[N,N′-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties

We developed N,N′-bis(salicylidene)-1,2-phenylenediamine (salophene, 1) as a chelating agent for metal ions such as Mn(II/III), Fe(II/III), Co(II), Ni(II), Cu(II), and Zn(II). The resulting complexes, from which owing to the carrier ligand a selective mode of action is assumed, were tested for antiproliferative effects on the MCF-7 breast cancer cell line. The cytotoxicity in this assay depended on the nature of the transition metal used. Iron complexes in oxidation states +II and +III (3, 4) strongly reduced cell proliferation in a concentration-dependent manner, whereas, e.g., the manganese analogues 5 and 6 were only marginally active. Therefore, the [N,N′-bis(salicylidene)-1,2-phenylenediamine]iron(II/III) complexes 3 and 4 were selected for studies on the mode of action. Both complexes possessed high activity against various tumor cells, for instance, MDA-MB-231 mammary carcinoma cells as well as HT-29 colon carcinoma cells. They were able to generate reactive oxygen species, showed DNA binding, and induced apoptosis. Exchange of 1 by N,N′-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) yielding complexes 7 and 8 reduced the in vitro effects drastically. An unequivocal mode of action cannot be deduced from these results, but it seems to be very likely that cell death is caused by interference with more than one intracellular target. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Dynamics of the ‘echo’ effect in a phytoplankton system with nitrogen fixation

Consideration of nitrogen fixation adds a positive nonlinear feedback to plankton ecosystem models. We investigate the consequences of this feedback for secondary phytoplankton blooms and the response of phytoplankton dynamics to physical forcing. The dynamics of phytoplankton, Trichodesmium (the nitrogen fixer), and nutrients is modeled with a system of three differential equations. The model includes two types of nonlinear interactions: the competition of phytoplankton and Trichodesmium for light, and the positive feedback resulting from Trichodesmium recycling. A typical simulation of the model in time, with forcing by a varying mixed-layer depth, reveals a clear successional sequence including a secondary or ‘echo’ bloom of the phytoplankton. We explain this sequence of events through the stability analysis of three different steady states of the model. Our analysis shows the existence of a critical biological parameter, the ratio of normalized growth rates, determining the occurrence of ‘echo’ blooms and the specific sequence of events following a physical perturbation. The interplay of positive and negative feedbacks appears essential to the timing and the type of events following such a perturbation.     

Analysis of chemotactic bacterial distributions in population migration assays using a mathematical model applicable to steep or shallow attractant gradients

The mathematical model developed by Riveroet al. (1989,Chem. Engng Sci. 44, 2881–2897) is applied to literature data measuring chemotactic bacterial population distributions in response to steep as well as shallow attractant gradients. This model is based on a fundamental picture of the sensing and response mechanisms of individual bacterial cells, and thus relates individual cell properties such as swimming speed and tumbling frequency to population parameters such as the random motility coefficient and the chemotactic sensitivity coefficient. Numerical solution of the model equations generates predicted bacterial density and attractant concentration profiles for any given experimental assay. We have previously validated the mathematical model from experimental work involving a step-change in the attractant gradient (Fordet al., 1991Biotechnol. Bioengng.37, 647–660; For and Lauffenburger, 1991,Biotechnol. Bioengng,37, 661–672). Within the context of this experimental assay, effects of attractant diffusion and consumption, random motility, and chemotactic sensitivity on the shape of the profiles are explored to enhance our understanding of this complex phenomenon. We have applied this model to various other types of gradients with successful intepretation of data reported by Dalquistet al. (1972,Nature New Biol. 236, 120–123) forSalmonella typhimurum validating the mathematical model and supportin the involvement of high and low affinity receptors for serine chemotaxis by these cells.     

The potassium A-current,low firing rates and rebound excitation in Hodgkin-Huxley models

It is widely believed, following the work of Connor and Stevens (1971,J. Physiol. Lond. 214, 31–53) that the ability to fire action potentials over a wide frequency range, especially down to very low rates, is due to the transient, potassium A-current (I _A). Using a reduction of the classical Hodgkin-Huxley model, we study the effects ofI _A on steady firing rate, especially in the near-threshold regime for the onset of firing. A minimum firing rate of zero corresponds to a homoclinic bifurcation of periodic solutions at a critical level of stimulating current. It requires that the membrane's steady-state current-voltage relation be N-shaped rather than monotonic. For experimentally based genericI _A parameters, the model does not fire at arbitrarily low rates, although it can for the more atypicalI _A parameters given by Connor and Stevens for the crab axon. When theI _A inactivation rate is slow, we find that the transient potassium current can mediate more complex firing patterns, such as periodic bursting in some parameter regimes. The number of spikes per burst increases asg _A decreases and as inactivation rate decreases. We also study howI _A affects properties of transient voltage responses, such as threshold and firing latency for anodal break excitation. We provide mathematical explanations for several of these dynamic behaviors using bifurcation theory and averaging methods.     

Incompatible pathogen infection results in enhanced reactive oxygen and cell death responses in transgenic tobacco expressing a hyperactive mutant calmodulin

Transgenic tobacco (Nicotiana tabacum L. cv. Wisconsin 38) lines expressing a mutant calmodulin (VU-3) that hyperactivates NAD kinase exhibit an enhanced elicitor-stimulated oxidative-burst reaction (S.A. Harding et al., 1997, EMBO J. 16: 1137–1144). VU-3 transgenic tobacco was used in the present study to investigate the relationship between calmodulin signalling, the production of active oxygen species and cell death in response to infection with an incompatible pathogen. Following P. syringae pv. syringae 61 infection, suspension cells derived from VU-3 transgenic plants exhibited a stronger oxidative burst (3- to 4-fold higher primary and secondary burst reactions), greater media alkalinization (3-fold) and more rapid cell death (4-fold greater mortality at 20 h post infection) than did infected control tobacco cells. Infection of leaf tissues with P. syringae pv. syringae 61 also resulted in an enhanced cell death response compared to control tobacco tissues. This cell death response of VU-3 leaf tissues, but not control leaf tissues, was further enhanced by the presence of 50 μM salicylic acid, suggesting that this transgenic line is more sensitive to the effects of this agent. Overall, the data support the model that calmodulin signalling pathways are involved in the plant oxidative burst and contribute to the regulation of cell death in infected plant tissues undergoing the hypersensitive response. Received: 6 January 1998 / Accepted: 7 March 1998     

A stochastic model of the effects of ionizing radiation on mammalian cellsin vitro

A new, more realistic model of the action of ionizing radiation on mammalian cells growingin vitro is presented. Although this model requires a large number of parameters, these are linked to biologically observable quantities rather than being abstract sensitivities, as had previously been the case. Three different stochastic processes are required: {X(t);t ∈ [0, τ]}, representing damage alterations during irradiation; {(X(t), S(t));t ∈ [τ, τ+T _D]}, representing changes in both damageX(t) and cell cycle positionS(t) during the post-irradiation cell cycle; and {N _x(t);t ∈ [0,T _G]}, representing the subsequent colony growth process conditioned on the value ofX(τ+T _D). The assumptions used to define these processes extend a previous model of short term DNA damage formation and repair (Nelson S. J. 1982,Radiat. Res. 92, 120–145) to include the influence of cell cycle progression on damage in the irradiated cell and the effect of permanent inherited damage on the daughter cells' colony growth pattern. Expressions corresponding to commonly measured radiation effects are derived from the model and compared with predictions from previous models. It is found that these previous models oversimplified the mechanism of radiation action because they did not adequately represent repair during irradiation, the influence of radiation-induced cycle delays and damage inheritance by any daughter cells. Suggestions are then made for ways in which the new model can be used to test the importance of these effects.     

A calcium-based phantom bursting model for pancreatic islets

Insulin-secreting β-cells, located within the pancreatic islets of Langerhans, are excitable cells that produce regular bursts of action potentials when stimulated by glucose. This system has been the focus of mathematical investigation for two decades, spawning an array of mathematical models. Recently, a new class of models has been introduced called ‘phantom bursters’ [Bertram et al. (2000) Biophys. J. 79, 2880–2892], which accounts for the wide range of burst frequencies exhibited by islets via the interaction of more than one slow process. Here, we describe one implementation of the phantom bursting mechanism in which intracellular Ca²⁺ controls the oscillations through both direct and indirect negative feedback pathways. We show how the model dynamics can be understood through an extension of the fast/slow analysis that is typically employed for bursting oscillations. From this perspective, the model makes use of multiple degrees of freedom to generate the full range of bursting oscillations exhibited by β-cells. The model also accounts for a wide range of experimental phenomena, including the ubiquitous triphasic response to the step elevation of glucose and responses to perturbations of internal Ca²⁺ stores. Although it is not presently a complete model of all β-cell properties, it demonstrates the design principles that we anticipate will underlie future progress in β-cell modeling.     

A theoretical explanation of “Concomitant resistance”

Concomitant resistance is a tumor growth dynamic which results when the growth of a second tumor implant is inhibited by the presence of the first. Recently, we modeled tumor growth in the presence of a regenerating liver after partial hepatectomy (Michelson and Leith,Bull. Math. Biol. 57, 345–366, 1995), with an interlocking pair of growth control triads to account for the accelerated growth observed in both tissues. We also modeled tumor dormancy and recurrence as a dynamic equilibrium achieved between proliferating and quiescent subpopulations. In this paper those studies are extended to initially model the concomitant resistance case. Two interlocking model systems are proposed. In one an interactive competition between the tumor implants is described, while in the other purely proportional growth inhibition is described. The equilibria and dynamics of each system when the coefficients are held constant are presented for three subcases of model parameters. We show that the dynamic called concomitant resistance can be real or apparent, and that if the model coefficients are held constant, the only way to truly achieve concomitant resistance is by forcing one of the tumors into total quiescence. If this is the true state of the inhibited implant, then a non-constant recruitment signal is required to insure regrowth when the inhibitor mass is excised. We compare these theoretical results to a potential explanation of the phenomenon provided by Prehn (Cancer Res. 53, 3266–3269, 1993).     

The effect of heterogeneously-distributed RyR channels on calcium dynamics in cardiac myocytes

Calcium plays an essential role in excitation-contraction coupling in muscle, and derangements in calcium handling can produce a variety of potentially harmful conditions, especially in cardiac muscle. In cardiac tissue specialized invaginations of the sarcolemma, called T-tubules, penetrate deep into each sarcomere, and depolarization of the SL leads to an influx of calcium through voltage-sensitive channels in the T-tubules that in turn triggers further calcium release from the sarcoplasmic reticulum via ryanodine-sensitive calcium channels. Under certain conditions, such as elevated external Ca²⁺, cardiac cells can release calcium from the sarcoplasmic reticulum spontaneously, producing a calcium ’spark’ and propagating traveling waves of elevated Ca²⁺ concentration, without depolarization of the SL (Wier and Blatter, 1991a, Cell Calcium 12, 241–254; Williams, 1993, Cell Calcium 14, 724–735; Cheng et al., 1993a, Science 262, 740–744). However, under normal resting conditions these potentially harmful waves seldom occur. In this paper we investigate the role of the periodic distribution of ryanodine-sensitive channels in determining whether a spark can trigger a wave, using a modification of the kinetic model proposed by Tang and Othmer, 1994b, Biophys. J. 67, 2223–2235, for calcium-induced calcium release. We show that the spatial localization of these channels near the T-tubules has a significant effect on both wave propagation and the onset of oscillations in this system. Spatial localization provides a possible explanation for the differing effects of various experimental protocols on the system’s ability to propagate a traveling wave. Supported in part by NIH Grant GM29123.     

Spatial and temporal correlations of spike trains in frog retinal ganglion cells

For a neuron, firing activity can be in synchrony with that of others, which results in spatial correlation; on the other hand, spike events within each individual spike train may also correlate with each other, which results in temporal correlation. In order to investigate the relationship between these two phenomena, population neurons’ activities of frog retinal ganglion cells in response to binary pseudo-random checker-board flickering were recorded via a multi-electrode recording system. The spatial correlation index (SCI) and temporal correlation index (TCI) were calculated for the investigated neurons. Statistical results showed that, for a single neuron, the SCI and TCI values were highly related—a neuron with a high SCI value generally had a high TCI value, and these two indices were both associated with burst activities in spike train of the investigated neuron. These results may suggest that spatial and temporal correlations of single neuron’s spiking activities could be mutually modulated; and that burst activities could play a role in the modulation. We also applied models to test the contribution of spatial and temporal correlations for visual information processing. We show that a model considering spatial and temporal correlations could predict spikes more accurately than a model does not include any correlation.     

Using zeta-potential measurements to quantify peptide partition to lipid membranes

Many cellular phenomena occur on the biomembranes. There are plenty of molecules (natural or xenobiotics) that interact directly or partially with the cell membrane. Biomolecules, such as several peptides (e.g., antimicrobial peptides) and proteins, exert their effects at the cell membrane level. This feature makes necessary investigating their interactions with lipids to clarify their mechanisms of action and side effects necessary. The determination of molecular lipid/water partition constants (K _p ) is frequently used to quantify the extension of the interaction. The determination of this parameter has been achieved by using different methodologies, such as UV-Vis absorption spectrophotometry, fluorescence spectroscopy and ζ-potential measurements. In this work, we derived and tested a mathematical model to determine the K _p from ζ-potential data. The values obtained with this method were compared with those obtained by fluorescence spectroscopy, which is a regular technique used to quantify the interaction of intrinsically fluorescent peptides with selected biomembrane model systems. Two antimicrobial peptides (BP100 and pepR) were evaluated by this new method. The results obtained by this new methodology show that ζ-potential is a powerful technique to quantify peptide/lipid interactions of a wide variety of charged molecules, overcoming some of the limitations inherent to other techniques, such as the need for fluorescent labeling.     

Structural diversity and defensive properties of diterpenoid alkaloids

Diterpenoid alkaloids are compounds of pharmacological interest. Forty four C₁₉ norditerpenoid (NDAs) and 23 C₂₀ diterpenoid (DAs) alkaloids isolated from Aconitum, Delphinium and Consolida species were tested for their insecticidal effects (antifeedant and toxic) on Spodoptera littoralis and Leptinotarsa decemlineata, their cytotoxicity on tumoral cell lines with several multidrug resistance mechanisms, and their antiparasitic effects against Trypanososma cruzi and Leishmania infantum. Overall, C₁₉ norditerpene alkaloids (NDAs) resulted better insect antifeedants and post-ingestive toxicants than the related C₂₀ diterpene alkaloids (DAs). Their antifeedant or insecticidal potencies did not parallel their reported nAChR binding activity, but did correlate␣with the␣agonist/antagonist insecticidal/ antifeedant model proposed for nicotininc insecticides.␣Among the most potent antifeedants (EC₅₀ < 0.2 μg/cm²) are␣the NDAs 1,14 diacetylcardiopetaline (10),␣18-hydroxy-14-O-methylgadesine (34) and 14-O-acetyldelectinine (28) (to CPB) and the DA 19-oxodihydroatisine (55) (to S.␣littoralis). DAs had strong antiparasitic effects with molecular selectivity while NDAs were inactive. Delphigraciline (53), 15,22-O-Diacetyl-19-oxo-dihydroatisine (56), azitine (64) and isoazitine (65) were active against L. infantum promastigotes and had a moderate effect on T. cruzi epimastigotes, while atisinium chloride (59) and 13-oxocardiopetamine (48) had a potent effect on T. cruzi epimastigotes. These compounds were not toxic to the host cell, significantly reduced parasite infection capacity and severely affected the multiplication of their extracellular forms. Several NDAs exhibited selective cytotoxicity to cancerous cells and some of these had irreversible effects on SW480, HeLa and SkMel25 cell lines (neoline 5, pubescenine 16, 14-deacetylajadine 26, lycoctonine 27, dehydrotakaosamine 35, and ajadelphinine 38). These cytotoxic effects could be related to the inhibition of ATP production.     

A Mathematical Model of Cell Cycle Progression Applied to the MCF-7 Breast Cancer Cell Line

In this paper, we present a model of cell cycle progression and apply it to cells of the MCF-7 breast cancer cell line. We consider cells existing in the three typical cell cycle phases determined using flow cytometry: the G1, S, and G2/M phases. We further break each phase up into model phases in order to capture certain features such as cells remaining in phases for a minimum amount of time. The model is also able to capture the environmentally responsive part of the G1 phase, allowing for quantification of the number of environmentally responsive cells at each point in time. The model parameters are carefully chosen using data from various sources in the biological literature. The model is then validated against a variety of experiments, and the excellent fit with experimental results allows for insight into the mechanisms that influence observed biological phenomena. In particular, the model is used to question the common assumption that a ‘slow cycling population’ is necessary to explain some results. Finally, an extension is proposed, where cell death is included in order to accurately model the effects of tamoxifen, a common first line anticancer drug in breast cancer patients. We conclude that the model has strong potential to be used as an aid in future experiments to gain further insight into cell cycle progression and cell death.     

Alfalfa and tobacco cells react differently to chitin oligosaccharides and Sinorhizobium meliloti nodulation factors

Alfalfa (Medicago sativa L.) suspension cultures respond to yeast elicitors with a strong alkalinization of the culture medium, a transient synthesis of activated oxygen species, and typical late defence reactions such as phytoalexin accumulation and increased peroxidase activity. The alkalinization reaction as well as the oxidative burst were also observed when tobacco (Nicotiana tabacum L.) cell-suspension cultures were treated with yeast elicitors. Depending on the degree of polymerization, N-acetyl chitin oligomers induced the alkalinization response in both plant cell-suspension cultures, while only tobacco cell cultures developed an oxidative burst. Suspension-cultured tobacco cells responded to Sinorhizobium meliloti nodulation factors with a maximal alkalinization of 0.25 pH units and a remarkable oxidative burst. In contrast, addition of Sinorhizobium meliloti nodulation factors to suspension-cultured alfalfa cells induced a slight acidification of the culture medium, instead of an alkalinization, but no oxidative burst. Received: 23 November 1998 / Accepted: 23 June 1999     

Linearized oscillations in population dynamics

A linearized oscillation theorem due to Kulenović, Ladas and Meimaridou (1987,Quart. appl. Math. XLV, 155–164) and an extension of it are applied to obtain the oscillation of solutions of several equations which have appeared in population dynamics. They include the logistic equation with several delays, Nicholson's blowflies model as described by Gurney, Blythe and Nisbet (1980,Nature, Lond. 287, 17–21) and the Lasota-Wazewska model of the red blood cell supply in an animal. We also developed a linearized oscillation result for difference equations and applied it to several equations taken from the biological literature.     

Chilling and forcing temperatures interact to predict the onset of wood formation in Northern Hemisphere conifers

The phenology of wood formation is a critical process to consider for predicting how trees from the temperate and boreal zones may react to climate change. Compared to leaf phenology, however, the determinism of wood phenology is still poorly known. Here, we compared for the first time three alternative ecophysiological model classes (threshold models, heat‐sum models and chilling‐influenced heat‐sum models) and an empirical model in their ability to predict the starting date of xylem cell enlargement in spring, for four major Northern Hemisphere conifers (Larix decidua, Pinus sylvestris, Picea abies and Picea mariana). We fitted models with Bayesian inference to wood phenological data collected for 220 site‐years over Europe and Canada. The chilling‐influenced heat‐sum model received most support for all the four studied species, predicting validation data with a 7.7‐day error, which is within one day of the observed data resolution. We conclude that both chilling and forcing temperatures determine the onset of wood formation in Northern Hemisphere conifers. Importantly, the chilling‐influenced heat‐sum model showed virtually no spatial bias whichever the species, despite the large environmental gradients considered. This suggests that the spring onset of wood formation is far less affected by local adaptation than by environmentally driven plasticity. In a context of climate change, we therefore expect rising winter–spring temperature to exert ambivalent effects on the spring onset of wood formation, tending to hasten it through the accumulation of forcing temperature, but imposing a higher forcing temperature requirement through the lower accumulation of chilling.     

Cobalt and zinc salicylates as functional analogs of an initiating actor in the molluscan nervous system

We showed that applications of cobalt and zinc salicylates lead to restoration of the impulse activity of a PPa1 neuron of the snail, Helix pomatia, under conditions of the blockade of synaptic transmission by cadmium ions. In the case where a PPa1 neuron demonstrated no background activity and/or under conditions of total isolation of this cell, the above-mentioned salicylates initiate generation of action potentials, as well as exert an excitatory effect on “silent” non-identified cells of the parietal and visceral ganglia. Based on the data obtained, we conclude that the activating effect of cobalt and zinc salicylates on the PPa1 cell is similar to that of the so-called initiating factor (IF), which initiates generation of the burst activity. These effects are independent of the inward calcium current. Using an activator of cAMP phosphodiesterase, imidazole, we showed that the effects of the above salicylates (similar to the effect of IF) are related to the influence of these agents on the system of cyclic nucleotides. Neirofiziologiya/Neurophysiology, Vol. 38, No. 1, pp. 11–17, January–February, 2006.     

The Sleep Cycle Modelled as a Cortical Phase Transition

We present a mean-field model of the cortex that attempts to describe the gross changes in brain electrical activity for the cycles of natural sleep. We incorporate within the model two major sleep modulatory effects: slow changes in both synaptic efficiency and in neuron resting voltage caused by the ∼90-min cycling in acetylcholine, together with even slower changes in resting voltage caused by gradual elimination during sleep of somnogens (fatigue agents) such as adenosine. We argue that the change from slow-wave sleep (SWS) to rapid-eye-movement (REM) sleep can be understood as a first-order phase transition from a low-firing, coherent state to a high-firing, desychronized cortical state. We show that the model predictions for changes in EEG power, spectral distribution, and correlation time at the SWS-to-REM transition are consistent not only with those observed in clinical recordings of a sleeping human subject, but also with the on-cortex EEG patterns recently reported by Destexhe et al. [J. Neurosci. 19(11), (1999) 4595–4608] for the sleeping cat.     

Effectiveness of using an unskilled model in action observation combined with motor imagery training for early motor learning in elderly people: a preliminary study

Abstract

Aim of the study: To investigate a more available model for the early phase of motor learning after action observation combined with motor imagery training in elderly people. To address the purpose, we focused on a slow, unskilled model demonstrating an occasional error.

Materials and methods: A total of 36 elderly people participated in the current study and were assigned to either the unskilled or skilled model observation groups (n?=?12, respectively), or the control group (n?=?12). The participants in the observation groups observed the assigned a video clip of an unskilled or skilled model demonstrating a ball rotation task. During the observation, the participants were instructed to imagine themselves as the person in the video clip. The participants in the control group read a scientific paper during the equivalent period of action observation and motor imagery. We measured ball rotation performance (the time required for five rotations, the number of ball drops) in pre- and post-intervention (observation combined with motor imagery training for intervention groups or reading for control group).

Results: Ball rotation performance (ball rotation speed) significantly improved in the unskilled model observation group compared to the other two groups.

Conclusions: Intervention for action observation using unskilled model combined with motor imagery was effective for improving motor performance during the early phase of motor learning.     

What is culture? Systems of people,places, and practices

Abstract

Culture is a fuzzy concept without fixed boundaries, meaning different things according to situations. To address this issue, I introduce a p-model to understand culture as a system of people, places, and practices, for a purpose such as enacting, justifying, or resisting power. People refers to population dynamics, social relations, and culture in groups. Places refers to ecological dynamics, institutional influences, and culture in contexts. Practices refers to participatory dynamics, community engagement, and culture in action. Power refers to forcing others into compliance (power-over people), controlling access to spaces (power in places), and behaving as desired (power-to practice). I use racism to illustrate the p-model and suggest applications in theory, research, and practice in developmental sciences.