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C J Lumsden

Publications and source records attributed to C J Lumsden.

At least 19 recordsLinked to original sources
PubMed1996

How profilin/barbed-end synergy controls actin polymerization: a kinetic model of the ATP hydrolysis circuit.

The role of ATP hydrolysis in the regulation of the actin cytoskeleton continues to be a subject of controversy. Since actin polymerization can occur in the absence of ATP, the energy of hydrolysis is not needed for filament assembly. Recent work has instead suggested a regulatory role for ATP in cytoskeletal remodeling. In particular, both profilin and free filament barbed ends have been shown to play major roles in the processing of ATP by actin. We have developed a new integrated kinetic model to examine how the maintenance of the pool of unpolymerized actin and the flux of actin subunits through filaments are controlled by profilin and free filament barbed ends through their interaction with ATP. An analysis of the model's steady states predicts how two novel regulatory pathways may regulate the cytoskeleton in vivo. Coordinated changes in the availability of both profilin and free barbed ends mediate the following regulatory effects: (1) both the nucleotide composition and the absolute amount of free G-actin can be changed separately or together to substantially alter the total amount of F-actin; and (2) uncapping the barbed ends of only a modest fraction of filaments causes all filaments to begin slowly depolymerizing from their pointed ends, resulting in the total depolymerization of the remaining capped filaments. We report that the phenomenon of treadmilling, wherein the barbed end growth of each filament is exactly balanced by pointed end loss at steady state, is only possible in the limiting case when all barbed ends are uncapped. The capping of any fraction of barbed ends increases the critical concentration of ATP-G-actin, causing the remaining free barbed ends to grow faster than their pointed ends can shrink. On the basis of these findings we propose a major revision to the treadmilling model for actin-based motility, in which the rapidly growing filaments with free barbed ends are continuously severed toward their rear followed by capping of the newly exposed barbed ends. This revised model, herein referred to as "treadsevering," allows sustained and rapid barbed end growth to occur indefinitely at a steady state provided a continuous input of ATP.

Actins↗
PubMed1994

Fractal analysis of renal cortical perfusion.

RATIONALE AND OBJECTIVES: Contrast-enhanced computed tomography (CT) images of canine renal cortex were analyzed to determine if the heterogeneous pixel intensity patterns met the requirements for fractal analysis and if the heterogeneity could be quantified by a fractal dimension, Df. METHODS: Contrast-enhanced CT images were obtained after injection of iodipamide ethyl ester (IDE), a vascular marker, or iohexol, a freely filtered interstitial marker, into the catheterized renal artery of an anesthetized dog. Images were mounted on a graphics workstation for analysis. A computer program was written to determine the fractal dimension of the pixel-intensity pattern within selected regions. RESULTS: All regions of renal cortex examined met the requirements for fractal analysis. Three seconds after injection of IDE, the mean fractal dimension decreased significantly from 1.21 +/- 0.05 to 1.12 +/- 0.06 (P < .05). Although the mean fractal dimensions were not significantly different, the variation in the fractal dimension around the renal cortex was significantly different with IDE as compared with iohexol at 3 seconds (P < .05). Differences in the change in fractal dimension over time were also observed with IDE as compared with iohexol. CONCLUSIONS: Fractal dimension measurement provides a new means to examine the in-vivo organization of renal vascular perfusion by quantifying pixel heterogeneity in contrast-enhanced CT. This may prove useful in understanding and quantifying the pathophysiologic changes in renal disease.

Animals↗
PubMed1993

Epithelial cell detachment in the nephrotic glomerulus: a receptor co-operativity model.

Detachment of epithelial cells from the glomerular capillary wall correlates with the massive increase in protein leakage across the capillary wall that is characteristic of many renal diseases. We introduce the hypothesis that this detachment process involves three classes of physical events acting at the subcellular level: the receptor-mediated binding of epithelial cells to basement membrane, the transglomerular hydraulic pressure gradient acting to lift the cells off the basement membrane, and a receptor-receptor co-operativity induced by mechanical deformations of the epithelial cell surface. After presenting the available evidence, we explore the hypothesis by means of a simplified, quantitative model of the detachment process. The model is developed by mapping between the stochastic events of cell adhesion receptor binding and the equilibrium statistical mechanics of the Ising model. Monte Carlo simulations predict cell attachment under normal conditions, as expected from experimental data, and detachment at lower receptor binding affinity and/or increased pressure gradient. The normal attached state in the model is found to be particularly sensitive to changes in the receptor-binding affinity. The amount of resistance the cell surface offers to deformation forces is a key determinant of whether the detachment of small clusters of receptors spreads to involve large areas of the plasma membrane, precipitating bulk detachment.

Cell Adhesion↗
PubMed1993

Cellular automaton model of the actin cytoskeleton.

We describe a cellular automaton model of the actin cytoskeleton. The model incorporates spatial and temporal behavior at the macromolecular level and is relevant to the viscous nonequilibrium conditions suspected to occur in vivo. The model includes cation and nucleotide binding to actin monomers, actin nucleation and polymerization into filaments, cross-linking with alpha-actinin, monomer sequestration with profilin, filament severing, capping and nucleation with gelsolin, binding of profilin and gelsolin to membrane-bound phosphatidylinositide biphosphate (PIP2), and regulation of cross-linking and severing by changing calcium levels. We derive 1) equations for the molecular translation and rotation probabilities required for the cellular automaton simulation in terms of molecular size, shape, cytoplasmic viscosity, and temperature; and 2) equations for the binding probabilities of adjacent molecules in terms of experimentally determined reaction rate constants. The model accurately captures the known characteristics of actin polymerization and subsequent ATP hydrolysis under different cation and nucleotide conditions. An examination of gelation and sol-gel transitions resulting from calcium regulation of alpha-actinin and gelsolin predicts an inhomogeneous distribution of bound alpha-actinin and F-actin. The double-bound alpha-actinin (both ends bound to F-actin) is tightly bunched, while single-bound alpha-actinin is moderately bunched and unbound alpha-actinin is homogeneously distributed. The spatial organization of the alpha-actinin is quantified using estimates of fractal dimension. The simulation results also suggest that actin/alpha-actinin gels may shift from an isotropic to an amorphous phase after shortening of filaments. The gel-sol transition of the model shows excellent agreement with the present theory of polymer gels. The close correspondence of the model's predictions with previous experimental and theoretical results suggests that the model may be pertinent to better understanding the spatial and temporal properties of complex cytoskeletal processes.

Actinin↗
PubMed1993

High microfilament concentration results in barbed-end ADP caps.

Current theory and experiments describing actin polymerization suggest that site-specific cleavage of bound nucleotide following F-actin filament formation causes the barbed ends of microfilaments to be capped first with ATP subunits, then with ADP bound to inorganic phosphate (ADP.Pi) at steady-state. The barbed ends of depolymerizing filaments consist of ADP subunits. The decrease in stability of the barbed-end cap accompanying the transition from ADP.Pi to ADP allows nucleotide hydrolysis and subsequent loss of Pi to regulate F-actin filament dynamics. We describe a novel computational model of nucleotide capping that simulates both the spatial and temporal properties of actin polymerization. This model has been used to test the effects of high filament concentration on the behavior of the ATP hydrolysis cycle observed during polymerization. The model predicts that under conditions of high microfilament concentration an ADP cap can appear during steady-state at the barbed ends of filaments. We show that the presence of the cap can be accounted for by a kinetic model and predict the relationship between the nucleotide concentration ratio [ATP]/[ADP], the F-actin filament concentration, and the steady-state distribution of barbed-end ADP cap lengths. The possible consequences of this previously unreported phenomenon as a regulator of cytoskeletal behavior are discussed.

Actin Cytoskeleton↗
PubMed1993

Explaining glomerular pores with fiber matrices. A visualization study based on computer modeling.

The extracellular space of the glomerular capillary wall is occupied by a complex meshwork of fibrous molecules. Little is understood about how the size, shape, and charge recognition properties of glomerular ultrafiltration arise from this space-filling fiber matrix. We studied the problem of size recognition by visualizing the void volume accessible to hard spheres in computer-generated three-dimensional homogeneous random fiber matrices. The spatial organization of the void volume followed a complex "blob-and-throat" pattern in which circumscribed cavities of free space within the matrix ("blobs") were joined to adjacent cavities by narrower throats of void space. For sufficiently small solutes, chains of blobs and throats traversed the matrix, providing pathways for trans-matrix permeation. The matrices showed threshold or gating properties with respect to permeation: solutes whose radius exceeded a critical value, at which a throat on the last connected trans-matrix pathway pinched off, could not cross, whereas smaller solutes had nonzero permeability. The thresholds may give the glomerular fiber matrix porelike response properties and explain why pore models have been such a useful means of treating permselectivity.

Capillaries↗
PubMed1993

Vascular exchange in the kidney. Regional characterization by multiple indicator tomography.

In previous work with the method of multiple indicator dilution (MID), we have established that a spatially distributed model of transcapillary exchange proposed by Goresky, Ziegler, and Bach (GZB) accurately describes, at the in vivo whole-organ level, the handling of extracellular indicators in the canine renal cortex. To date, however, it has not been possible to assess the key hypothesis that GZB corresponds to the actual local mechanism of exchange in vivo and is not just a compact summary of the kidney's average whole-organ behavior. By adapting the MID method to high speed computed tomography (CT), we are now able to report that the GZB mechanism is an accurate description of renal cortical transcapillary exchange down to volumes of cortical tissue comprising no more than a few per cent of the total cortical mass, i.e., containing no more than a few thousand nephrons. A small bolus of iohexol (radiopaque extracellular indicator) or iodipamide ethyl ester microparticles (radiopaque plasma indicator) injected into the renal artery was followed by CT as it passed through the kidney and into the renal vein. Time-attenuation value curves of the two contrast media obtained from the renal vein and from regions of interest in the cortex were then modeled with the GZB mechanism and with a more complex formulation that includes GZB as a limiting case. When applied to the data, the models converged to GZB as the best fit for each region examined. The GZB mechanism is found to provide excellent agreement with the regional data.

Animals↗
PubMed1993

Demonstration of renal tubular flow by selective angiographic computed tomography.

A high-speed computed tomography scanner was used to study the bulk flow of a small bolus of nonionic contrast medium through the renal tubules of five dogs. A 0.5-mL bolus of iohexol 300 (150 mg iodine) was injected rapidly into the renal artery, and transverse images of the kidney were obtained at 15-second intervals over 300 seconds. The mean attenuation values measured in regions of interest in the papilla and the cortex were displayed as a function of time. Curves from the papillary regions of interest showed two peaks, the first corresponding to the passage of the bolus through the loops of Henle that extend into the papilla and the second to the passage of the bolus through the terminal collecting tubules. The cortical regions of interest showed the cortical return peak, which corresponded to the passage of the bolus through the distal convoluted tubules. The peaks generated by this method can be used to measure the transit times of the bolus from the glomeruli to the loops of Henle in the papilla, from the loops of Henle to the distal convoluted tubules, and from the distal convoluted tubules to the distal collecting tubules. The mean total transit time in dehydrated dogs was 169 seconds. The method is compared with contrast-enhanced magnetic resonance imaging (with gadolinium diethylenetriaminepentaacetic acid), which has been used by other researchers for the same purpose.

Animals↗
PubMed1991

A new computer-assisted three-dimensional reconstruction method provides accurate measurement of glomerular mesangial volume.

Many glomerulopathies are characterized by progressive mesangial (interstitial) expansion which can be quantitated by morphometric analysis. The purpose of this study was to analyze mesangial and glomerular volumes using a new computer-assisted reconstruction (CAR) method. CAR was compared to two standard planar methods, point-counting and linear integration, for accuracy and time efficiency. In Phase I of the study, a computer-based model of the mesangial space was created by placing spherical and ellipsoidal objects of known volume into an enclosing volume mimicking the glomerulus. The simulated mesangium occupied approximately 10 percent of the glomerular volume. The model glomerulus was sectioned serially into ten sections of equal thickness and the three morphometric methods applied to determine the mesangial/glomerular volume. The complexity of the mesangial model was varied by increasing the number of mesangial regions from one to ten to 100. The CAR method estimated the model mesangial volume more accurately (1-9 percent error) through each level of complexity compared to point-counting (3-17 percent error) and linear integration (3-18 percent error). The point-counting method consistently overestimated (P less than 0.05) the fractional mesangial volume for the ten- and 100-region mesangium models. In Phase II of the study, a normal rat glomerulus was sectioned serially (215 sections) and a transmission electron micrograph (TEM) of every fifth section (n = 43) was obtained. Each TEM image (2% of glomerular surface) was digitized for analysis by CAR. Point-counting and linear integration were also performed on the whole glomerular TEMs (n = 10, randomly chosen). The estimated relative mesangial/glomerular volume was 6.6 +/- 0.1 percent by CAR (mean +/- SD), 9.7 +/- 1.5 by linear integration, and 14.9 +/- 3.4 by point-counting. The point-counting method was most efficient, requiring 40 +/- 8 sec/section, followed by CAR at 85 +/- 24 sec/section. Linear integration was least efficient (93 +/- 23 sec/section). We conclude that CAR is the most accurate morphometric method of the three compared for estimating mesangial and glomerular methods, although it is more time consuming than the point-counting method and requires more complex instrumentation. CAR is the only method that will analyze the shape and three-dimensional complexity of glomerular structures using TEMs.

Animals↗
PubMed1991

Color categorization and color constancy in a neural network model of V4.

We develop a neural network model that instantiates color constancy and color categorization in a single unified framework. Previous models achieve similar effects but ignore important biological constraints. Color constancy in this model is achieved by a new application of the double opponent cells found in the "blobs" of the visual cortex. Color categorization emerges naturally, as a consequence of processing chromatic stimuli as vectors in a four-dimensional color space. A computer simulation of this model is subjected to the classic psychophysical tests that first uncovered these phenomena, and its response matches psychophysical results very closely.

Animals↗
PubMed1989

Behavioral evolution and biocultural games: vertical cultural transmission.

We consider an evolutionary game model in which strategies are transmitted culturally from parents to offspring rather than inherited biologically. Our analysis yields two noteworthy results. First, biocultural games show a greater diversity of dynamical behaviors than their purely biological counterparts, including multiple fully polymorphic equilibria. Second, biocultural games on average exhibit greater equilibrium strategy diversity because of the countervailing influences of cultural transmission and natural selection. Therefore, knowledge of a strategy's influence on Darwinian fitness is not sufficient to infer the evolutionary consequences of biocultural games. Further, our results suggest that cultural transmission in the presence of natural selection may be an important mechanism maintaining behavioral diversity in natural populations.

Animals↗
PubMed1989

In vivo indicator dilution kinetics of PAH transport in dog kidney.

In vivo multiple indicator-dilution (MID) data were analyzed using a computer-assisted mathematical model of transepithelial cell transport to determine p-aminohippuric acid (PAH) transport kinetics across the proximal tubular antiluminal (ALM) and luminal (LM) membranes. A bolus of 125I-labeled albumin (plasma reference), [14C]creatinine (interstitial reference), and tracer [3H]PAH was injected into the left renal artery of anesthetized mongrel dogs (n = 21), and immediate serial sampling of the left renal venous and left and right urine outputs was performed (control). MID runs were then repeated in the same dog following intravenous infusion of unlabeled PAH. For all plasma PAH concentrations ([PAH]P), the steady-state unidirectional flux coefficients were calculated at the ALM and LM. The computer-derived unidirectional flux coefficients were in keeping with active ALM transport and passive, carrier-mediated LM transport. The Km calculated for ALM uptake (interstitium to cell) was 0.51 mM. PAH transport was completely inhibited by probenecid. As [PAH]P increased, the renal vein mean transit time ratio t[3H]PAH/t[14C]creatinine was greater than 1.0, indicating backflux from cells into the interstitium, then declined toward unity, as ALM and LM transport became saturated. This study, which used PAH as a model substrate demonstrated the feasibility of utilizing computer-assisted mathematical models to quantitate the kinetics of transepithelial transport from in vivo experimentation.

Animals↗
PubMed1989

Transglomerular cationic macromolecular flux is mediated by a convection-binding mechanism.

Glomerular polyanion function was explored using charged and neutral [3H]dextrans in the multiple indicator-dilution experiment. Anesthetized dogs received an intrarenal bolus of 125I-labeled albumin (plasma reference), [14C]inulin (glomerular reference) and [3H]dextran (test solute), followed by rapid serial sampling of the renal venous and urine outflows. Reduced urinary recovery of cationic diethylaminoethyl dextrans (DEAE) [3H]dextrans [19.0- to 31.5-A Stokes-Einstein radius (SER)], compared with neutral [3H]dextran indicated intrarenal binding reversed by excess unlabeled cationic dextran. Tubular microperfusion with cationic [3H]dextran confirmed a pretubular binding site (presumed glomerular). The application of a computer-assisted mathematical model of convective flux plus reversible binding revealed that binding affinity increased with molecular size. In vitro high-affinity binding of the same cationic [3H]dextrans to isolated rat glomeruli was also found to increase with molecular size and was inhibited by protamine sulfate. Intrarenal polycation perfusion with protamine sulfate (1.0-3.8 mg/g kidney) or lysozyme (1.1-2.2 mg/g body wt) resulted in intraglomerular binding of anionic [3H]dextran without increased proteinuria or altered glomerular permselectivity to neutral [3H]dextrans less than or equal to 33.0-A SER. Hence, transglomerular cationic solute flux is mediated by a convection-binding mechanism that creates an effective polyvalent barrier.

Animals↗
PubMed1988

Gene-culture coevolution: a test of the steady-state hypothesis for gene-culture translation.

Although there has been considerable discussion of the gene-culture theory (GCT) approach to biocultural systems, relatively little critical attention has focused on the specific approximations used in GCT, or on their improvement. Here we consider the steady-state hypothesis used in GCT models to connect activity on the level of individual choice behavior to the level of societies taken as wholes. The hypothesis is tested by using Monte Carlo techniques to estimate solutions to the dynamical equation for social order. The steady-state hypothesis is found generally to be invalid for all the categories of choice function originally considered by Lumsden and Wilson, but acceptable for the highly restricted parameter ranges used in their treatments of the gene-frequency change. The implications for the development of improved gene-culture modeling techniques are discussed.

Computer Simulation↗
PubMed1988

In vivo characterization of insulin uptake by dog renal cortical epithelium.

In vivo 125I-labeled insulin uptake by dog renal tubular epithelium was studied using the single-pass multiple indicator dilution (MID) method and analyzed by a computer-assisted model of transcapillary exchange and substrate-cell interaction. Anesthetized dogs received an intrarenal arterial bolus of multiple tracers: [3H]dextran greater than 70 kDa (plasma reference), [14C]inulin (extracellular reference), and 125I-insulin. Rapid serial sampling of the renal venous and urine outflows was performed. The renal venous outflow curves of 125I-insulin fell below [14C]inulin implying postglomerular extraction and antiluminal membrane (ALM) uptake. The fractional urine recovery of 125I-insulin was less than 0.03, indicating luminal tubular uptake of filtered hormone. After intravenous infusion of unlabeled insulin, repeat MID runs with tracer revealed saturable ALM uptake as evidenced by the 125I-insulin renal venous outflow curves approaching [14C]inulin. Luminal tubular uptake was unchanged and therefore unsaturable. The 125I-insulin renal venous data were studied using three mathematical models, incorporating postglomerular reversible binding, irreversible binding or transport. The best fit was obtained using the transport model. The modeling analysis is consistent with either uptake into a virtual epithelial membrane space (i.e., insulin never enters the cell but binds to or is distributed along the ALM) or insulin actually enters the intracellular compartment. In vivo uptake of 125I-insulin ALM is characterized by a Km of 15.44 nM.

Animals↗
PubMed1986

Gene-culture coevolution of complex social behavior: human altruism and mate choice.

The hypothesis is examined that genes bias the development of complex social behavior in one direction over alternatives. Studies of altruism and political attitudes in twins estimate that approximately 50% of the variance is associated with direct genetic inheritance, virtually 0% with the twin's common family environment, and the remainder with each twin's specific environment. Studies of human marriages show that spouses choose each other on the basis of similarity, assorting on the most genetically influenced of a set of homogeneous attributes. These data imply a genetic canalization of social influences such that, within the constraints allowed by the total spectrum of cultural alternatives, people create environments maximally compatible with their genotypes.

Altruism↗