Negative growth effectors and cellular senescence.

Current studies suggest a genetic program governs the lifespan of each organism. Using cellular senescence as a model system, components of this program for aging have been sought. Human diploid fibroblasts, upon reaching senescence, express active inhibitors of DNA synthesis. It is believed that such inhibitors could be members of a new family of negative growth effectors involved in the pathway to senescence. Factors capable of inhibiting DNA synthesis in a similar manner have also been identified from human quiescent fibroblasts and liver cells as well as from quiescent rodent liver cells. The relationship of these inhibitors to previously identified negative growth effectors and aging are discussed.     

Regulation of cellular growth by sodium pump activity.

Cellular growth has been found to be directly related to the amount of sodium pumping activity in mouse lymphoblasts (L5178-Y) cultured in varying concentrations of the cardiac glycoside, ouabain. No short-term adaptation (within one generation) occured; i.e., neither growth rate nor (Na+ + K+)-ATPase activity increased in cells cultured for 1-2 days in ouabain. Growth inhibition commenced after two hours, occurring concomitantly with decreased 3H-leucine incorporation into protein. The time course of this inhibition of protein synthesis, measured by leucine incorporation was similar to, but slightly slower than the time course or the dissipation of the sodium gradient. On the other hand, 3H-thymidine incorporation is unaffected by ouabain treatment over the same period. The uptake of 3H-alanine, a neutral amino acid thought to be transported via a Na+-dependent carri-r, was depressed concurrently with the sodium gradient dissipation. It is suggested, therefore, that ouabain inhibition of cellular growth results primarily from the dissipation of the sodium gradient leading to decreased Na+-dependent transport of amino acids (e.g., alanine) and, therefore, decreased protein synthesis, as observed by leucine incorporation. A sensitive and rapid method for determining ouabain inhibition of cell volume regulation is also described, which may prove potentially useful for assaying Na pump activity.     

Calcium-dependent oxidation of thioredoxin during cellular growth initiation.

The fraction of cell thiol proteins in the oxidized disulfide form were quantified during mitogen-induced HaCaT keratinocyte growth initiation. Oxidized thioredoxin increased from 11 +/- 1.2% in resting cells to 80 and 61% 2 min after addition of bradykinin or EGF. Thioredoxin oxidation was transient returning toward normal values by 20 min. The disulfide forms of other cellular proteins rose in parallel with thioredoxin oxidation. The oxidation of thioredoxin depended on a rise in cytosolic calcium. It was prevented by preloading cells with BAPTA, a Ca(2+) chelator and induced by addition of Ca(2+)-ionophore A23187 or of thapsigargin. In cell extracts, thioredoxin reductase was inhibited by micromolar calcium. The rise in cytosolic Ca(2+) led to a concomitant burst of H(2)O(2) formation. The oxidizing intracellular milieu suggests that redox regulation actively participates in the growth initiation cascade. The role of peroxiredoxins and ASK 1 cascade activation are discussed in this context.     

Dynamics of learning-induced cellular modifications in the cortex

This aim of this review is to describe the dynamics of learning-induced cellular modifications in the rat piriform (olfactory) cortex after olfactory discrimination learning and to describe their functional significance to long-term memory consolidation. The first change to occur is in the intrinsic properties of the neurons. One day after learning, pyramidal neurons show enhanced neuronal excitability. This enhancement results from reduction in calcium-dependent conductance that mediates the post burst after-hyperpolarization. Such enhanced excitability lasts for 3 days and is followed by a series of synaptic modifications. Several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons in the piriform cortex accompany olfactory learning. Enhanced synaptic release is indicated by reduced paired-pulse facilitation. Post-synaptic enhancement of synaptic transmission is indicated by reduced rise time of post-synaptic potentials and formation of new synaptic connections is indicated by increased spine density along dendrites of these neurons. Such modifications last for up to 5 days. Thus, olfactory discrimination rule learning is accompanied by a series of cellular modifications which occur and then disappear at different times. These modifications overlap partially, allowing the maintenance of the cortical system in a ‘learning mode’ in which memories for specific odors can be acquired rapidly and efficiently.     

Dynamics of pore growth in membranes and membrane stability.

Pores can form and grow in biomembranes because of factors such as thermal fluctuation, transmembrane electrical potential, and cellular environment. We propose a new statistical physics model of the pore growth treated as a non-Markovian stochastic process, with a free energy barrier and memory friction from the membrane matrix treated as a quasi-two-dimensional viscoelastic and dielectric fluid continuum. On the basis of the modern theory of activated barrier crossing, an analytical expression for membrane lifetime and the phase diagram for membrane stability are obtained. The memory effect due to membrane viscoelasticity and the elasticity due to cytoskeletal network are found to induce sharp transitions to membrane stability against pore growth and compete with other factors to manifest rich dynamic transitions over the membrane lifetime.     

Dynamics and mechanisms of quantum dot nanoparticle cellular uptake

Background  

The rapid growth of the nanotechnology industry and the wide application of various nanomaterials have raised concerns over their impact on the environment and human health. Yet little is known about the mechanism of cellular uptake and cytotoxicity of nanoparticles. An array of nanomaterials has recently been introduced into cancer research promising for remarkable improvements in diagnosis and treatment of the disease. Among them, quantum dots (QDs) distinguish themselves in offering many intrinsic photophysical properties that are desirable for targeted imaging and drug delivery.     

Dynamics of a class of immune networks. II. Oscillatory activity of cellular and humoral components

Simulations show that for a certain range of its free parameters, a model of the immune network including both cellular and humoral components is capable of self-sustained oscillations. The model also possesses a number of fixed points which appear to be unstable. These results, taken together, suggest the hypothesis that the immune network may be able to sustain a non-degenerate diversity of active clones which are actively connected to each other only on condition that the activities of these clones are oscillatory.     

Dynamics of anaerobic growth of Saccharomyces cerevisiae in the chemostat.

A kinetic Monod model has been used to describe the dynamic response of a continuous stirred tank fermentor (CSTF) to changes in dilution rate. A general analytical solution of a linearized model was obtained. Experimental results (Vairo et al. 1977) of continuous anaerobic culture of Saccharomyces cerevisiae have verified the model quantitatively. For step disturbances on the dilution rate the responses of biomass concentration and the outlet substrate concentration were calculated on a digital computer and compared with the experimental data.     

Autophagy in cellular growth control

Cell growth is regulated by two antagonistic processes: TOR signaling and autophagy. These processes integrate signals including growth factors, amino acids, and energy status to ensure that cell growth is appropriate to environmental conditions. Autophagy responds indirectly to the cellular milieu as a downstream inhibitory target of TOR signaling and is also directly controlled by nutrient availability, cellular energy status, and cell stress. The control of cell growth by TOR signaling and autophagy are relevant to disease, as altered regulation of either pathway results in tumorigenesis. Here we give an overview of how TOR signaling and autophagy integrate nutritional status to regulate cell growth, how these pathways are coordinately regulated, and how dysfunction of this regulation might result in tumorigenesis.     

Dynamics of root growth in microgravity

An experiment to study the growth of garden cress roots in microgravity is described. The experiment, denoted RANDOM, was an ESA Biorack experiment in the IML-2 flight in July 1994. In the absence of gravity, it can be anticipated that the roots would show random growth, changing their direction randomly. The hypothesis that such random growth movements occur according to random walk theory, leads to predictions as to the detailed manner in which deviations increase with time. The experiment was designed to test this random walk hypothesis. The paper concentrates on the technological aspects of studying the roots in microgravity. The development of suitable plant chambers, fitting containers developed by ESA, is described as well as the techniques used to grow the seeds between agar slices. hardware was developed to record photographically root movements between the agar slices. Photos were taken once per hour. Some plant chambers were designed to allow fixation of plant material in space. The practical solutions found using glutaraldehyde for prefixation in the Spacelab, within the restrictions given, are described. The experimental results show that the growth pattern in fact followed the prediction from the random walk approach. The average changes in the growth direction stayed constant and equal to zero during the experiment while the squared angular deviations increased proportional to time. Furthermore, plant material prefixed in orbit was permanently fixed after the flight. Light microscopy and electron microscopy pictures are shown as examples of the results achieved. The long prefixation period meant a drawback for the quality of the fixation process. However, sections suitable for study were achieved. The main goals of the RANDOM experiment were therefore achieved.     

The cellular control of growth in cultures of Tetrahymena 2 In fluence of Fe medium and aeration on culture growth and cellular exchange of Ca.

Cultures of Tetrahymena pyriformis were grown exponentially with and without the addition of Fe and with no aeration. During the prestationary growth phase of all the cultures, there was a decrease in the cellular Fe concentration in the water insoluble cell fraction (IS) containing membranes and mitochondria, simultaneous with an increase in the Ca concentration in the water soluble cell fraction (S) containing ribosomes. This has been correlated to an energy deficit in the cells at the transition to the prestationary growth phase. In spite of the ability of Fe-deficient cultures to concentrate Fe, cultures grown in media with low Fe levels soon showed the lowest cellular Fe content. The high Fe levels seen in cultures grown with no aeration may reflect cellular adaptation to a different gaseous tension in the medium. Determinations with 45Ca showed an initial, large and rapid increase in cell radioactivity which was not correlated to cellular metabolism. After this there was differentiated increase due to the metabolic status of the cells. The following sequence was seen in all the cultures: (1) an increase in the exchange of S-and (mostly) IS-Ca at the end of the exponential growth phase, (2) an accumulation of Ca in the S fraction without an increased exchange (the IS-Ca is less exchangeable), and (3) a renewed increase in the exchange of Ca when the concentration is further increased at the end of the prestationary growth phase.     

Inhibition of growth and cellular aggregation of Dictyostelium discoideum by steroid compounds.

A study of the effects of steroid hormones on the development of Dictyostelium discoideum has shown that 4 × 10^?5M progesterone, and to a lesser extent dehydro-epiandrosterone, oestradiol and testosterone, inhibit both the growth and aggregation of these amoebae. Pregnenolone is active at lower concentrations (3 × 10^?6M), but at the level of growth only. Progesterone exerts its inhibitory action throughout the aggregation phase. The steroid prevents starved cells from becoming aggregation competent, and inhibits the aggregation of amoebae previously allowed to achieve the competent stage. However, unlike other agents such as dinitrophenol or EDTA, the steroid does not considerably affect cell morphology. Upon addition of progesterone cells become rounded, but after a brief lag they regain their ability to adhere to solid supports and form pseudopods. The fact that the steroids active on Dictyostelium are among the most liposoluble might indicate that their inhibitory action is dependent upon their incorporation into membrane lipids.     

Dynamics of Bacillus colony growth

A growing bacterial colony is not an amorphous mass but is a dynamic and differentiated system. It may appear chaotic in the details of its structure but it can be accurately described by simple models for fractal geometry. As Benoit Mandelbrot said: ‘Surprise, simple rules càn generate rich structures’.