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Biomedical subjects

G F Oster

Publications and source records attributed to G F Oster.

16 recordsLinked to original sources

What drives the translocation of proteins?

We propose that protein translocation across membranes is driven by biased random thermal motion. This "Brownian ratchet" mechanism depends on chemical asymmetries between the cis and trans sides of the membrane. Several mechanisms could contribute to rectifying the thermal motion of the protein, such as binding and dissociation of chaperonins to the translocating chain, chain coiling induced by pH and/or ionic gradients, glycosylation, and disulfide bond formation. This helps explain the robustness and promiscuity of these transport systems.

Biological Transport

Dynamics of single-motor molecules: the thermal ratchet model.

We present a model for single-motor molecules--myosin, dynein, or kinesin--that is powered either by thermal fluctuations or by conformational change. In the thermally driven model, the cross-bridge fluctuates about its equilibrium position against an elastic restoring force. The attachment and detachment of the cross-bridge are determined by modeling the electrostatic attraction between the cross-bridge and the fiber binding sites, so that binding depends on the strain in the cross-bridge and its velocity with respect to the fiber. The model correctly predicts the empirical force-velocity characteristics for populations of motor molecules. For a single motor, the apparent cross-bridge step size per ATP hydrolysis depends nonlinearly on the load. When the elastic energy driving the cross-bridge is generated by a conformational change, the velocity and duty cycle are much larger than is observed experimentally for myosin.

Actomyosin

Effect of ATP on actin filament stiffness.

Actin is an adenine nucleotide-binding protein and an ATPase. The bound adenine nucleotide stabilizes the protein against denaturation and the ATPase activity, although not required for actin polymerization, affects the kinetics of this assembly Here we provide evidence for another effect of adenine nucleotides. We find that actin filaments made from ATP-containing monomers, the ATPase activity of which hydrolyses ATP to ADP following polymerization, are stiff rods, whereas filaments prepared from ADP-monomers are flexible. ATP exchanges with ADP in such filaments and stiffens them. Because both kinds of actin filaments contain mainly ADP, we suggest the alignment of actin monomers in filaments that have bound and hydrolysed ATP traps them conformationally and stores elastic energy. This energy would be available for release by actin-binding proteins that transduce force or sever actin filaments. These data support earlier proposals that actin is not merely a passive cable, but has an active mechanochemical role in cell function.

Actins

Vesicle formation in the Golgi apparatus.

In this paper we examine the mechanics of vesicle budding from the Golgi apparatus. We propose a model for this process based on the notion that molecular surfactants can release the elastic energy stored in the lipid bilayer. The same physical process may drive other vesiculation processes, including coated vesicle formation and budding of enveloped viruses from the plasma membrane.

Golgi Apparatus

Pattern formation models and developmental constraints.

Most schemes for embryonic pattern formation are built around the notion of lateral inhibition. Models of this type arise in many settings, and all share some common characteristics. In this paper we examine a number of pattern formation models and show how the phenomenon of lateral inhibition constrains the possible geometries that can arise.

Animals

The physics of cell motility.

Cell locomotion begins with a protrusion from the leading periphery of the cell. What drives this extension? Here we present a model for the extension of cell protuberances that unifies certain aspects of this phenomenon, and is based on the hypothesis that osmotic pressure drives cell extensions. This pressure arises from membrane-associated reactions, which liberate osmotically active particles, and from the swelling of the actin network that underlies the membrane.

Acrosome

Nonlinear pattern selection in a mechanical model for morphogenesis.

We present a numerical study of the nonlinear mechanical model for morphogenesis proposed by Oster et al. (1983) with the aim of establishing the pattern forming capability of the model. We present a technique for mode selection based on linear analysis and show that, in many cases, it is a reliable predictor for nonlinear mode selection. In order to determine the set of model parameters that can generate a particular pattern we develop a technique based on nonlinear least square fitting to a dispersion relation. As an application we present a scenario for sequential pattern formation of dermal aggregations in chick embryos which leads to the hexagonal array of cell aggregations observed in feather germ formation in vivo.

Animals

Kinematics of gray crescent formation in Xenopus eggs: the displacement of subcortical cytoplasm relative to the egg surface.

Specification of the amphibian dorso-ventral axis takes place in the period between fertilization and first cleavage when the gray crescent forms. In the course of gray crescent formation, the egg reorganizes its periphery by a movement for which two descriptions have been given. According to the "rotation hypothesis," which was originated and supported for Rana eggs, the entire egg cortex rotates by an arc of 30 degrees relative to the stationary subcortical cytoplasm, leaving the crescent as a zone of altered coloration. The "contraction hypothesis" on the other hand, which was proposed for Xenopus and Rana eggs, asserts that there is a cortical contraction focused at the sperm entry point that leads to stretching of the opposite equatorial zone at which the crescent appears. We have reinvestigated the case of Xenopus eggs by imprinting one kind of fluorescent dye pattern (Nile blue) onto the subcortical cytoplasm and another kind (fluorescein-lectin) onto the egg surface. When the egg surface is held fixed by embedding the egg in gelatin, two major movements of the subcortical cytoplasm are observable. First, starting at time 0.3 (30% of the time between fertilization and first cleavage), the animal hemisphere subcortical cytoplasm converges toward a point, while the vegetal hemisphere is quiescent. This convergence continues with decreasing strength until approximately 0.8 of the first cell cycle. Second, at 0.45, an overall rotation of the animal and vegetal subcortical cytoplasm commences, superimposed on the animal hemisphere convergence. By 0.8-0.9 the rotation is complete, having accomplished a 30 degrees displacement of the subcortical cytoplasm relative to the surface. This rotation reliably locates the future dorsal midline of the embryo at the meridian on which the displacement of the subcortical cytoplasm is greatest in a vegetal direction. In normal unembedded eggs, when the egg surface is free to move, it rotates 30 degrees relative to the subcortical cytoplasm, which remains stationary in a position of gravitational equilibrium. Although both a convergence and rotation occur in the Xenopus egg, we give evidence that the rotation, not the convergence (perhaps equated with contraction), specifies the embryo's prospective axis. Even though the Xenopus egg does not form a classical gray crescent, due to its particular pigment distribution, the reorganization process which specifies the future embryonic axis resembles that of the Rana egg.

Animals

Neurulation and the cortical tractor model for epithelial folding.

We present here a new model for epithelial morphogenesis, which we call the 'cortical tractor model'. This model assumes that the motile activities of epithelial cells are similar to those of mesenchymal cells, with the added constraint that the cells in an epithelial sheet remain attached at their apical circumference. In particular, we assert that there is a time-averaged motion of cortical cytoplasm which flows from the basal and lateral surfaces to the apical region. This cortical flow carries with it membrane and adhesive structures that are inserted basally and resorbed apically. Thus the apical seal that characterizes epithelial sheets is a dynamic structure: it is continuously created by the cortical flow which piles up components near where they are recycled in the apical region. By use of mechanical analyses and computer simulations we demonstrate that the cortical tractor motion can reproduce a variety of epithelial motions, including columnarization (placode formation), invagination and rolling. It also provides a mechanism for driving active cell rearrangements within an epithelial sheet, while maintaining the integrity of the apical seal. Active repacking of epithelial cells appears to drive a number of morphogenetic processes. Neurulation in amphibians provides an example of a process in which all four of the above morphogenetic movements appear to play a role. Here we reexamine the process of neurulation in amphibians in light of the cortical tractor model, and find that it provides an integrated view of this important morphogenetic process.

Amphibians

A model for chondrogenic condensations in the developing limb: the role of extracellular matrix and cell tractions.

The hyaluronate component of the extracellular matrix is a powerfully hydrophilic polymer, capable of osmotically swelling and deswelling by a volume factor of 5 or more. At the time of cartilage condensation in the limb bud the chondrocytes start to produce hyaluronidase, an enzyme which degrades hyaluronate. The consequent deswelling brings the chondrocytes closer together - close enough for intercellular cell tractions to become effective and intercellular junctions to form. By analysing the physicochemical situation we show how these processes, principally the coupling of the osmotic deswelling with cellular traction forces, can produce cartilage condensation patterns resembling those in the early limb bud. In distinction from our earlier model for chondrogenic condensations this mechanism does not depend on cell motions other than convective transport by contraction.

Animals

Optimal strategies in immunology. II. B memory cell production.

After a first encounter with most antigens, the immune system responds to susequent encounters with a faster, more efficient and more strenuous antibody response. The memory of previous antigen contacts is carried by lymphocytes. Expanding on the model developed in Part 1 of this paper, we examine the optimal strategy available to the immune system for B memory cell production. We again find that the strategy should be of the bang-bang variety. The model we consider assumes that antigen triggers a subpopulation of B-lymphocytes. These triggered lymphocytes can proliferate and secrete modest amounts of antibody, or differentiate into non-dividing plasma cells which secrete large amounts of antibody, or differentiate into non-antibody secreting memory cells. Given injections of antigen at two widely spaced times we compute the strategy which minimizes a linear combination of the primary and secondary response times. We find that for all biologically reasonable parameter values the best strategies are ones in which memory cells are produced at the end of the primary response. Exerimental results which bear on the actual strategies employed are discussed.

Antibody Formation

Optimal strategies in immunology. I. B-cell differentiation and proliferation.

The optimal strategy available to the immune system for responding to a non-replicating thymus-independent antigen is examined. By applying Pontryagin's maximum principle to a set of mathematical models of lymphocyte populations and their antibody production, it is found that the optimal strategy of bang-bang control appears robust. In a variety of structurely related biological models, similar behaviour is observed. The models that we consider assume that antigen triggers a population of B-lymphocytes. These triggered lymphocytes can either proliferate and secrete modest amounts of antibody or differentiate into nondividing plasma cells which secrete large amounts of antibody. For biologically reasonable parameter values it is found that for low doses of antigen, immediate differentiation into plasma cells is optimal, while for high antigen doses a proliferative state followed by differentiation is the best strategy.

Antibody Formation