single gene in a rabbit reticulocyte in vitro transcription/translation system serves to isolate individually synthesized enzymes from each other. In each compartment, an active enzyme cleaves only its own encoding gene, whereas genes encoding inactive enzymes remain intact. Affinity selection of the cleaved DNA encoding active restriction endonucleases was accomplished by the use of streptavidin-immobilized beads and dUTP-biotin, which was efficiently incorporated into the cohesive end of the cleaved DNA using a DNA polymerase. We confirmed that genes encoding active restriction endonuclease FokI could be selected from a randomized library. This method overcomes the limitations of current in vivo technologies and should prove useful for rapid screening and evolution of novel restriction enzymes from diverse mutant libraries, as well as for studies of catalytic and evolutionary mechanisms of restriction enzymes.

Amino Acid Sequence↗
PubMed2000

Molecular evidence for drug-induced compartmentalization of HIV-1 quasispecies in a patient with periodic changes to HAART.

OBJECTIVE: To perform molecular analysis of the predominant viral populations and drug-resistance mutations from plasma and peripheral blood mononuclear cell (PBMC) compartments over time from an HIV infected patient, who experienced virological failure while on different HAART regimens. MATERIALS AND METHODS: In a longitudinal study proviral and plasma HIV-1 sequences were amplified in the pol, protease and env genes and were sequenced directly and analysed phylogenetically. Virus was recovered from time points corresponding to viral load peaks using co-culturing techniques. The periodic failure of different highly active antiretroviral therapy (HAART) regimens was analysed sequencing. RESULTS: Longitudinal follow-up studies revealed four inflection peaks of plasma viraemia associated with the recovery of culturable virus in vitro, which indicated failure of the concurrent HAART regimen. Molecular analysis of viral strains revealed evidence of continual evolution and compartmentalization of drug-resistance mutants/quasispecies between plasma and PBMC, with the widest spectrum of mutations isolated from plasma. Importantly, these data show the periodic appearance and clearance of drug-resistance mutants concomitant with the introduction and withdrawal of zidovudine over time. CONCLUSION: This report is unique in showing drug-induced compartmentalization of viral quasispecies under the control of different HAART regimens in both plasma and PBMC. Introduction and withdrawal of zidovudine from the HAART regimen had direct bearing on the appearance and disappearance of specific zidovudine drug-resistance mutations in plasma-derived virus. This data has important implications for the management of HIV-infected patients with poor compliance with certain HAART regimens, and also in predicting the late emergence of drug-resistance mutations via the latent integrated provirus.

Adult↗
PubMed1989

A microcomputer algorithm for solving first-order compartmental models involving recycling.

A general algorithm for solving first-order compartmental models including recycling systems has been developed and its implementation on a microcomputer is described. Matrix algebra is used to obtain for any compartmental model an analytical solution, which is expressed as the exponential of a matrix of rate constants. A special technique is used in the algorithm to enable this exponential to be evaluated with a rapidly converging series. Truncation errors incurred in this process are estimated automatically. Thus, in an extreme case, where these errors may be significant, the appropriate action can be taken. Given a particular model, the user enters the model parameters into a rate matrix according to a simple rule. The algorithm then uses this matrix to solve the model, and thus no specialized mathematical knowledge is needed. The algorithm is given in a short BASIC program (60 lines) listed in an appendix. No additional software is required. By running this program on a standard microcomputer, the user can solve models of any complexity: those up to 15 compartments in seconds and those up to 30 compartments within a minute. The algorithm is thus ideally suited to solve kinetic models describing the transport of radionuclides in the environment or the translocation of elements in biological systems such as the metabolic models recommended by the International Commission on Radiological Protection (ICRP). Given the initial amount of material in each compartment at time t = 0, together with its radioactive decay constant, the algorithm gives both the amount in each compartment at any future time t and the number of disintegrations that will have occurred in each compartment up to time t. The computer program, shown in an appendix, could easily be used to calculate disintegrations over any time interval of interest, or to predict the quantities or fractions of an intake expected to be present in any in vivo or excretion compartments of interest. Thus, the algorithm can be useful in both the design and conduct of bioassay and internal dose assessment procedures.

Algorithms↗
PubMed2003

Mathematical techniques for solving analytically large compartmental systems.

The flow of radioactive particles inside the body from internally deposited radioisotopes in people exposed to inhalation, ingestion, injection, or other ways is usually evaluated using compartmental models. The biokinetic models included in the documents of the International Commission on Radiological Protection such as International Commission on Radiological Protection 66 and 78 involve many compartments. Usually numeric methods are applied. Very often analytical solutions are not possible. New computer programs that include symbolic capability can be used to solve compartmental systems. In this paper some techniques are developed in order to make feasible a computer program that gives not only faster and more accurate solutions, but also analytic solutions for these kind of models. The main idea is to make a partition of subsystems and solve them sequentially. The concept of pseudotrap compartments in a subsystem is crucial at this point. Impulse (acute), constant, and continuous (such as exponential) intakes are considered. This technique has been applied to develop a computer code called Humorap to solve the International Commission on Radiological Protection 66 and 78 models.

Air Pollutants↗
PubMed1998

Synergistic effects of relaxation and susceptibility in differentiation between compartmentalized and noncompartmentalized tissues.

RATIONALE AND OBJECTIVES: This study illustrates the synergistic effects of relaxation- and susceptibility-based contrast enhancement. Using a combination of gadolinium (Gd) and dysprosium (Dy) complexes and a sequence capable of taking advantage of the particular relaxation behavior of this combination, the difference between compartmentalized and noncompartmentalized regions was significantly enhanced. METHODS: Magnetic resonance imaging of the rat kidney was performed before and immediately after the administration of a combination of Gd and Dy chelates (Gd-DTPA-BMA and Dy-DTPA-BMA). RESULTS: The signal intensity (SI) of the renal parenchyma was reduced by 85%, whereas the collecting tubes had a 100% increase of their SI as demonstrated by a short repetition time (600 msec), long echo time (50 msec), and spin-echo sequence. CONCLUSIONS: The high R2* effect, specific to the compartmentalized tissues, associated with the moderately high R1 and R2 developed in the remaining areas, results in an important improvement in tissue differentiation, which potentially is useful for the evaluation of pathological changes as in tubular necrosis.

Animals↗
PubMed2001

Compartmental modeling of technetium-99m-labeled teboroxime with dynamic single-photon emission computed tomography: comparison with static thallium-201 in a canine model.

UNLABELLED: Di Bella EVR, Ross SG, Kadrmas DJ, et al. Compartmental modeling of technetium-99m-labeled teboroxime with dynamic single-photon emission computed tomography: Comparison with static thallium-201 in a canine model. Invest Radiol 2001;36:178-185. RATIONALE AND OBJECTIVES: A compartmental modeling approach to deriving kinetic parameters from a time series of single-photon emission computed tomography (SPECT) images of technetium-99m-labeled (99mTc-) teboroxime may have value for semiquantitative assessment of myocardial perfusion. This study investigated the value of the kinetic parameters derived from a two-compartment model of 99mTc-teboroxime for measuring myocardial perfusion and compared it with static thallium-201 (201Tl) uptake and microsphere-measured blood flow in dogs. METHODS: Experiments were successfully conducted in 9 of 11 open-chest dogs. During adenosine stress, a single complete set of projections of 201Tl uptake was acquired. 99mTc-teboroxime was then injected during adenosine stress, and a complete set of projections was acquired every 5.7 seconds for 17 minutes. Resting studies were performed on 4 of the animals. All of the projection sets were reconstructed with an iterative algorithm and incorporated corrections for attenuation and the geometric response of the collimators. Regional kinetic parameters (washin and washout) were determined semiautomatically from the time series of reconstructed 99mTc-teboroxime images and registered with microsphere data. Regional washin estimates were compared with 201Tl intensities and myocardial blood flows determined from microspheres. RESULTS: Optimally scaled 99mTc-teboroxime washin parameters and 201Tl uptakes were correlated with microsphere-determined blood flows (r = 0.91, y = 0. 99x + 0.01, and r = 0.92, y = 0.88x + 0.28, respectively). In six of the studies, the left anterior descending coronary artery was occluded, and stress occluded-to-normal (O/N) ratios were calculated. The O/N ratios were 0.32 +/- 0.17 as determined from microspheres injected with 201Tl and 0.38 +/- 0.29 from microspheres injected with 99mTc-teboroxime (P = NS). The O/N ratios were 0.48 +/- 0.16 for static 201Tl uptake and 0.27 +/- 0.21 for 99mTc-teboroxime washin (P < 0.05). CONCLUSIONS: Both 201Tl uptake and 99mTc-teboroxime kinetic parameters were well correlated with flow. The 99mTc-teboroxime washin parameters offer semiquantitative flow values and provide greater defect contrast than can be obtained with 201Tl uptake values.

Animals↗
PubMed1999

Which linear compartmental systems can be analyzed by spectral analysis of PET output data summed over all compartments?

General linear time-invariant compartmental systems were examined to determine which systems meet the conditions necessary for application of the spectral analysis technique to the sum of the concentrations in all compartments. Spectral analysis can be used to characterize the reversible and irreversible components of the system and to estimate the minimum number of compartments, but it applies only to systems in which the measured data can be expressed as a positively weighted sum of convolution integrals of the input function with an exponential function that has real-valued nonpositive decay constants. The conditions are met by compartmental systems that are strongly connected, have exchange of material with the environment confined to a single compartment, and do not contain cycles, i.e., there is no possibility for material to pass from one compartment through two or more compartments back to the initial compartment. Certain noncyclic systems with traps, systems with cycles that obey a specified loop condition, and noninterconnected collections of such systems also meet the conditions. Dynamic positron emission tomographic data obtained after injection of a radiotracer, the kinetics of which can be described by any model in the class of models identified here, can be appropriately analyzed with the spectral analysis technique.

Algorithms↗
PubMed2001

Positron emission tomography compartmental models.

The current article presents theory for compartmental models used in positron emission tomography (PET). Both plasma input models and reference tissue input models are considered. General theory is derived and the systems are characterized in terms of their impulse response functions. The theory shows that the macro parameters of the system may be determined simply from the coefficients of the impulse response functions. These results are discussed in the context of radioligand binding studies. It is shown that binding potential is simply related to the integral of the impulse response functions for all plasma and reference tissue input models currently used in PET. This article also introduces a general compartmental description for the behavior of the tracer in blood, which then allows for the blood volume-induced bias in reference tissue input models to be assessed.

Blood↗
PubMed2002

Water compartmentalization and spread of ischemic injury in thick-slice ischemia model.

Water compartmentalization was studied in a thick-slice (1000 microm) model of ischemia by combining water-content measurements with extracellular diffusion analysis. Thick slices bathed in artificial cerebrospinal fluid continually gained water. Total tissue water content was increased by 67% after 6 hours of the incubation. Diffusion measurements using the tetramethylammonium method showed that the extracellular space, typically occupying 20% of brain tissue in vivo, was decreased to 10% at 30 minutes and 15% at 6 hours in both deep and superficial layers of thick slices. Quantification of water compartmentalization revealed that water moved initially from the extracellular space into the cells. Later, however, both compartments gained water. The initial cell swelling was accompanied by dramatic shifts in potassium. An initial rise of extracellular potassium to about 50 mmol/L was measured with a potassium-selective microelectrode positioned in the center of the thick slice; the concentration decreased slowly afterwards. Potassium content analysis revealed a 63% loss of tissue potassium within two hours of the incubation. In thick slices, ionic shifts, water redistribution, and a loss of synaptic transmission occur in both deep and superficial layers, indicating the spread of ischemic conditions even to areas with an unrestricted supply of nutrients.

Animals↗
PubMed1987

Acute anterior compartmental syndrome of the thigh following contusion. A case report and review of the literature.

Contusion is a rare cause of acute compartmental syndrome in the thigh. To date, no case report has described blunt trauma precipitating this limb-threatening condition. The patient in this case report developed rapidly progressive signs and symptoms which required emergency fasciotomy. Delayed primary closure was possible and recovery was complete. The etiologies, diagnosis and management of thigh compartmental syndrome are reviewed.

Adult↗
PubMed1999

Monitoring for compartmental syndrome using near-infrared spectroscopy: a noninvasive, continuous, transcutaneous monitoring technique.

BACKGROUND: The diagnosis of compartmental syndrome (CS) may be delayed because current monitoring techniques are invasive and intermittent and the compartment pressure (CP) that predicts ischemia is variable. Fiber-optic devices using near-infrared (NIR) wavelength reflection can determine the redox state of light-absorbing molecules and have been used to monitor venous hemoglobin saturation to detect ischemia during low-flow states. The purpose of this study was to determine if NIR spectroscopy can provide continuous, transcutaneous, noninvasive monitoring for muscle ischemia in an animal model of CS. METHODS: Nine swine were anesthetized and a 20-mm NIR probe was placed over the anterolateral compartment of the hind leg to provide continuous determination of muscle oxyhemoglobin level. Needles were inserted into the compartment to measure CP. A nerve stimulator was placed over the peroneal nerve to induce dorsiflexion twitch. Albumin was infused into the muscle to incrementally increase CP until there was complete loss of dorsiflexion, then after 20 minutes fasciotomy was performed. RESULTS: All animals lost dorsiflexion at CP of 43+/-14 mm Hg. There was a significant inverse correlation between CP and oxyhemoglobin level (r = -0.78; p < 0.001) and a correlation between oxyhemoglobin and perfusion pressure (mean arterial pressure minus CP) (r = 0.66; p < 0.001). Redox state was a more consistent predictor of twitch loss than perfusion pressure. CONCLUSION: Muscle oxyhemoglobin level measured by NIR spectroscopy strongly reflected CP, perfusion pressure, and loss of dorsiflexion twitch. Currently available portable NIR devices may provide the benefit of continuous, noninvasive monitoring for CS. Further studies to determine the role of this technology in the detection of compartmental syndrome are warranted.

Animals↗
PubMed2001

Fitting linear compartmental models by a matrix diagonalization method.

A general method is presented for fitting experimental data to arbitrary linear compartmental models, based on readily available public domain software. The model is defined by input data so that the same program can be used for different compartmental models. Its use is exemplified by application to the four-compartment problem recently treated by Charkes and Siegel.

Computer Simulation↗
PubMed1992

The effect of simultaneous internal tamponade on fluid compartmentalization and its relationship to cell proliferation.

To determine whether the residual free spaces within the vitreous chamber that result after vitreoretinal surgery and internal tamponade may be avoided, and to verify whether such compartmentalization is of real importance in the recurrence of postoperative proliferative vitreoretinopathy (PVR), the use of simultaneous double filling with polydimethylsiloxane (PDMS) and fluorosilicone (FSiO) in the repair of complicated retinal detachment is evaluated in 12 selected cases. Initial retinal reattachment was achieved in all cases. PVR recurred in 10 patients (83%), 6 of whom showed partial retinal detachment. Inferior and superior postoperative residual free spaces were abolished by this procedure, but a new residual fluid space was created, lying horizontally between the bubbles and expanding in a triangular shape nasal to the optic disc and temporal to the macula. Overall, 9 of 10 eyes with PVR after surgery had proliferation involving these areas. These findings support the concept that compartmentalization is of major importance in determining postoperative cell proliferation.

Adult↗
PubMed2002

Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling.

A kinetic modeling approach for the quantification of in vivo tracer studies with dynamic positron emission tomography (PET) is presented. The approach is based on a general compartmental description of the tracer's fate in vivo and determines a parsimonious model consistent with the measured data. The technique involves the determination of a sparse selection of kinetic basis functions from an overcomplete dictionary using the method of basis pursuit denoising. This enables the characterization of the systems impulse response function from which values of the systems macro parameters can be estimated. These parameter estimates can be obtained from a region of interest analysis or as parametric images from a voxel-based analysis. In addition, model order estimates are returned that correspond to the number of compartments in the estimated compartmental model. Validation studies evaluate the methods performance against two preexisting data led techniques, namely, graphical analysis and spectral analysis. Application of this technique to measured PET data is demonstrated using [11C]diprenorphine (opiate receptor) and [11C]WAY-100635 (5-HT1A receptor). Although the method is presented in the context of PET neuroreceptor binding studies, it has general applicability to the quantification of PET/SPECT radiotracer studies in neurology, oncology, and cardiology.

Artifacts↗
PubMed2000

Compartmentalized reaction-diffusion systems.

Reaction-diffusion systems consisting of a collection of reactive domains separated by chemically inactive regions are considered. The reactive dynamics is governed by a multistep reaction mechanism and each reactive domain is specific to a particular elementary step or collection of elementary steps of the global reaction mechanism. Far-from-equilibrium situations where the global kinetics can give rise to complex states such as bistability or oscillations are studied. A general method for the calculation of the average concentration on each reactive domain is presented. The effects of compartmentalization are illustrated by a study of the influence of diffusion, reactive domain size, and domain distribution on the nature of the stationary states of the Schlögl model. Compartmentalization can drive the system into and out of the bistable regime of this reactive system.

Journal Article↗
PubMed2005

Small-world properties emerge in highly compartmentalized networks with intermediate group sizes and numbers.

Many recent studies have focused on two statistical properties observed in diverse real-world networks: the small-world property and compartmentalization [D. J. Watts and S. H. Strogatz, Nature 393, 440 (1998); M. Girvan and M. E. J. Newman, Proc. Natl. Acad. Sci. 99, 7821 (2002)]. Models that include group affiliations have been shown to produce networks with high clustering coefficients, a necessary condition for small-world properties [M. E. J. Newman, Phys. Rev. E, 68, 026121 (2003); M. E. J. Newman and J. Park, Phys. Rev. E 68, 036122 (2003)]. However, the consequences of varying the number and size of groups in a network are not well understood. In order to investigate the consequences of group organization, we examined sets of networks that varied simultaneously in the size and number of groups, while maintaining the same overall size and average degree. Here we show that the small-world property arises in maximally compartmentalized and clustered networks that occur in the intermediate region between few, very large groups and many, very small groups.

Journal Article↗