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PubMed1989

A compartmental model to quantitate in vivo glucose transport in the human forearm.

Glucose transport is a critical step in the control of glucose disposal that, until presently, has not been quantitated in vivo in humans. We have employed the perfused forearm and euglycemic insulin-clamp techniques in combination with a dual-tracer injection to measure basal and insulin-mediated glucose transport in six normal subjects. L-[3H]glucose, which is not transported, was used to trace extracellular glucose kinetics; 3-O-[14C]-methyl-D-glucose, transportable but not metabolizable, was used to monitor glucose movement across the cell membrane. After bolus intra-arterial injection of the two tracers, plasma samples were obtained every 15-30 s for 10 min from a deep forearm vein to determine the washout curves. A linear compartmental model was developed that accounts for blood flow heterogeneity. It consists of three parallel, two-compartment chains merging into the sampling compartment to which cellular compartments are appended. A priori identifiability analysis was performed. The uniquely identifiable parameterization includes the transport rate constants of glucose into and out of the cell. The model was identified using nonlinear least-squares parameter estimation. Transport parameters are estimated with very good precision, and their reproducibility is satisfactory. The model also allows the estimation of the mean arteriovenous transit times of both the extracellular and the transported tracer. The compartmental model provides a novel approach to investigate glucose transport in vivo in humans.

3-O-Methylglucose↗
PubMed2006

Dynamic disorder in receptor-ligand forced dissociation experiments.

Recently experiments showed that some biological noncovalent bonds increase their lifetimes when they are stretched by an external force, and their lifetimes will decrease when the force increases further. Several specific quantitative models have been proposed to explain the intriguing transitions from the "catch bond" to the "slip bond." In this work we propose that the dynamic disorder of the force-dependent dissociation rate can account for the counterintuitive behaviors of the bonds. A Gaussian stochastic rate model is used to quantitatively describe the transitions observed recently in the single bond P-selctin glycoprotein ligand 1-P-selectin force rupture experiment [Marshall, Nature 423, 190 (2003)]. Our model agrees well with the experimental data. We conclude that the catch bonds could arise from the stronger positive correlation between the height of the intrinsic energy barrier and the distance from the bound state to the barrier; classical pathway scenario or a priori catch bond assumption is not essential.

Biophysics↗
PubMed1975

Interactions between K+ and ATP binding to the (Na+ + K+)-dependent ATPase.

K+ appears to decrease the affinity of the (Na+ + K+)-dependent ATPase (ATP phosphohydrolase, EC 3.6.1.3) for its substrate, Mg2+ - ATP, and Mg2+ - ATP, in turn, appears to decrease the affinity of the enzyme for K+. These antagonisms have been investigated in terms of a quantitative model defining the magnitude of the effects as well as identifying the class of K+ sites on the enzyme involved. K+ increased the apparent Km for Mg2+ - ATP, an effect that was antagonized competitively by Na+. The data can be fitted to a model in which Mg2+ - ATP binding is prevented by occupancy of alpha-sites on the enzyme by K+ (i.e. sites of moderate affinity for K+ accessible on the "free" non-phosphorylated enzyme, in situ on the external membrane surface). By contrast, occupancy of these alpha-sites by Na+ has no effect on Mg2+ - ATP binding to the enzyme. On the other hand, Mg2+ - ATP decreased the apparent affinity of the enzyme for K+ at the alpha-sites, in terms of (i) the KD for K+ measured by K+-accelerated inactivation of the enzyme by F-, and (ii) the concentration of K+ for half-maximal activation of the K+-dependent phosphatase reaction (which reflects the terminal hydrolytic steps of the overall ATPase reaction). These data fit the same quantitative model. Although this formulation does not support schemes in which ATP binding effects the release of transported K+ from discharge sites, it is consistent with observations that K+ can inhibit the enzyme at low substrate concentrations, and that Li+, which has poor efficacy when occupying these alpha-sites, can stimulate enzymatic activity at high K+ concentrations by displacing the inhibitory K+.

Adenosine Triphosphatases↗
PubMed1988

A model for quantitative strength training of hindlimb muscles of the rat.

Rats were taught to lift up a lever to train the plantar flexors. After 2 wk of adaptation the rats were trained for 36 wk. The mass of weights on the lever rose by 85% over the 36-wk period (P less than 0.05) The estimated force that the plantar flexors had to develop to lift the lever rose by 32% (P less than 0.05), just as the work per lift rose by 28% (P less than 0.05). For the trained group of rats the soleus muscles of the right and the left limb were 34% (P less than 0.05) and 31% (P less than 0.05) heavier, respectively, after the training period than those of the control group. Similarly, the plantaris muscles of both the right and the left limb were 24% heavier (P less than 0.05). For the trained group the maximum twitch and tetanus tensions of the soleus were 63% (P less than 0.05) and 65% (P less than 0.05) higher, respectively. Relative to the plantaris these measures were 79% (P less than 0.05) and 37% (P less than 0.05), respectively. The described model, therefore, seems appropriate for the study of the skeletal muscles' adaptation to usage.

Acclimatization↗
PubMed2005

Parametric and quantitative analysis of MR renographic curves for assessing the functional behaviour of the kidney.

The aim of this study was to refine the description of the renal function based on MR images and through transit-time curve analysis on a normal population and on a population with renal failure, using the quantitative model of the up-slope. Thirty patients referred for a kidney MR exam were divided in a first population with well-functioning kidneys and in a second population with renal failure from ischaemic kidney disease. The perfusion sequence consisted of an intravenous injection of Gd-DTPA and of a fast GRE sequence T1-TFE with 90 degrees magnetisation preparation (Intera 1.5 T MR System, Philips Medical System). To convert the signal intensity into 1/T1, which is proportional to the contrast media concentration, a flow-corrected calibration procedure was used. Following segmentation of regions of interest in the cortex and medulla of the kidney and in the abdominal aorta, outflow curves were obtained and filtered to remove the high frequency fluctuations. The model of the up-slope method was then applied. Significant reduction of the cortical perfusion (Qc = 0.057+/-0.030 ml/(s 100 g) to Qc = 0.030 +/- 0.017 ml/(s 100 g), P < 0.013) of the medullary perfusion (Qm = 0.023 +/- 0.018 ml/(s 100 g) to Qm = 0.011 +/- 0.006 ml/(s 100 g), P < 0.046) and of the accumulation of contrast media in the medulla (Qa = 0.005 +/- 0.003 ml/(s 100 g) to Qa = 0.0009 +/- 0.0008 ml/(s 100 g), P < 0.001) were found in presence of renal failure. High correlations were found between the creatinine level and the accumulation Qa in the medulla (r2 = 0.72, P < 0.05), and between the perfusion ratio Qc/Qm and the accumulation Qa in the medulla (r2 = 0.81, P < 0.05). No significant difference was found in times to peak between both populations despite a trend showing Ta the time to the end of the increasing contrast accumulation period in the medulla, arriving later for renal failure. Advances in MR signal calibration with the building of quantitative model such as the up-slope allow to assess kinetic and haemodynamic and functional parameters of the diseased kidney.

Contrast Media↗
PubMed1991

Multivariate clinical models and quantitative dipyridamole-thallium imaging to predict cardiac morbidity and death after vascular reconstruction.

Patients with peripheral vascular disease have a high prevalence of coronary artery disease and are at increased risk for cardiac morbidity and death after vascular reconstruction. The present study was undertaken to assess the value of 18 clinical parameters, of 7 clinical scoring systems, and of quantitative dipyridamole-thallium imaging for predicting the occurrence of postoperative myocardial infarction or cardiac death. Vascular surgery was performed in 125 patients. Thirteen postoperative cardiac events occurred, including 10 cardiac deaths and 3 nonfatal infarctions. Clinical parameters were not useful in predicting postoperative outcome. All 63 patients with normal scan results or fixed perfusion defects underwent surgery uneventfully, whereas 21% (13/62) of patients with reversible defects had a postoperative cardiac complication. By use of quantitative scintigraphic indexes we found that patients with reversible defects could be stratified into intermediate and high-risk subgroups with postoperative event rates of 5% (2/47) and 85% (11/13), respectively, despite intensive postoperative monitoring and antianginal medication. Thus in patients unable to complete a standard exercise stress test, postoperative outcome cannot be predicted clinically, whereas dipyridamole-thallium imaging successfully identified all patients who had a postoperative cardiac event. By use of quantification we found that patients with reversible defects can be stratified into an intermediate risk subgroup that can undergo surgery with minimal complication rate and a high-risk subgroup that requires coronary angiography.

Canada↗
PubMed1995

Growth kinetics and treatment response of the intracerebral rat 9L brain tumor model: a quantitative in vivo study using magnetic resonance imaging.

We report the use of magnetic resonance imaging (MRI) for in situ tumor growth rate studies of experimental intracranial 9L tumors. T2-weighted spin-echo coronal magnetic resonance images of rat brains with 9L tumors were obtained every 2 days beginning at 8-11 days postimplantation using a 7 tesla MRI system. Tumors were clearly delineated in the images as a hyperintense region with a relatively well-demarcated border and minimal peritumoral edema. Tumor volumes from individual slices were summed together to yield the total tumor volume. The accuracy of this methodology for volumetric determination was verified by MRI phantom studies. Tumor growth rates determined from sequential MRI measurements of tumor volumes were quantitated in terms of volumetric doubling time. Tumor doubling times were found to range from 50 to 81 h, with an average of 66 +/- 8 h (n = 10). Intracranial 9L tumors were found to grow exponentially over the entire life span of the animal, allowing treated animals to serve as their own controls since the volumetric doubling time could be determined from three to four MRI scans before treatment administration. The intracerebral tumor growth delay following a single injection of 1, 3-bis(2-chloroethyl)-1-nitrosourea (13.3 mg/kg i.p.) allowed for noninvasive determination of in vivo log cell kill. A 2.0 +/- 0.2 (n = 3) log cell kill from 1,3-bis(2-chloroethyl)-1-nitrosourea treatment was found from post-treatment MRI volume measurements. These results demonstrate that MRI provides a powerful and sensitive method for assessing the growth and treatment response of intracranial 9L tumors in the rat.

Animals↗
PubMed1999

X-ray crystal structure of human dopamine sulfotransferase, SULT1A3. Molecular modeling and quantitative structure-activity relationship analysis demonstrate a molecular basis for sulfotransferase substrate specificity.

Humans are one of the few species that produce large amounts of catecholamine sulfates, and they have evolved a specific sulfotransferase, SULT1A3 (M-PST), to catalyze the formation of these conjugates. An orthologous protein has yet to be found in other species. To further our understanding of the molecular basis for the unique substrate selectivity of this enzyme, we have solved the crystal structure of human SULT1A3, complexed with 3'-phosphoadenosine 5'-phosphate (PAP), at 2.5 A resolution and carried out quantitative structure-activity relationship (QSAR) analysis with a series of phenols and catechols. SULT1A3 adopts a similar fold to mouse estrogen sulfotransferase, with a central five-stranded beta-sheet surrounded by alpha-helices. SULT1A3 is a dimer in solution but crystallized with a monomer in the asymmetric unit of the cell, although dimer interfaces were formed by interaction across crystallographic 2-fold axes. QSAR analysis revealed that the enzyme is highly selective for catechols, and catecholamines in particular, and that hydrogen bonding groups and lipophilicity (cLogD) strongly influenced K(m). We also investigated further the role of Glu(146) in SULT1A3 using site-directed mutagenesis and showed that it plays a key role not only in defining selectivity for dopamine but also in preventing many phenolic xenobiotics from binding to the enzyme.

Alanine↗
PubMed2004

Calcium mobilization and spontaneous transient outward current characteristics upon agonist activation of P2Y2 receptors in smooth muscle cells.

A quantitative model is provided that links the process of metabotropic receptor activation and sequestration to the generation of inositol 1,4,5-trisphosphate, the subsequent release of calcium from the central sarcoplasmic reticulum, and the consequent release of calcium from subsarcolemma sarcoplasmic reticulum that acts on large-conductance potassium channels to generate spontaneous transient outward currents (STOCs). This model is applied to the case of STOC generation in vascular A7r5 smooth muscle cells that have been transfected with a chimera of the P2Y(2) metabotropic receptor and green fluorescent protein (P2Y(2)-GFP) and exposed to the P2Y(2) receptor agonist uridine 5'-triphosphate. The extent of P2Y(2)-GFP sequestration from the membrane on exposure to uridine 5'-triphosphate, the ensuing changes in cytosolic calcium concentration, as well as the interval between STOCs that are subsequently generated, are used to determine parameter values in the model. With these values, the model gives a good quantitative prediction of the dynamic changes in STOC amplitude observed upon activation of metabotropic P2Y(2) receptors in the vascular smooth muscle cell line.

Animals↗
PubMed1997

Model for quantitative immunohistochemical assessment of pulpal response to biomaterials.

The purpose of this study was to propose a new method for quantitative evaluation of the pulpal inflammation to restorative materials using immunohistochemistry and image analysis. Class V cavities were prepared and filled with different restorative materials in 20 healthy premolars to be extracted for orthodontic reasons. Teeth were extracted at different time intervals, fixed, demineralized, and embedded in paraffin. Six-micrometer-thick sections were cut serially and mounted on slides and every fifth section was stained using hematoxylin and eosin or Masson's trichrome, and served to localize the inflammatory reaction. The slides corresponding to the bulk of the inflammatory reaction were then used for immunohistochemical detection of the inflammatory cells using monoclonal antibodies: CD15 (granulocytes and histiocytes), CD45RO (T lymphocytes and monocytes), Pan-B cell (B lymphocytes, macrophages, and a subpopulation of T lymphocytes), CD45RA (B lymphocytes and monocytes), and EMA (plasma cells). The slides were observed and submitted to computerized image analysis using a SAMBA 2000 system for counting of the cells. The CD15, CD45RO, Pan-B-cell, and CD45RA antibodies positively stained the target cells, which could be counted with the computer. The EMA antibody did not permit staining of cells. These results indicate that polymorphonuclears, T lymphocytes, and B lymphocytes are present in inflamed human dental pulp. The immunologic detection of inflammatory cells followed by computerized image analysis allows an accurate characterization of pulpal pathology, and could be useful for the study of pulp reactions to restorative biomaterials.

Dental Materials↗
PubMed2006

Quantitative survival model for short-term survival after adult-to-adult living donor liver transplantation.

Adult-to-adult living donor liver transplantation (ALDLT) has been accepted as an important option for end-stage liver disease, but information regarding the risk factors remains fragmentary. We aimed to establish a predictive model for 90-day survival. In the first step, a total of 286 cases who had received primary ALDLT using a right lobe graft between 1998 and 2004 were randomly divided into 2 cohorts at a ratio of 2:1 (191 vs. 95 recipients). The larger cohort of patients was used to develop a model. The outcome was defined as 90-day survival, and a total of 39 preoperative and operative variables, including the period of surgery (1998-2001 vs. 2002-2004), were included using Cox's proportional hazard regression model. Two mismatches of human leukocyte antigen (HLA) type DR (hazard ratio [HR] = 4.45; confidence interval [CI] = 1.96-10.1), log(e)[blood loss volume] (HR = 2.43; CI = 1.64-3.60), period of surgery (1998-2001 vs. 2002-2004) (HR = 2.41; CI = 1.04-5.57), and log(e)[serum C-reactive protein or CRP] (HR = 1.64; CI = 1.13-2.38) were found to be independent risk factors. In the second step, we tried to establish a realistic survival model. In this step, we created 2 models, 1 that used all 4 variables (model 1) and 1 (model 2) in which blood loss volume was replaced with the past history of upper abdominal surgery and Model for End-Stage Liver Disease (MELD) score (> or =25), both of which showed associations with blood loss volume. These models were applied to the smaller cohort of 95 patients. Receiver operating characteristic analyses demonstrated that both models showed similar significant c-statistics (0.63 and 0.62, respectively). In conclusion, model 2 can provide a rough estimation of the 90-day survival after ALDLT.

Adult↗
PubMed1997

Non-linear selection response in Drosophila: a strategy for testing the rare-alleles model of quantitative genetic variability.

Quantitative genetic theory predicts that variation due to rare alleles at many loci will generate a transient acceleration in the response to directional selection. We have tested this prediction by constructing experimental lines of Drosophila melanogaster that carry positively selected ethanol resistance alleles at low frequencies, and then subjecting the lines to directional selection for ethanol resistance. Approximately 468,000 files were subjected to artificial selection over 30 generations. The predicted non-linear selection responses were observed in all experimental lines and replicates, on three genetic backgrounds. In contrast, un-selected controls and lines carrying random alleles at low frequencies on the same genetic backgrounds exhibited linear selection responses. These results demonstrate that non-linearities due to rare alleles are detectable and repeatable, provided that experiments are done on a sufficiently large scale. The results suggest that it may be possible to test for rare-alleles as a component of naturally occurring genetic variation by careful examination of selection response curves.

Alleles↗
PubMed1977

A quantitative rotational model for studying serotonergic function in the rat.

Unilateral injection of 5,7-dihydroxytryptamine (4 mug/4 mul) into the medial forebrain bundle of rats produced serotonin depletions of 65% and 70% in the ipsilateral corpus striatum and ipsilateral forebrain, respectively. These animals showed a dose-dependent increase in contralateral turning (rotational behavior) when pretreated with a peripheral decarboxylase inhibitor and then injected with L-5-hydroxytryptophan in doses ranging from 5 to 100 mg/kg i.p. Injections of p-chloroamphetamine, which releases endogenous stores of serotonin, produced ipsilateral turning which could be blocked by prior serotonin depletion. Systemic administration of the catecholamine drugs L-DOPA, apomorphine and D-amphetamine never elicited consistent turning in either direction in these animals. These data indicate that the turning response of rats with unilateral destruction of brain serotonin nerve terminals provides a sensitive tool for quantifiably studying changes in serotonergic function.

5-Hydroxytryptophan↗
PubMed2005

Amplitude modulation of nuclear Ca2+ signals in human skeletal myotubes: a possible role for nuclear Ca2+ buffering.

Video-rate confocal microscopy of Indo-1-loaded human skeletal myotubes was used to assess the relationship between the changes in sarcoplasmic ([Ca(2+)](S)) and nuclear ([Ca(2+)](N)) Ca(2+) concentration during low- and high-frequency electrostimulation. A single stimulus of 10 ms duration transiently increased [Ca(2+)] in both compartments with the same time of onset. Rate and amplitude of the [Ca(2+)] rise were significantly lower in the nucleus (4.0- and 2.5-fold, respectively). Similarly, [Ca(2+)](N) decayed more slowly than [Ca(2+)](S) (mono-exponential time constants of 6.1 and 2.5 s, respectively). After return of [Ca(2+)] to the prestimulatory level, a train of 10 stimuli was applied at a frequency of 1 Hz. The amplitude of the first [Ca(2+)](S) transient was 25% lower than that of the preceding single transient. Thereafter, [Ca(2+)](S) increased stepwise to a maximum that equalled that of the single transient. Similarly, the amplitude of the first [Ca(2+)](N) transient was 20% lower than that of the preceding single transient. In contrast to [Ca(2+)](S), [Ca(2+)](N) then increased to a maximum that was 2.3-fold higher than that of the single transient and equalled that of [Ca(2+)](S). In the nucleus, and to a lesser extent in the sarcoplasm, [Ca(2+)] decreased faster at the end of the stimulus train than after the preceding single stimulus (time constants of 3.3 and 2.1 s, respectively). To gain insight into the molecular principles underlying the shaping of the nuclear Ca(2+) signal, a 3-D mathematical model was constructed. Intriguingly, quantitative modelling required the inclusion of a satiable nuclear Ca(2+) buffer. Alterations in the concentration of this putative buffer had dramatic effects on the kinetics of the nuclear Ca(2+) signal. This finding unveils a possible mechanism by which the skeletal muscle can adapt to changes in physiological demand.

Buffers↗
PubMed2002

Quantitative genetic modeling of regional brain volumes and cognitive performance in older male twins.

As part of an ongoing longitudinal twin study, data from both MRI brain scanning and from neuropsychological testing were obtained from 139 male-male twin pairs (72 monozygotic [MZ] and 67 dizygotic [DZ]), 69-80 years old at the time of examination. For descriptive purposes, we examined the MZ and DZ intraclass correlations (ICC) of four lobar brain volumes (frontal, temporal, parietal, and occipital), two cerebrospinal fluid (CSF) volumes (lateral ventricle and temporal horn of the lateral ventricles), and two measures of cognitive functioning (verbal memory and executive function). We found that for lobar brain and CSF space volumes, the MZ ICC were significantly greater than zero (r=0.37-0.77) and greater than the corresponding DZ correlations (r=0.02-0.49). Similarly, within-pair correlations for the two neuropsychological factors were statistically significant and significantly larger in MZ twin pairs than in DZ pairs, suggesting the presence of genetic variance. Bivariate genetic analysis revealed that while close to 60% of individual differences in neuropsychological performance were due to genetic influences, less than 50% of genetic effects were in common with those influencing brain volumes. These data may shed light on the genetic liability for brain diseases that affect the elderly.

Aged↗
PubMed1997

Quantitative kinetic model for photoassembly of the photosynthetic water oxidase from its inorganic constituents: requirements for manganese and calcium in the kinetically resolved steps,.

The process of photoactivation, the assembly of a functional water-oxidizing complex (WOC) from the apoproteins of photosystem II of higher plants and inorganic cofactors (Mn2+, Ca2+, and Cl-), was known from earlier works to be a two-step kinetic process, requiring two light-induced processes separated by a slower dark period. However, these steps had not been directly resolved in any kinetic experiment, until development of an ultrasensitive polarographic O2 electrode and synthesis of an improved chelator for cofactor removal allowed direct kinetic resolution of the first pre-steady state intermediate [Ananyev, G. M. & Dismukes, G. C. (1996a) Biochemistry 35, 4102-4109]. Herein, the dependence of the rates of each of the first two light steps and the dark step of photoactivation was directly determined in spinach PSII membranes over a range of calcium and manganese concentrations at least 10-fold lower than those possible using commercial O2 electrodes. The following results were obtained. (1) One Mn2+ ion binds and is photooxidized to Mn3+ at a high-affinity site, forming the first light-induced intermediate, IM1. Formation of IM1 is coupled to the dissociation of a bound Ca2+ ion either located in the Mn site or coupled to it. (2) The inhibition constant for Ca2+ dissociation from this site is equal to 1.5 mM. (3) The dissociation constant of Mn2+ at this high-affinity site is equal to 8 microM at the optimum calcium concentration for O2-evolving activity of 8 mM, in agreement with the high-affinity site for electron donation to PSII. (4) Prior to the next photolytic step, one Ca2+ ion must bind at its effector site so that stable photooxidation of a second Mn2+ ion can occur, forming the second light-induced intermediate, IM2. This dark process is the rate-determining step. (5) The Michaelis constant for recovery of O2 evolution by Ca2+ binding at this effector site (Km) is equal to 1.4 mM, a value that is the same as that measured for the calcium requirement for O2 evolution in intact PSII. (6) The low quantum yield for the formation of IM2 from IM1 increases linearly with the duration of the dark period up to the longest period we could examine (10 s). Accordingly, the rate limitation in the second photolytic step originates from a slow calcium-induced dark rearrangement of the first intermediate, IM1, which we propose to be a protein conformational change that allows stable binding of the next Mn2+ ion. We further propose that the single Ca2+ ion which is required for assembly of the Mn4 cluster is equivalent to the Ca2+ ion which functions at the "gatekeeper" site in intact O2-evolving centers, where it plays a role in limiting substrate access to the Mn4 cluster [Sivaraja, M., et al. (1989) Biochemistry 28, 9459-9464; Tso, J., et al., (1991) Biochemistry 30, 4734-4739]. A molecular model for photoactivation is proposed and discussed.

Calcium↗
PubMedDate not supplied

GRID formalism for the comparative molecular surface analysis: application to the CoMFA benchmark steroids, azo dyes, and HEPT derivatives.

Shape analysis is a powerful tool in chemistry and drug design, and molecular surface defines shape in the molecular scale. In the current publication we presented a novel formalism for the comparative molecular surface analysis (s-CoMSA). The method enables both quantitative modeling of 3D-QSAR and finding possible pharmacophoric sites. The method provides very predictive models for the CBG activity of the benchmark steroid series, tinctorial properties of the heterocyclic azo dyes and anti-HIV activity of the HEPT series.

Anti-HIV Agents↗