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PubMed1998

The interaction of Na+ and K+ in voltage-gated potassium channels. Evidence for cation binding sites of different affinity.

Voltage-gated potassium (K+) channels are multi-ion pores. Recent studies suggest that, similar to calcium channels, competition between ionic species for intrapore binding sites may contribute to ionic selectivity in at least some K+ channels. Molecular studies suggest that a putative constricted region of the pore, which is presumably the site of selectivity, may be as short as one ionic diameter in length. Taken together, these results suggest that selectivity may occur at just a single binding site in the pore. We are studying a chimeric K+ channel that is highly selective for K+ over Na+ in physiological solutions, but conducts Na+ in the absence of K+. Na+ and K+ currents both display slow (C-type) inactivation, but had markedly different inactivation and deactivation kinetics; Na+ currents inactivated more rapidly and deactivated more slowly than K+ currents. Currents carried by 160 mM Na+ were inhibited by external K+ with an apparent IC50 <30 microM. K+ also altered both inactivation and deactivation kinetics of Na+ currents at these low concentrations. In the complementary experiment, currents carried by 3 mM K+ were inhibited by external Na+, with an apparent IC50 of approximately 100 mM. In contrast to the effects of low [K+] on Na+ current kinetics, Na+ did not affect K+ current kinetics, even at concentrations that inhibited K+ currents by 40-50%. These data suggest that Na+ block of K+ currents did not involve displacement of K+ from the high affinity site involved in gating kinetics. We present a model that describes the permeation pathway as a single high affinity, cation-selective binding site, flanked by low affinity, nonselective sites. This model quantitatively predicts the anomalous mole fraction behavior observed in two different K+ channels, differential K+ and Na+ conductance, and the concentration dependence of K+ block of Na+ currents and Na+ block of K+ currents. Based on our results, we hypothesize that the permeation pathway contains a single high affinity binding site, where selectivity and ionic modulation of gating occur.

Binding Sites↗
PubMed2002

Spermine block of the strong inward rectifier potassium channel Kir2.1: dual roles of surface charge screening and pore block.

Inward rectification in strong inward rectifiers such as Kir2.1 is attributed to voltage-dependent block by intracellular polyamines and Mg(2+). Block by the polyamine spermine has a complex voltage dependence with shallow and steep components and complex concentration dependence. To understand the mechanism, we measured macroscopic Kir2.1 currents in excised inside-out giant patches from Xenopus oocytes expressing Kir2.1, and single channel currents in the inside-out patches from COS7 cells transfected with Kir2.1. We found that as spermine concentration or voltage increased, the shallow voltage-dependent component of spermine block at more negative voltages was caused by progressive reduction in the single channel current amplitude, without a decrease in open probability. We attributed this effect to spermine screening negative surface charges involving E224 and E299 near the inner vestibule of the channel, thereby reducing K ion permeation rate. This idea was further supported by experiments in which increasing ionic strength also decreased Kir2.1 single channel amplitude, and by mutagenesis experiments showing that this component of spermine block decreased when E224 and E299, but not D172, were neutralized. The steep voltage-dependent component of block at more depolarized voltages was attributed to spermine migrating deeper into the pore and causing fast open channel block. A quantitative model incorporating both features showed excellent agreement with the steady-state and kinetic data. In addition, this model accounts for previously described substate behavior induced by a variety of Kir2.1 channel blockers.

Animals↗
PubMed2005

Evaluation of potentially significant increase of lead in the blood during long-term bed rest and space flight.

We address a gap in the knowledge of lead turnover under conditions of prolonged bed rest and microgravity by developing a quantitative model of the amount of lead returned to blood circulation from bone. We offer the hypothesis that skeletal unloading, such as typically occurs during extended bed rest or microgravity, will result in bone lead being released to the blood, as has already been demonstrated in the case of calcium. We use initial bone lead concentrations to develop predictive models of blood lead elevation. Our theoretical calculations with typical bone lead loads measured in today's 40-60-year-old generation, suggest that the estimated blood lead concentrations in long duration (e.g., 100 days) space flight could average between 20 and 40 microg dl(-1), a range with well-established toxic effects. For a similar duration of bed rest, estimated blood lead concentration could be as high as 10-20 microg dl(-1), which is a level of concern, particularly if we consider females of childbearing age. The preliminary experimental results were obtained under multi-institutional collaborations, with the main outcome received from an on-going bed rest study, Prevention of Microgravity-Induced Stone Risk by KMgCitrate, conducted at the General Clinical Research Center (GCRC) of the University of Texas Southwestern Medical Center, Dallas. Based on theoretical modeling and some preliminary experimental results, this concept may have important clinical implications by allowing prediction of the magnitude of blood lead elevation, thereby establishing the means to prevent lead toxicity during long duration space flight of astronauts and in conditions of prolonged bed rest such as complicated pregnancy, spinal cord injury induced paralysis and comatose patients.

Bed Rest↗
PubMed2006

Mobility of Min-proteins in Escherichia coli measured by fluorescence correlation spectroscopy.

In the bacterium Escherichia coli, selection of the division site involves pole-to-pole oscillations of the proteins MinD and MinE. Different oscillation mechanisms based on cooperative effects between Min-proteins and on the exchange of Min-proteins between the cytoplasm and the cytoplasmic membrane have been proposed. The parameters characterizing the dynamics of the Min-proteins in vivo are not known. It has therefore been difficult to compare the models quantitatively with experiments. Here, we present in vivo measurements of the mobility of MinD and MinE using fluorescence correlation spectroscopy. Two distinct timescales are clearly visible in the correlation curves. While the faster timescale can be attributed to cytoplasmic diffusion, the slower timescale could result from diffusion of membrane-bound proteins or from protein exchange between the cytoplasm and the membrane. We determine the diffusion constant of cytoplasmic MinD to be approximately 16 microm(2) s(-1), while for MinE we find about 10 microm(2) s(-1), independently of the processes responsible for the slower time-scale. The implications of the measured values for the oscillation mechanism are discussed.

Adenosine Triphosphatases↗
PubMed2006

Computer-aided design of modular protein devices: Boolean AND gene activation.

Many potentially useful synthetic gene networks require the expression of an engineered gene if and only if two different DNA-binding proteins exist in sufficient concentration. While some natural and engineered systems activate gene expression according to a logical AND-like behavior, they often utilize allosteric or cooperative protein-protein interactions, rendering their components unsuitable for a toolbox of modular parts for use in multiple applications. Here, we develop a quantitative model to demonstrate that a small system of interacting fusion proteins, called a protein device, can activate an engineered gene according to the Boolean AND behavior while using only modular protein domains and DNA sites. The fusion proteins are created from transactivating, DNA-binding, non-DNA binding, and protein-protein interaction domains along with the corresponding peptide ligands. Using a combined kinetic and thermodynamic model, we identify the characteristics of the molecular components and their rates of constitutive production that maximize the fidelity of AND behavior. These AND protein devices facilitate the creation of complex genetic programs and may be used to create gene therapies, biosensors and other biomedical and biotechnological applications that turn on gene expression only when multiple DNA-binding proteins are simultaneously present.

Computer Simulation↗
PubMed1998

Iterative stepwise discriminant analysis: a meta-algorithm for detecting quantitative sequence motifs.

An algorithm is presented for detecting a quantitative pattern in peptide fragments that bind class II major histocompatibility complex (MHC) molecules. It is referred to as a meta-algorithm because it requires successive applications of Stepwise Discriminate Analysis (SDA). On every iteration the best subsequence candidates are selected from sequences known to bind class II MHC molecules. When SDA compares probable binding subsequences with subsequences known not to bind class II MHC molecules, a quantitative model emerges that is capable of classifying subsequences as binding or non-binding. In an iterative manner, the resultant model is utilized as a criterion for selecting probable binding subsequence candidates. The procedure is repeated until models converge. In the illustrated examples, the final models correctly classify over 95% of the peptides in a database of peptides whose binding affinity for HLA-DR1 is known. The final model can then be used to predict the binding affinity of peptides that have not yet been laboratory tested.

Algorithms↗
PubMed2003

Adding lactate to the prime solution during hypothermic cardiopulmonary bypass: a quantitative acid-base analysis.

BACKGROUND: The effect of adding lactate to the cardiopulmonary bypass (CPB) prime was investigated using Stewart's quantitative acid-base approach. According to this quantitative model, serum pH and bicarbonate are determined by three independent factors: the partial pressure of carbon dioxide (PCO(2)), the total concentration of weak acids (e.g. albumin), and the strong ion difference. The apparent strong ion difference is calculated as the sum of sodium, potassium, magnesium and calcium minus chloride concentrations. The pH decreases with a smaller strong ion difference and vice versa. METHODS: Twenty patients scheduled for coronary surgery were studied prospectively. All patients were treated identically, except for the prime, which either contained lactate or was lactate free. Just before bypass and before coming off bypass, haemoglobin, glucose, plasma osmolality and colloid osmotic pressure were determined; albumin, lactate, sodium, potassium, ionized calcium, magnesium, phosphate, arterial pH, PCO(2), bicarbonate, and base excess were measured for use in Stewart's analysis. RESULTS: Metabolic acidosis had resolved by the end of bypass with the lactated prime. Although the strong ion gap (apparent minus effective strong ion difference) increased significantly in both groups, its composition differed significantly between the groups. The Stewart technique detected polyanionic gelatin as a weak acid component contributing to the unidentified anion fraction. Colloid osmotic pressure was maintained in both groups. CONCLUSION: Exogenous lactate attenuates acidosis related to CPB. The oncotic and weak acid deficits produced by hypoalbuminaemia may be compensated for temporarily during CPB by polyanionic synthetic colloids such as succinylated gelatin.

Acid-Base Equilibrium↗
PubMed2004

Brainstem reflex circuits revisited.

Our current understanding of brainstem reflex physiology comes chiefly from the classic anatomical-functional correlation studies that traced the central circuits underlying brainstem reflexes and establishing reflex abnormalities as markers for specific areas of lesion. These studies nevertheless had the disadvantage of deriving from post-mortem findings in only a few patients. We developed a voxel-based model of the human brainstem designed to import and normalize MRIs, select groups of patients with or without a given dysfunction, compare their MRIs statistically, and construct three-plane maps showing the statistical probability of lesion. Using this method, we studied 180 patients with focal brainstem infarction. All subjects underwent a dedicated MRI study of the brainstem and the whole series of brainstem tests currently used in clinical neurophysiology: early (R1) and late (R2) blink reflex, early (SP1) and late (SP2) masseter inhibitory reflex, and the jaw jerk to chin tapping. Significance levels were highest for R1, SP1 and R2 afferent abnormalities. Patients with abnormalities in all three reflexes had lesions involving the primary sensory neurons in the ventral pons, before the afferents directed to the respective reflex circuits diverge. Patients with an isolated abnormality of R1 and SP1 responses had lesions that involved the ipsilateral dorsal pons, near the fourth ventricle floor, and lay close to each other. The area with the highest probabilities of lesion for the R2-afferent abnormality was in the ipsilateral dorsal-lateral medulla at the inferior olive level. SP2 abnormalities reached a low level of significance, in the same region as R2. Only few patients had a crossed-type abnormality of SP1, SP2 or R2; that of SP1 reached significance in the median pontine tegmentum rostral to the main trigeminal nucleus. Although abnormal in 38 patients, the jaw jerk appeared to have no cluster location. Because our voxel-based model quantitatively compares lesions in patients with or without a given reflex abnormality, it minimizes the risk that the significant areas depict vascular territories rather than common spots within the territory housing the reflex circuit. By analysing statistical data for a large cohort of patients, it also identifies the most frequent lesion location for each response. The finding of multireflex abnormalities reflects damage of the primary afferent neurons; hence it provides no evidence of an intra-axial lesion. The jaw jerk, perhaps the brainstem reflex most widely used in clinical neurophysiology, had no apparent topodiagnostic value, probably because it depends strongly on peripheral variables, including dental occlusion.

Adult↗
PubMed1992

Interpretation of labeling indices in the presence of cell death.

A simple method is presented for the analysis of data on labeling indices in populations of cells undergoing division and apoptosis. The method is applicable to continuous, osmotic pump labeling experiments, and provides estimates of cell division rates. Cell replication kinetics play an important role in carcinogenesis, and the interpretation presented here should help in the incorporation of data on labeling indices into quantitative models for cancer risk assessment.

Animals↗
PubMed1996

The BN rat strain carries dominant hepatocarcinogen resistance loci.

The phylogenetically distant F344 and BN rat strains and their (BN x F344) F1 hybrids were compared for susceptibility to hepatocarcinogenesis using the 'resistant hepatocyte' model. Quantitative stereological analysis of frequency (number/liver) and size (mean volume and volume fraction) of placental form glutathione S-transferase (GST-P)-positive lesions was carried out at 8, 15 and 32 weeks after diethylnitrosamine initiation. The number/liver of GST-P-positive lesions at any time point was slightly higher in BN and (BN x F344) F1 rats than in F344 rats, but not statistically different. However, mean volume and volume fraction of GST-P positive lesions were much higher in F344 than in both BN and (BN x F344) F1 rats at any time point, with a difference of up to > 10-fold. GST-P-positive lesions exhibited a significantly higher labeling index and much lower remodeling in male F344 than in BN and (BN x F344) F1 rats. HCCs were present at 54-57 weeks after initiation in 77% of male F344 and in no (BN x F344) F1 rats and at 70 weeks HCCs were observed in 100% of male F344 and in 23% of (BN x F344) F1 rats. These results suggest that the BN rat strain is resistant to hepatocarcinogenesis and that its resistance is genetically transmitted as a dominant character to F1 hybrids of the BN strain with the F344 susceptible strain.

2-Acetylaminofluorene↗
PubMed1989

Coevolution of the major histocompatibility complex and the t-complex in the mouse. I. Generation and maintenance of high complementarity associations.

A quantitative model is developed to explore the effects of prezygotic and postzygotic incompatibility on the origin and maintenance of associations between the major histocompatibility complex (MHC) and the t-complex in the mouse. Incompatibility is represented by a reduction in the rate of conception or gestation of offspring derived from sperm bearing MHC antigens in common with the mother. Incompatibility encourages the evolution of associations from a state of complete independence between the two complexes by promoting the invasion of all novel antigens, including those that exhibit associations with the t-complex. Incompatibility can modify the relative numbers of antigens associated with each haplotype by actively promoting the exclusion or invasion of recombinants that bear formerly +-specific or t-specific antigens on the alternative haplotype. The results of the analysis indicate that the state of complete independence between the MHC and the t-complex is not preserved over evolutionary time in the presence of incompatibility. Further, the expression of incompatibility maintains fully associated states that include a single antigen associated with the t-haplotype and up to three to five antigens associated with the +-haplotype within a single population.

Animals↗
PubMed1989

Coevolution of the major histocompatibility complex and the t-complex in the mouse. II. Modification of response to sharing of histocompatibility antigens.

Selective pressures imposed by high complementarity associations between the major histocompatibility complex (MHC) and the t-complex on a locus that modifies the expression of prezygotic and postzygotic incompatibility are investigated through the analysis of a quantitative model. Sharing of MHC antigens between mates or between mother and offspring elicits weak inhibition of conception or gestation. In the presence of high complementarity associations between the MHC and the t-complex, weak incompatibility depresses the mean fitness of the population. Nevertheless, natural selection favors the enhancement of the expression of incompatibility if the number of antigens associated with the +-haplotype exceeds the number associated with the t-haplotype by a sufficient margin. Under absolute linkage between the modifier locus and the t-complex, the number associated with the +-haplotype need only be greater than the number associated with the t-haplotype. In the absence of linkage, a twofold difference is sufficient to ensure the initial increase of modifier alleles that intensify the expression of incompatibility.

Alleles↗
PubMed1975

Gene flow and selection in a natural population of Drosophila melanogaster.

A marked genetic differentiation to the presence of alcohol in the environment has been shown to occur between inside cellar and adjacent outside sections of a vineyard population of D. melanogaster (McKenzie and Parsons 1974). Estimates of migration during the vintage period suggest considerable movement occurs from outside into the cellar and that the most tolerant genotypes are the most successful migrants. A quantitative model of this system suggests that the selection intensity may not be a limiting factor in maintaining the differentiation. It also suggests that gene flow must be restricted between sections of the population at all but vintage periods if this differentiation is to persist.

Alcohols↗
PubMed1995

Age changes in the distribution of visual attention.

Two experiments examined adult age differences in the controlled allocation of visual selective attention. Both experiments were identical with the exception of the stimulus display where targets and distractors were linearly increased with eccentricity in Experiment 2. A spatial cuing task was used with four cue-target presentation intervals (SOAs) of 250, 500, 1000, and 2000 msec (Experiment 1) and 250, 500, 750, and 1000 msec (Experiment 2). Results were fit to three quantitative models based on attentional distribution metaphors (spotlight, zoom lens, and ring) in order to determine the best fitting model of attentional distribution. Data from Experiment 1 indicated that older subjects distributed attention in a qualitatively different manner than younger subjects and suggested a different time course of processing. When stimuli visibility was controlled a single flexible resource allocation (ring) model of attention could account for the results of both age groups at all SOAs. Results further suggested that older adults employ compensatory strategies to offset visual processing difficulties.

Adult↗
PubMed2004

Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy.

Aspartylglycosaminuria (AGU) is caused by deficient enzymatic activity of glycosylasparaginase (GA). The disease is characterized by accumulation of aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines in tissues and body fluids of AGU patients and in an AGU mouse model. In the current study, we characterized a glycoasparagine carrying the tetrasaccharide moiety of alpha-D-Man-(1-->6)-beta-D-Man-(1-->4)-beta-D-GlcNAc-(1-->4)-beta-D-GlcNAc-(1-->N)-Asn (Man2GlcNAc2-Asn) in urine of an AGU patient and also in the tissues of the AGU mouse model. Quantitative analysis demonstrated a massive accumulation of the compound especially in nonneuronal tissues of the AGU mice, in which the levels of Man2GlcNAc2-Asn were typically 30-87% of those of GlcNAc-Asn. The highest level of Man2GlcNAc2-Asn was found in the liver, spleen, and heart tissues of the AGU mice, the respective amounts being 87%, 76%, and 57% of the GlcNAc-Asn levels. In the brain tissue of AGU mice the Man2GlcNAc2-Asn storage was only 9% of that of GlcNAc-Asn. In contrast to GlcNAc-Asn, the storage of Man2GlcNAc2-Asn markedly increased in the liver and spleen tissues of AGU mice as they grew older. Enzyme replacement therapy with glycosylasparaginase for 3.5 weeks reduced the amount of Man2GlcNAc2-Asn by 66-97% in nonneuronal tissues, but only by 13% in the brain tissue of the AGU mice. In conclusion, there is evidence for a role for storage of glycoasparagines other than aspartylglucosamine in the pathogenesis of AGU, and this possibility should be taken into consideration in the treatment of the disease.

Animals↗
PubMed1989

Nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate (NO3-) in drinking water in Denmark is of concern due to the possibility of an associated increase in long-term exposure to endogeneously formed N-nitroso compounds. Using a duplicate portion technique in combination with a qualitative description of diet and other background variables, the total nitrate intake in a Danish rural population and the contribution of drinking water to the total nitrate exposure is estimated. People drinking nitrate-free water have an intake of 37 mg NO3- per day. At 47 mg NO3- per litre, the exposure is increased to 89 mg, about 60% of which originates from the water. At 84 mg NO3- per litre, the daily exposure is 123 mg, 70% of which originates from the drinking water. These crude comparisons between three groups of people are supplemented with quantitative modelling of nitrate exposure at individual level. Apart from drinking water, consumption of vegetables is a major source of nitrate in this population. Using nitrate in overnight urine samples to quantify exposure is less accurate than the duplicate dietary portion technique and tends, in the present study, to underestimate the contribution of water-derived nitrate to total nitrate intake.

Adult↗
PubMed2006

The proliferative response of CD4 T cells to steady-state CD8+ dendritic cells is restricted by post-activation death.

CD8(+) splenic dendritic cells (DCs) from steady-state mice are less effective than the CD8(-) DC subset in their capacity to stimulate CD4 T cell proliferation in culture. However, we found that the two DC subtypes were equally potent at activating CD4 T cells, based on up-regulation of CD69 and CD25 expression. Also, we found no difference in the rate of T cell death prior to entry into the first division. We then tracked carboxyfluorescein diacetate succinimidyl ester-labeled T cells and employed a quantitative model to assess in detail the CD4 T cell expansion process in response to stimulation with CD8(+) or with CD8(-) DCs. The time required for most T cells to replicate their DNA prior to the first division was similar in both DC cultures. However, progression of the CD4 T cell population through subsequent divisions was reduced in CD8(+) DCs compared with CD8(-) DC culture. This was associated with an increased loss of viable T cells at each division. Post-activation, division-associated T cell death is therefore a major factor in the reduced response of CD4 T cells to CD8(+) DCs.

Animals↗
PubMed2001

Departmental consumption of antibiotic drugs and subsequent resistance: a quantitative link.

OBJECTIVE: To look for a quantitative model linking departmental consumption of antibiotic drugs to the subsequent isolation of resistant hospital-acquired coliform pathogens. MATERIALS AND METHODS: Included in the study were all patients with hospital-acquired bloodstream infections caused by a coliform pathogen, detected in six departments of internal medicine of one university hospital during the period 1991-1996, who had not been hospitalized in the month before the infection (n = 394). Departmental consumption of antibiotics in the year before the infection [expressed as defined daily dosages (DDD)/100 patient days], antibiotic treatment given to the individual patient before the infection, the day of hospital stay on which the infection occurred, and the department and the calendar year were all included in a logistic model to predict the isolation of a resistant pathogen. We looked at five drugs: gentamicin, amikacin, cefuroxime, ceftazidime and ciprofloxacin. RESULTS: Five logistic models were fitted for the resistance to each of the antibiotic drugs. The multivariable-adjusted odds ratios for a pathogen resistant to the specific antibiotic were 1.03 [95% confidence interval (CI) 0.70-1.50] for gentamicin, 1.80 (95% CI 1.00-3.24) for amikacin, 1.12 (95% CI 1.02-1.23) for cefuroxime, 1.45 (95% CI 1.19-1.76) for ceftazidime and 1.06 (95% CI 0.57-1.97) for ciprofloxacin, per 1 DDD/100 patient days. CONCLUSIONS: The departmental consumption of cephalosporin drugs and amikacin in six autonomous departments of medicine in the same hospital was associated with a measurable and statistically significant increase in the probability of infection caused by a resistant pathogen.

Amikacin↗