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Biomedical subjects

C G Gray

Publications and source records attributed to C G Gray.

14 recordsLinked to original sources
PubMed2006

Nonequilibrium molecular dynamics calculation of the conductance of the KcsA potassium ion channel.

We have developed an efficient method for the atomistic determination of the conductance of a biological ion channel model by applying an external field to the conducting ions only. The underlying theory is discussed and demonstrated in a simple test system consisting of two ions in a box of water. Finally, the theory is applied to the experimentally determined structure of the KcsA potassium channel from which a conductance in reasonable agreement with the experimental result is predicted.

Bacterial Proteins↗
PubMed2006

Unified modeling of conductance kinetics for low- and high-conductance potassium ion channels.

A kinetics model is proposed for the description of ion conductance of low- and high-conductance potassium ion channels. The model describes ion permeation through the selectivity filter, which is assumed to be the only conductance determining part of the open channel. The filter occupancy can vary from zero to three ions, affecting the ion entry and exit rates. Ion motion between the binding sites inside the filter is assumed fast compared to the latter rates allowing averaging the equilibrium entry and exit rate constants over the possible ion configurations in the filter with a particular occupancy. Averaged rate constants related to a pair of adjacent occupancy states characterize a particular ion permeation mechanism. An expression for the channel conductance as a function of the symmetrical external ion concentration is derived. It comprises a sum of concentration independent conductance amplitudes for different ion permeation mechanisms weighted by the equilibrium filter occupancy probabilities. It is shown that each amplitude (i.e., maximum contribution to the channel conductance from each conductance mechanism) is proportional to an averaged exit rate constant and to quantities characterizing the effect of the applied electric field on the rate constants and the equilibrium ion distribution in the filter. The conductance expression derived provides a good description of the experimentally observed conductance-concentration curves for low-conductance (e.g., Kir2.1) and high-conductance (e.g., KcsA) potassium channels. It enables one to obtain equilibrium ion binding constants at different filter occupancies and to calculate the average number of ions in the selectivity filter for a given external ion concentration. For KcsA this number (2.0 at 200 mM) is in a good agreement with the available experimental value (2.1 at 200 mM). For the high-conductance potassium channels the net negative electrical charge around the selectivity filter increases the ion binding constants, thereby causing the larger occupancy probabilities to occur at smaller external ion concentrations compared to the low-conductance channels. This substantially increases the contributions of the two- and three-ion permeation mechanisms, with the larger conductance amplitudes leading to increased channel conductance compared to the low-conductance channels.

Animals↗
PubMed2005

Thermal conductivity and bulk viscosity in quartic oscillator chains.

We propose a relation which predicts the low-frequency thermal conductivity of a one-dimensional (1D) system from the thermal conductivity and bulk viscosity at higher frequency. Our theory is based on the assumption that "ballistic" transport by sound waves dominates the heat transport. For a system with equal heat capacities (c(p) = c(v)) this relation is particularly simple. We test the prediction by simulating a chain of particles with quartic interparticle potentials under zero pressure conditions. As the frequency omega --> 0 the theory predicts that the energy current power spectrum diverges as omega(-1/2), not seen in previous simulations. Because we simulate very long chains to long times we do observe the crossover into this regime. The bulk viscosity of a 1D chain has been determined via simulation. It is found to be finite for our system, in contrast to the thermal conductivity which is infinite.

Journal Article↗
PubMed2005

Non-Michaelis-Menten kinetics model for conductance of low-conductance potassium ion channels.

A reduced kinetics model is proposed for ion permeation in low-conductance potassium ion channels with zero net electrical charge in the selectivity filter region. The selectivity filter is assumed to be the only conductance-determining part of the channel. Ion entry and exit rate constants depend on the occupancy of the filter due to ion-ion interactions. The corresponding rates are assumed slow relative to the rates of ion motion between binding sites inside the filter, allowing a reduction of the kinetics model of the filter by averaging the entry and exit rate constants over the states with a particular occupancy number. The reduced kinetics model for low-conductance channels is described by only three states and two sets of effective rate constants characterizing transitions between these states. An explicit expression for the channel conductance as a function of symmetrical external ion concentration is derived under the assumption that the average electrical mobility of ions in the selectivity filter region in a limited range of ion concentrations does not depend on these concentrations. The simplified conductance model is shown to provide a good description of the experimentally observed conductance-concentration curve for the low-conductance potassium channel Kir2.1, and also predicts the mean occupancy of the selectivity filter of this channel. We find that at physiological external ion concentrations this occupancy is much lower than the value of two ions observed for one of the high-conductance potassium channels, KcsA.

Animals↗
PubMed2001

Monte Carlo studies of model Langmuir monolayers.

This paper examines some of the basic properties of a model Langmuir monolayer, consisting of surfactant molecules deposited onto a water subphase. The surfactants are modeled as rigid rods composed of a head and tail segment of diameters sigma(hh) and sigma(tt), respectively. The tails consist of n(t) approximately 4-7 effective monomers representing methylene groups. These rigid rods interact via site-site Lennard-Jones potentials with different interaction parameters for the tail-tail, head-tail, and head-head interactions. In a previous paper, we studied the ground-state properties of this system using a Landau approach. In the present paper, Monte Carlo simulations were performed in the canonical ensemble to elucidate the finite-temperature behavior of this system. Simulation techniques, incorporating a system of dynamic filters, allow us to decrease CPU time with negligible statistical error. This paper focuses on several of the key parameters, such as density, head-tail diameter mismatch, and chain length, responsible for driving transitions from uniformly tilted to untilted phases and between different tilt-ordered phases. Upon varying the density of the system, with sigma(hh)=sigma(tt), we observe a transition from a tilted (NNN)-condensed phase to an untilted-liquid phase and, upon comparison with recent experiments with fatty acid-alcohol and fatty acid-ester mixtures [M. C. Shih, M. K. Durbin, A. Malik, P. Zschack, and P. Dutta, J. Chem. Phys. 101, 9132 (1994); E. Teer, C. M. Knobler, C. Lautz, S. Wurlitzer, J. Kildae, and T. M. Fischer, J. Chem. Phys. 106, 1913 (1997)], we identify this as the L'(2)/Ov-L1 phase boundary. By varying the head-tail diameter ratio, we observe a decrease in T(c) with increasing mismatch. However, as the chain length was increased we observed that the transition temperatures increased and differences in T(c) due to head-tail diameter mismatch were diminished. In most of the present research, the water was treated as a hard surface, whereby the surfactants are only allowed to move within the plane of this surface. However, we have also utilized a more realistic model for the surfactant-water interactions, developed by Karaborni and Toxvaerd, in order to examine the role which the coupled effects of head group size and head group-subphase interactions plays in determining tilt ordering and on the stability of the monolayer. It is found that increasing the head diameter results in a widening of the air-water interface and an associated destruction of orientational order. Furthermore, the onset of capillary waves at lower temperatures for larger head diameters implies that the L2-L1 phase boundary for acids and acetates should move to lower temperatures relative to the L'(2)/Ov-L1 phase boundary for alcohols and esters. This feature has yet to be seen in experimental studies.

Journal Article↗
PubMed1997

Confocal analysis of primary cilia structure and colocalization with the Golgi apparatus in chondrocytes and aortic smooth muscle cells.

Detyrosinated and acetylated alpha-tubulins represent a stable pool of tubulin typically associated with microtubules of the centrosome and primary cilium of eukaryotic cells. Although primary cilium-centrosome and centrosome-Golgi relationships have been identified independently, the precise structural relationship between the primary cilium and Golgi has yet to be specifically defined. Confocal immunohistochemistry was used to localize detyrosinated (ID5) and acetylated (6-11B-1) tubulin antibodies in primary cilia of chondrocytes and smooth muscle cells, and to demonstrate their relationship to the Golgi complex identified by complementary lectin staining with wheat germ agglutinin. The results demonstrate the distribution and inherent structural variation of primary cilia tubulins, and the anatomical interrelationship between the primary cilium, the Golgi apparatus and the nucleus. We suggest that these interrelationships may form part of a functional feedback mechanism which could facilitate the directed secretion of newly synthesized connective tissue macromolecules.

Acetylation↗
PubMed1996

Hypertonic saline/dextran treatment for severe pressure-driven hemorrhage in dehydrated conscious swine.

Although dehydration impairs the response to a fixed volume hemorrhage, both 7.5% hypertonic saline/6% dextran 70 (HSD: 4 mL/kg) and standard Ringer's lactate (33 mL/kg) are effective resuscitation fluids. However, the efficacy of resuscitation during continuing hemorrhage remains in question. Using a conscious swine model of continuous pressure-driven hemorrhage, we evaluated the effects of dehydration and HSD resuscitation on survival time, hemorrhage volume, regional blood flows, and central hemodynamics. Three groups of pigs were compared: euhydrated control (EC), dehydrated control (48 h water deprived) (DC); and dehydrated and resuscitated with HSD (D + HSD). All pigs were subjected to an initial 37% blood volume hemorrhage for 60 min followed by a continuous hemorrhage proportional to the instantaneous mean arterial pressure. The D + HSD pigs were resuscitated at the end of the 37% blood volume hemorrhage. Dehydration reduced body weight (-6.5 +/- .3%) and increased hematocrit (8.9 +/- 1.8%), serum osmolality (11.6 +/- .9%), serum sodium (11.9 +/- .9%), and serum total protein (9.4 +/- 1.8%). Compared with the EC group, DC had a greater increase in heart rate and arterial base deficit in response to the pressure-driven hemorrhage and a reduced pH and survival time (159 vs. 107 min). In contrast to the DC group, D + HSD had increased mean arterial pressure, cardiac output, oxygen delivery, and regional blood flows to the gut (superior mesenteric artery), kidneys, liver (hepatic artery), and adrenals at 5 min after HSD resuscitation. The HSD did not increase blood loss but tended to prolong survival (+26 min; p = .1079). thus, dehydration compromises survival time (-33%) and the hemodynamic and metabolic responses to pressure-driven hemorrhage, while treatment with HSD improves the hemodynamic responses.

Acid-Base Equilibrium↗
PubMed1995

Low-carbohydrate diet alters intracellular glucose metabolism but not overall glucose disposal in exercise-trained subjects.

Dietary composition has been strongly implicated as an important determinant of in vivo insulin sensitivity. However, the metabolic alterations associated with extreme changes in diet have not been well described. We compared glucose metabolism after a standard diet ([STD] 35% fat, 51% carbohydrate, and 14% protein) with the effects of a 3-week adaptation to a low-carbohydrate, high-fat diet ([LCD] 75% fat, 8% carbohydrate, and 17% protein). Ten healthy men were studied using the euglycemic clamp technique, indirect calorimetry, and percutaneous vastus lateralis muscle biopsies for analysis of glycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities in the basal and insulin-stimulated states. Insulin-stimulated glucose disposal was unchanged (STD 46.1 +/- 4.3 v LCD 46.0 +/- 4.3 mumol/kg.min, P = NS), but marked alterations in the routes of glucose disposal were noted. Insulin-stimulated glucose oxidation (Gox) was markedly reduced following LCD (STD 18.6 +/- 1.9 v LCD 8.23 +/- 1.9 mumol/kg.min, P = .0001), and nonoxidative glucose metabolism (Gnox) was enhanced by LCD (STD 24.9 +/- 0.9 v LCD 38.9 +/- 4.3 mumol/kg.min, P = .03). Following LCD, both the total and active forms of PDH (PDHt and PDHa) were significantly depressed. After LCD, GS activates (FV0.1, %I, and A0.5) were unaffected in the basal state, but were greater than for STD (P = .004) after insulin stimulation. The apparent increase in the sensitivity of GS to activation by insulin following LCD correlated strongly with maximal O2 consumption ([VO2max] r = .97, P = .001), suggesting that physical conditioning interacted with the metabolic impact of LCD. In summary, LCD did not induce changes in net glucose disposal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Nitric oxide synthesis inhibition does not improve the hemodynamic response to hemorrhagic shock in dehydrated conscious swine.

Nitric oxide (NO) may influence the hemodynamic response to hemorrhage. To test this hypothesis, the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was administered to conscious, dehydrated swine during a 37% blood volume hemorrhage and a 180 min recovery period without fluid resuscitation. L-NAME (.75 mg/kg bolus plus constant infusion of .75 mg/kg/h) was given via a central intravenous catheter during the bleed. The selectivity and specificity of L-NAME as a NO synthesis inhibitor in pigs was validated in pilot studies. The present study shows that inhibition of NO synthesis with L-NAME had no significant effect on the major hemodynamic parameters during and after hemorrhage when compared to dehydrated and euhydrated control groups. Only stroke volume and A-VO2 were significantly different from controls. Mortality was 83% for the L-NAME group and 44% for controls at 180 min of recovery (NS). The results suggest that NO synthesis inhibition provides no hemodynamic benefit during hemorrhage in dehydrated, conscious swine.

Animals↗
PubMed1994

Hypertonic saline/dextran versus lactated Ringer's treatment for hemorrhage in dehydrated swine.

To determine the efficacy of low-volume resuscitation in dehydrated subjects, 7.5% hypertonic saline/6% dextran 70 (HSD) and lactated Ringer's (LR) treatments were compared in conscious pigs dehydrated for 48 hr prior to a 37% blood volume hemorrhage. Pigs randomized to treatment were resuscitated with equivalent sodium loads of either HSD (4 ml/kg) or LR (33.3 ml/kg) following the 60-min hemorrhage. Dehydration resulted in a 7-8% body weight loss. Mortality through 180 min of recovery was 1/13 (7.7%) for HSD, 1/11 (9.1%) for LR, and 4/8 (50%) for a group of dehydrated and untreated controls (DC). HSD and LR solutions elicited similar heart rate, cardiac output, arterial pressure, and oxygen transport responses in the recovery period following hemorrhage and resuscitation. HSD was as effective as LR in expanding plasma volume in dehydrated hemorrhaged pigs. Serum chemistries provided no evidence for a sustained systemic toxicity from HSD treatment. These findings support low-volume HSD resuscitation of hemorrhagic shock in moderately dehydrated subjects.

Animals↗
PubMed1991

Effects of feeding on muscle blood flow during prolonged exercise in miniature swine.

Eight exercise-trained miniature swine were studied during prolonged treadmill runs (100 min) under fasting and preexercise feeding conditions. Each animal ran at identical external work loads that corresponded to 65% of the heart rate reserve (210-220 beats/min) for the two exercise bouts. Cardiac outputs and stroke volumes were higher and heart rates lower for fed than for fasting runs (P less than 0.05). Preexercise feeding did not alter oxygen consumption, core temperature, mean arterial pressure, and arterial-mixed venous oxygen difference during prolonged exercise; however, mixed venous lactate concentration was lower at end exercise than during fasting conditions (1.2 vs. 2.6 mM, P less than 0.05). Microsphere measurements of regional blood flow revealed significantly higher total gastrointestinal flow (23%) for fed than for fasting conditions. Throughout the exercise bout, blood flow to the biceps femoris, semitendinosus, and tibialis anterior muscles was lower in fed than in fasted animals (P less than 0.05). Combined hindlimb muscle blood flow averaged 15 ml.min-1.100 g-1 (18%, P less than 0.05) lower under feeding than fasting run conditions. These findings provide further evidence that cardiovascular reflexes originate in the gut after feeding to increase cardiac output and redistribute a portion of the blood flow away from active muscle to the gastrointestinal tract during prolonged exercise.

Animals↗
PubMed1989

Plateau in muscle blood flow during prolonged exercise in miniature swine.

Cardiovascular, metabolic, and thermoregulatory responses were studied in eight male miniature swine during a prolonged treadmill run. Each animal underwent 8-10 wk of exercise training, thoracic surgery, and 3 wk of retraining before the experimental run. This regimen enabled the animals to run at 65% of the heart rate range (210-220 beats/min) for approximately 100 min. Skin wetting and a fan were used to cool the pigs during the run. Regional blood flow was significantly altered with the onset of exercise; however, hindlimb muscle and total gastrointestinal blood flow were unchanged throughout the exercise period. Compared with 5-min values, heart rate and cardiac output were significantly elevated by 17 beats/min and 31 ml.min-1.kg-1 at 60 min and by 20 beats/min and 33 ml.min-1.kg-1 at end exercise, respectively. Core temperatures increased between 5 and 30 min of exercise (39.4 vs. 39.9 degrees C) but then remained unchanged to the end of exercise. Mean arterial pressure, O2 consumption, and blood lactate did not change during the exercise bout. These data indicate that limiting increases in core temperature during prolonged exercise was associated with a plateau in active muscle blood flow.

Animals↗
PubMed1989

Hyperemesis gravidarum and thyrotoxicosis--a diagnostic and therapeutic problem.

We report a case of hyperemesis gravidarum complicated by thyrotoxicosis which was managed conservatively during pregnancy. Problems of diagnosing mild thyrotoxicosis in pregnancy are discussed. Although no specific antithyroid therapy was given, the patient had an uneventful pregnancy after the first trimester. Neither she nor her baby exhibited any subsequent features of thyroid dysfunction. This suggests that treatment of thyrotoxicosis in early pregnancy is not always required because of the spontaneous improvement which is likely to occur as pregnancy progresses.

Female↗