A time contraction effect of acute tail-pinch stress on the associative learning of rats

The effect of tail-pinch stress interpolated between the saccharin conditioned stimulus (CS) and the illness-inducing unconditioned stimulus (US) during long-trace taste-aversion conditioning was examined in young- and old adult rats with a two-cylinder (saccharin versus water) test. A 2 x 2 x 4 factorial ANOVA was performed on percent-preference-for-saccharin data, with age (young, old), stress condition (stressed, non-stressed), and CS-US interval (22.5-, 45-, 90-, and 180-min) being the factors under consideration. The ANOVA yielded only significant main effects of stress condition and CS-US interval. These findings indicate that stress weakens the CS-US association as evidenced by a higher percent preference for saccharin in the stressed rats than in non-stressed rats at all CS-US intervals. A comparison of the stressed and non-stressed conditioned rats with pseudo-conditioned controls showed that the non-stressed rats formed strong aversions up to the 45-min CS-US interval whereas the stressed rats showed no conditioning beyond the 22.5 min CS-US interval, indicating that stress decreases the effective CS-US interval. Results were interpreted in terms of time-contraction and an internal biological countdown timer hypothesized to govern processes involved in associative learning over long delays.     

Postnatal development of heart rate patterns elicited by an aversive CS and US in cats

Heart rate and motor responses were recorded in cats of different ages during classical conditioning. A deceleratory-acceleratory heart rate pattern observed during the CS-US interval in one- and four-week-old kittens is an alpha conditioned response, a potentiated original response to the CS. At eight weeks of age two new distinct patterns of pure acceleration or pure deceleration are acquired during conditioning and in the absence of motor learning. At 12 weeks of age and in adult subjects, heart rate patterns during the CS-US interval become more complex and conditioned motor responses can be observed. A covariance of HR acceleration and motor responses during the CS-US interval is absent in eight-week-old subjects, but quite high in 12-week-old subjects and adult cats. The data are interpreted as suggesting separate elicitatory mechanisms of HR and motor responses which may show synchrony later in ontogeny.     

Regulation of mammalian cell growth by autocrine growth factors: analysis of consequences for inoculum cell density effects

Effects of inoculum cell density on mammalian cell growth in culture have been observed in a variety of experimental systems. Although these effects have been attributed generally to medium conditioning by the cells, there has previously been no quantitative theory proposed for this phenomenon based on developments in molecular and cell biology. In this article, we offer such a theory founded on the regulatory action of autocrine growth factors. A particularly relevant example of these is platelet- derived growth factor (PDGF), which is produced by fibroblastic cells in response to stimulation by transforming growth factor beta (TGFbeta), a common serum constituent, and provides a mitogenic signal for the same cells. A simple mathematical model for the production, diffusive transport, and binding of autocrine growth factors to cell surface receptors, coupled to a model for the dependence of cell proliferation on growth factor receptor binding allows prediction of initial cell population growth rate as a function of inoculum cell density. We focus on situations involving anchorage-dependent cell growth, in which the cells are attached to a surface. A number of clear results are obtained, most notably the following: 1) for cells cultured on spherical microcarrier bead surfaces, the inoculum cell density needed to produce a given growth rate is linearly proportional to the bead radius; and 2) all other factors being equal, the inoculum cell density on a unit surface area basis needed to produce a given growth rate is greater for spherical microcarrier surfaces than for flat culture dish surfaces. These two results are consistent with the experimental observations of Hu and coworkers(1,2) for fibroblast growth in minimal medium plus serum. The model also allows elucidation of the influence of other system parameters, both biological and physical, on initial cell proliferation rate and the inoculum cell density dependence.     

External inhibition in a goldfish (Carassius auratus) classical conditioning situation

Goldfish were classically conditioned with a light as the CS and shock as the US. The UR was a decrease in respiration. After 15 or 60 conditioning trials the fish were tested with novel stimuli (clicks) during the CS-US interval. High and moderate intensity novel stimuli produced a significant decrease in CRs (external inhibition) for fish with 60 conditioning trials (5.5 or 10.5 sec CS-US interval), but not fish with 15 conditioning trials. Low intensity novel stimuli produced no evidence for disinhibition (an increase in CRs). Control groups (e.g., groups with random presentations of the CS and US) showed that the external inhibition for fish with 60 conditioning trials was inhibition of a true CR.     

Critical Period of Memory Enhancement during Taste Avoidance Conditioning in Lymnaea stagnalis

The present study investigated the optimal training procedure leading to long-lasting taste avoidance behavior in Lymnaea. A training procedure comprising 5 repeated pairings of a conditional stimulus (CS, sucrose), with an unconditional stimulus (US, a tactile stimulation to the animal’s head), over a 4-day period resulted in an enhanced memory formation than 10 CS-US repeated pairings over a 2-day period or 20 CS-US repeated pairings on a single day. Backward conditioning (US-CS) pairings did not result in conditioning. Thus, this taste avoidance conditioning was CS-US pairing specific. Food avoidance behavior was not observed following training, however, if snails were immediately subjected to a cold-block (4°C for 10 min). It was critical that the cold-block be applied within 10 min to block long-term memory (LTM) formation. Further, exposure to the cold-block 180 min after training also blocked both STM and LTM formation. The effects of the cold-block on subsequent learning and memory formation were also examined. We found no long lasting effects of the cold-block on subsequent memory formation. If protein kinase C was activated before the conditioning paradigm, snails could still acquire STM despite exposure to the cold-block.     

A Mathematical Model for the Effects of HER2 Overexpression on Cell Proliferation in Breast Cancer

We present a mathematical model to study the effects of HER2 over-expression on cell proliferation in breast cancer. The model illustrates the proliferative behavior of cells as a function of HER2 and EGFR receptors numbers, and the growth factor EGF. This mathematical model comprises kinetic equations describing the cell surface binding of EGF growth factor to EGFR and HER2 receptors, coupled to a model for the dependence of cell proliferation rate on growth factor receptors binding. The simulation results from this model predict: (1) a growth advantage associated with excess HER2 receptors; (2) that HER2-over-expression is an insufficient parameter to predict the proliferation response of cancer cells to epidermal growth factors; and (3) the EGFR receptor expression level in HER2-over-expressing cells plays a key role in mediating the proliferation response to receptor-ligand signaling. This mathematical model also elucidates the interaction and roles of other model parameters in determining cell proliferation rate of HER2-over-expressing cells.     

A pitfall for the expectancy theory of human eyelid conditioning

Two simple eyeblink conditioning experiments with random intermittent reinforcement schedules were performed. In Experiment 1, subjects had to rate their expectancy for an unconditioned stimulus (US) on a seven-level scale prior to each trial. As anticipated, expectancy for US increased with a successive conditioned stimulus (CS) alone, and decreased with successive CS-US pairings. However, Experiments 1 and 2 showed that the frequency of eyeblink conditioned responses (CRs) evolved in a direction opposite to that of expectancy changes: CRs increased, whereas expectancy for US decreased, and vice versa. The possible effect of sensitization on eyeblink response was ruled out by the lack of a run effect in an unpaired control group in Experiment 2. These results tend to disconfirm the expectancy theory of conditioning. Although they were explicitly predicted by the conventional "strength" theory of conditioning, an alternative interpretation is proposed within a cognitive framework.     

Properties of olfactory conditioning in the housefly, Musca domestica

The housefly, Musca domestica, was conditioned to odours using the proboscis extension response to labellar stimulation with sucrose solution as an unconditioned response and the properties of conditioning were investigated. Among trials including forward pairing of the conditioned stimulus (CS) with the unconditioned stimulus (US), backward pairing and isolated presentations of CS and US, only forward pairing is effective on the acquisition of conditioning. Backward pairing combined with forward pairing does not influence the effectiveness of the forward pairing. CS given overlapping with a US presentation permits only weak conditioning. The acquisition of conditioning decreases with increase of the CS-US interval. In the differential conditioning situation to two odours, discriminative responses are observed. In the flies conditioned with one antenna, the conditioned response is elicited not only by stimulation of the antenna used for conditioning but also by stimulation of the antenna not used for conditioning, although the response using the former is higher than with the latter. The ability to be conditioned is reduced immediately after fastening on a clay bed and increases with time. Ability can also be improved by transection of the ventral nerve cord.     

The role of ependymin in the development of long lasting synaptic changes

1.) Three types of training experiments (a complex motor task, avoidance conditioning and classical conditioning) in the goldfish and one in the mouse (T-maze learning) indicate that the brain extracellular glycoprotein (ependymin) has a role in the consolidation process of long-term memory formation. 2.) Direct ELISA measures of the concentration of ependymin in the brain extracellular fluid (ECF) indicate that its level decreases after goldfish learn to associate a light stimulus (cs) with the subsequent arrival of a shock (US): paired CS-US gave changes whereas an unpaired presentation of CS-US gave no changes in comparison to unstimulated controls. 3.) Ependymin is released into ECF and CSF as mixtures of three types of disulfide-linked dimers of two acidic polypeptide chains (M. W. 37 kDa and 31 kDa). It contains 10% carbohydrate as an N-linked glycan. 4.) Ependymin has the capacity to polymerize in response to events that deplete Ca2+ from the brain extracellular environment. A molecular hypothesis relating polymerization properties to the process of formation of long-lasting synaptic changes is proposed. 5.) Investigations of the pattern of regeneration of goldfish optic nerve and the mechanisms of long-term potentiation (LTP) of rat brain hippocampal slices suggest that ependymin has a role in the formation of long-lasting synaptic changes. The E.M. data show that polymerized products which stain with anti-ependymin sera accumulate at synapses and in new spines after LTP.     

Packet theory of conditioning and timing

Packet theory is based on the assumption that the momentary probability of producing a bout or packet of responding is controlled by the conditional expected time function. Bouts of head entry responses of rats into a food cup appear to have the same characteristics across a range of conditions. The conditional expected time function is the mean expected time remaining until the next food delivery as a function of time since an event such as food or stimulus onset. The conditional expected time function encodes mean interval duration as well as the distribution form so that both the mean response rate and form of responding in time can be predicted. Simulations of Packet theory produced accurate quantitative predictions of: (1) the effect of reinforcement density (mean food-food interval) and distribution form on responding; (2) scalar variance in fixed interval responding; (3) CS-US and intertrial interval effects on the strength of conditioning; and (4) the effect of the ratio of cycle:trial time on the strength of conditioning.     

Hippocampal place cells acquire location-specific responses to the conditioned stimulus during auditory fear conditioning

We recorded neurons from the hippocampus of freely behaving rats during an auditory fear conditioning task. Rats received either paired or unpaired presentations of an auditory conditioned stimulus (CS) and an electric shock unconditioned stimulus (US). Hippocampal neurons (place and theta cells) acquired responses to the auditory CS in the paired but not in the unpaired group. After CS-US pairing, rhythmic firing of theta cells became synchronized to the onset of the CS. Conditioned responses of place cells were gated by their location-specific firing, so that after CS-US pairing, place cells responded to the CS only when the rat was within the cell's place field. These findings may help to elucidate how the hippocampus contributes to context-specific memory formation during associative learning.     

A mathematical model of in vitro cancer cell growth and treatment with the antimitotic agent curacin A

A mathematical model of cancer cell growth and response to treatment with the experimental antimitotic agent curacin A is presented. Rate parameters for the untreated growth of MCF-7/LY2 breast cancer and A2780 ovarian cell lines are determined from in vitro growth studies. Subsequent growth studies following treatments with 2.5, 25 and 50 nanomolar (nM), concentrations of curacin A are used to determine effects on the cell cycle and cell viability. The model's system of ordinary differential equations yields an approximate analytical solution which predicts the minimum concentration necessary to prevent growth. The model shows that cell growth is arrested when the apoptotic rate is greater than the mitotic rate and that the S-phase transition rate acts to amplify this effect. Analysis of the data suggests that curacin A is rapidly absorbed into both cell lines causing an increase in the S-phase transition and a decrease in the M-phase transition. The model also indicates that the rate of apoptosis remains virtually constant for MCF-7/LY2 while that of A2780 increases 38% at 2.5 nM and 59% at 50 nM as compared to the untreated apoptotic rate.     

Study and mathematical modeling of the production of propionic acid by Propionibacterium acidipropionici immobilized in a stirred tank fermentor

A mathematical model was developed that describes production of propionic acid by fermentation of sweet whey with Propionibacterium acidipropionici immobilized in calcium polygalacturonate beads in a fermentor-type stirred tank. This mathematical model is constituted by a partial differential equations system, which fits consumption, production, growth and internal diffusion rates in the support. Fermentation was experimentally studied with free cells and immobilized cells, effective diffusivities of lactose and propionic acid were estimated in the support, and typical parameters of the model were obtained by nonlinear regression of the experimental data. The variance analysis shows that the combination of micro(max) and K(d) parameters is the source of variation most significative, also they were found to be the most sensitive parameters of the model. Finally, an effectiveness factor was calculated in order to assess the effect of mass transfer on the overall reaction rate observed.     

Pavlovian conditioning: pigeon nictitating membrane

A new Pavlovian conditioning preparation was developed using the nictitating membrane of the restrained pigeon. Either visual or auditory stimuli served as conditioned stimuli (CSs) with an unconditioned stimulus (US) of a puff of air to the cornea. Movement of the nictitating membrane constituted the conditioned and unconditioned responses (CR and UR). Conditioning was studied with the Kamin blocking procedure. In agreement with findings from other conditioning preparations, responding to the redundant stimulus was attenuated relative to a stimulus that received the same number of CS-US pairings in a compound-conditioning procedure. Although response attenuation occurred, substantial individual variation was observed within the blocking procedure, a finding with some precedent in the experimental literature. Theoretical analysis and neural-network simulations indicate that inter-subject variation in response attenuation may result from differences in the extent to which contextual stimuli contribute to the functional CS.     

Modelling the effect of temperature, water activity and pH on the growth of Serpula lacrymans

Aims: To predict the risk factors for building infestation by Serpula lacrymans, which is one of the most destructive fungi causing timber decay in buildings. Methods and Results: The growth rate was assessed on malt extract agar media at temperatures between 1·5 and 45°C, at water activity (a_w) over the range of 0·800–0·993 and at pH ranges from 1·5 to 11·0. The radial growth rate (μ) and the lag phase (λ) were estimated from the radial growth kinetics via the plots radius vs time. These parameters were then modelled as a function of the environmental factors tested. Models derived from the cardinal model (CM) were used to fit the experimental data and allowed an estimation of the optimal and limit values for fungal growth. Optimal growth rate occurred at 20°C, at high a_w level (0·993) and at a pH range between 4·0 and 6·0. The strain effect on the temperature parameters was further evaluated using 14 strains of S. lacrymans. The robustness of the temperature model was validated on data sets measured in two different wood‐based media (Quercus robur L. and Picea abies). Conclusions: The two‐step procedure of exponential model with latency followed by the CM with inflection gives reliable predictions for the growth conditions of a filamentous fungus in our study. The procedure was validated for the study of abiotic factors on the growth rate of S. lacrymans. Significance and Impact of the Study: This work describes the usefulness of evaluating the effect of physico‐chemical factors on fungal growth in predictive building mycology. Consequently, the developed mathematical models for predicting fungal growth on a macroscopic scale can be used as a tool for risk assessment of timber decay in buildings.     

Testing a model for the dynamics of actin structures with biological parameter values

A simple mathematical model for the dynamics of network-bundle transitions in actin filaments has been previously proposed and some of its mathematical properties have been described. Other models in this class have since been considered and investigated mathematically. In this paper, we have made the first steps in connecting parameters in the model with biologically measurable quantities such as published values of rate constants for filament-crosslinker association. We describe how this connection was made, and give some preliminary numerical simulation results for the behavior of the model under biologically realistic parameter regimes. A key result is that filament length influences the bundle-network transition.     

Evaluation of two unstructured mathematical models for the penicillin G fedbatch fermentation

The mathematical model for the penicillin G fed-batch fermentation proposed by Heijnen et al. (1979) is compared with the model of Bajpai & Reuß (1980). Although the general structure of these models is similar, the difference in metabolic assumptions and specific growth and production kinetics results in a completely different behaviour towards product optimization. A detailed analysis of both models reveals some physical and biochemical shortcomings. It is shown that it is impossible to make a reliable estimation of the model parameters, only using experimental data of simple constant glucose feed rate fermentations with low initial substrate amount. However, it is demonstrated that some model parameters might be key factors in concluding whether or not altering the substrate feeding strategy has an important influence on the final amount of product.It is illustrated that feeding strategy optimization studies can be a tool in designing experiments for parameter estimation purposes.     

Model of Growth Cone Membrane Polarization via Microtubule Length Regulation

We present a mathematical model of membrane polarization in growth cones. We proceed by coupling an active transport model of cytosolic proteins along a two-dimensional microtubule (MT) network with a modified Dogterom-Leibler model of MT growth. In particular, we consider a Rac1-stathmin-MT pathway in which the growth and catastrophe rates of MTs are regulated by cytosolic stathmin, while the stathmin is regulated by Rac1 at the membrane. We use regular perturbation theory and numerical simulations to determine the steady-state stathmin concentration, the mean MT length distribution, and the resulting distribution of membrane-bound proteins. We thus show how a nonuniform Rac1 distribution on the membrane generates a polarized distribution of membrane proteins. The mean MT length distribution and hence the degree of membrane polarization are sensitive to the precise form of the Rac1 distribution and parameters such as the catastrophe-promoting constant and tubulin association rate. This is a consequence of the fact that the lateral diffusion of stathmin tends to weaken the effects of Rac1 on the distribution of mean MT lengths.