A connectionist model of development.

We present a phenomenological modeling framework for development. Our purpose is to provide a systematic method for discovering and expressing correlations in experimental data on gene expression and other developmental processes. The modeling framework is based on a connectionist or "neural net" dynamics for biochemical regulators, coupled to "grammatical rules" which describe certain features of the birth, growth, and death of cells, synapses and other biological entities. We outline how spatial geometry can be included, although this part of the model is not complete. As an example of the application of our results to a specific biological system, we show in detail how to derive a rigorously testable model of the network of segmentation genes operating in the blastoderm of Drosophila. To further illustrate our methods, we sketch how they could be applied to two other important developmental processes: cell cycle control and cell-cell induction. We also present a simple biochemical model leading to our assumed connectionist dynamics which shows that the dynamics used is at least compatible with known chemical mechanisms.     

A domain model for eukaryotic DNA organization: a molecular basis for cell differentiation and chromosome evolution

A model for eukaryotic chromatin organization is presented in which the basic structural and functional unit is the DNA domain. This simple model predicts that both chromosome replication and cell type-specific control of gene expression depend on a combination of stable and dynamic DNA-nuclear matrix interactions. The model suggests that in eukaryotes, DNA regulatory processes are controlled mainly by the intranuclear compartmentalization of the specific DNA sequences, and that control of gene expression involves multiple steps of specific DNA-nuclear matrix interactions. Predictions of the model are tested using available biochemical, molecular and cell biological data. In addition, the domain model is discussed as a simple molecular mechanism to explain cell differentiation in multi-cellular organisms and to explain the evolution of eukaryotic genomes consisting mainly of repetitive sequences and "junk" DNA.     

The role of membrane phosphoinositides in mediating hormonal effects

The present notions on the pathways of phosphoinositide metabolism in a cell and on the functional significance of the given process are reported. The enzymic systems providing catabolism of phosphoinositides are analyzed. The data indicating the dose interrelation between the stimulation of the phosphatidyl inosite and polyphosphoinositides metabolism by hormones and the Ca2+ transport into a cell are generalized. Universality, biochemical mechanisms and functional significance of the "phosphatidyl inosite" response are discussed. The phosphoinositide metabolism is considered from the standpoint of its significance for other cell processes: synthesis of eicosanoids, provision of Ca2+-dependent processes in the synapse, cell proliferation, activation and the "anchoring" of enzymes on membranes.     

Vector potential as a channel of informational effect on living objects

The physical properties of the vector potential were considered in terms of the problem of bioactivity of electromagnetic fields. A possible primary mechanism underlying the effect of vector potentials on elementary processes of charge transport were considered by analogy with the well-known Aharonov-Bohms and Josephsons effects. The possibility of using the curl-free vector potential for "force-free" information effect on biochemical processes in the living cell was grounded. The technical possibilities of creation of vector potential free of magnetic field in laboratory are discussed.     

Origins of Stochasticity and Burstiness in High-Dimensional Biochemical Networks

Two major approaches are known in the field of stochastic dynamics of intracellular biochemical networks. The first one places the focus of attention on the fact that many biochemical constituents vitally important for the network functionality may be present only in small quantities within the cell, and therefore the regulatory process is essentially discrete and prone to relatively big fluctuations. The second approach treats the regulatory process as essentially continuous. Complex pseudostochastic behavior in such processes may occur due to multistability and oscillatory motions within limit cycles. In this paper we outline the third scenario of stochasticity in the regulatory process. This scenario is only conceivable in high-dimensional highly nonlinear systems. In particular, we show that burstiness, a well-known phenomenon in the biology of gene expression, is a natural consequence of high dimensionality coupled with high nonlinearity. In mathematical terms, burstiness is associated with heavy-tailed probability distributions of stochastic processes describing the dynamics of the system. We demonstrate how the "shot" noise originates from purely deterministic behavior of the underlying dynamical system. We conclude that the limiting stochastic process may be accurately approximated by the "heavy-tailed" generalized Pareto process which is a direct mathematical expression of burstiness.     

Model of the developing tumorigenic phenotype in mammalian cells and the roles of sustained stress and replicative senescence

The molecular mechanisms that drive mammalian cells to the development of cancer are the subject of intense biochemical, genetic and medical studies. But for the present, there is no comprehensive model that might serve as a general framework for the interpretation of experimental data. This paper is an attempt to create a conceptual model of the mechanism of the developing tumorigenic phenotype in mammalian cells, defined as having high genomic instability and proliferative activity. The basic statement in the model is that mutations acquired by tumor cells are not caused directly by external DNA damaging agents, but instead are produced by the cell itself as an output of a Mutator Response similar to the bacterial "SOS response" and characterized by the initiation of error-prone cell cycle progression and an elevated rate of mutation. This response may be induced in arrested mammalian cells by intracellular and extracellular proliferative signals combined with blocked apoptosis. The mutant cells originated by this response are subjected to natural selection via apoptosis and turnover. This selection process favors the survival of cells with high proliferative activity and the suppression of apoptosis resulting in the long run in the appearance of immortalized cells with high proliferative activity. Either a sustained stressful environment accompanied by continuing apoptotic cell death, or replicative senescence, provides conditions suitable for activation of the Mutator Response, namely the emergence of arrested cells with blocked apoptosis and the induction of proliferative signal. It also accelerates the selection process by providing continuing cell turnover. The proposed mechanism is described at the level of involved metabolic pathways and proteins and substantiated by the related experimental data available in the literature.     

FRET and FRAP imaging: Approaches to characterise tau and stathmin interactions with microtubules in cells

Microtubules (MTs) are involved in many crucial processes such as cell morphogenesis, mitosis and motility. These dynamic structures resulting from the complex assembly of tubulin are tightly regulated by stabilising MT‐associated proteins (MAPs) such as tau and destabilising proteins, notably stathmin. Because of their key role, these MAPs and their interactions have been extensively studied using biochemical and biophysical approaches, particularly in vitro. Nevertheless, numerous questions remain unanswered and the mechanisms of interaction between MT and these proteins are still unclear in cells. Techniques coupling cell imaging and fluorescence methods, such as Förster resonance energy transfer and fluorescence recovery after photobleaching, are excellent tools to study these interactions in situ. After describing these methods, we will present emblematic data from the literature and unpublished experimental results from our laboratory concerning the interactions between MTs, tau and stathmin in cells.     

Dexamethasone-sensitive and -insensitive responses during in vitro differentiation of Friend erythroleukemia cells

We have investigated the mechanism(s) by which dexamethasone inhibit DMSO-induced Friend erythroleukemia cell differentiation in vitro. In particular, we examined the effects of dexamethasone on (a) the early events of differentiation such as cell volume alterations and 'memory response' and (b) the onset of biochemical events associated with terminal erythroid cell differentiation. By analysing kinetics of commitment of Friend cells to terminal erythroid differentiation on a clonal basis, we have observed that dexamethasone inhibited the completion of the latent period (time elapsed prior to commitment) and impaired "memory" (ability to inducer-treated cells to continue differentiation after a discontinuous exposure to inducer). Treatment of Friend cells with dexamethasone did not prevent the occurrence of DMSO-induced alterations in cell volume. However, dexamethasone treatment prevented a series of biochemical events associated with terminal Friend cell differentiation. These include the decrease in the rate of both cytoplasmic and nuclear RNA synthesis as well as the induction of cytidine deaminase activity and hemoglobin synthesis. These data indicate that the dexamethasone-sensitive process(es) operate during the early stages of Friend cell differentiation and that they are responsible for the inhibition of terminal erythroid maturation. These dexamethasone-sensitive processes, however, appear to be different from those regulating cell volume alterations during the early steps of DMSO-induced Friend cell differentiation.     

Mathematical modelling of the transport of low molecular weight solutes across biological membranes. The transport of Leu, His and Glu into human blood platelets

A model describing the transport of low molecular weight solutes across cell membranes is presented. The model accounts for many different systems which may mediate the fluxes of various solutes, for the effect of Na+ ions, and for time dependence of the processes. It generalizes the classical three-parameter equation for transport. Solutions to the model were employed to interprete experimental data obtained for the uptake of DL-leu, L-his and L-glu by human blood platelets.     

Kinetics of isotope exchange at equilibrium for a one substrate-one product enzyme mechanism

It is shown that the general solution of Morales, Horovitz &; Botts (1962) describing isotope exchange kinetics at equilibrium for the one substrateone product enzyme mechanism:

$\text{E+S?X?E+P}$

reduces to the steady-state solution normally applied to experimental data, under usual experimental conditions.The analysis provides a firmer theoretical basis for the equations generally used in analysing kinetic data from isotope exchange experiments.     

Structured modeling of recombinant protein production in batch and fed-batch culture of baculovirus-infected insect cells

The infection of insect cells with baculovirus was described in a mathematical model as a part of the structured dynamic model describing whole animal cell metabolism. The model presented here is capable of simulating cell population dynamics, the concentrations of extracellular and intracellularviral components, and the heterologous product titers. The model describes the whole processes of viral infection and theeffect of the infection on the host cell metabolism. Dynamic simulation of the model in batch and fed-batch mode gave goodagreement between model predictions and experimental data. Optimum conditions for insect cell culture and viral infectionin batch and fed-batch culture were studied using the model.     

An evolving paradigm for the secretory pathway?

The paradigm that the secretory pathway consists of a stable endoplasmic reticulum and Golgi apparatus, using discrete transport vesicles to exchange their contents, gained important support from groundbreaking biochemical and genetic studies during the 1980s. However, the subsequent development of new imaging technologies with green fluorescent protein introduced data on dynamic processes not fully accounted for by the paradigm. As a result, we may be seeing an example of how a paradigm is evolving to account for the results of new technologies and their new ways of describing cellular processes.     

Theoretical aspects and modelling of cellular decision making,cell killing and information-processing in photodynamic therapy of cancer

Background

The aim of this report is to provide a mathematical model of the mechanism for making binary fate decisions about cell death or survival, during and after Photodynamic Therapy (PDT) treatment, and to supply the logical design for this decision mechanism as an application of rate distortion theory to the biochemical processing of information by the physical system of a cell.

Methods

Based on system biology models of the molecular interactions involved in the PDT processes previously established, and regarding a cellular decision-making system as a noisy communication channel, we use rate distortion theory to design a time dependent Blahut-Arimoto algorithm where the input is a stimulus vector composed of the time dependent concentrations of three PDT related cell death signaling molecules and the output is a cell fate decision. The molecular concentrations are determined by a group of rate equations. The basic steps are: initialize the probability of the cell fate decision, compute the conditional probability distribution that minimizes the mutual information between input and output, compute the cell probability of cell fate decision that minimizes the mutual information and repeat the last two steps until the probabilities converge. Advance to the next discrete time point and repeat the process.

Results

Based on the model from communication theory described in this work, and assuming that the activation of the death signal processing occurs when any of the molecular stimulants increases higher than a predefined threshold (50% of the maximum concentrations), for 1800s of treatment, the cell undergoes necrosis within the first 30 minutes with probability range 90.0%-99.99% and in the case of repair/survival, it goes through apoptosis within 3-4 hours with probability range 90.00%-99.00%. Although, there is no experimental validation of the model at this moment, it reproduces some patterns of survival ratios of predicted experimental data.

Conclusions

Analytical modeling based on cell death signaling molecules has been shown to be an independent and useful tool for prediction of cell surviving response to PDT. The model can be adjusted to provide important insights for cellular response to other treatments such as hyperthermia, and diseases such as neurodegeneration.

     

Effects of radiation-ecological conditions and experimental hyperthyroid states on indicators of testis and prostate androgen receptors in rats

Dose-dependent changes of the molecular characteristics on androgen receptor (AR) systems in gonads of male rats were studied at experimental L-thyroxine-induced states after low doses irradiation exposures in different reference points of 10-km Chernobyl zone. The data obtained suggest a generalized working mechanism of "oscillatorous changes" for contents, affinities and cooperative properties of AR to its natural ligands as a "mirror" reflecting some adaptational reactions in target cells that modulates their androgen-controlled biochemical activity.     

Kinetics of pore-mediated release of marker molecules from liposomes or cells.

We present a general mathematical treatment of marker efflux from liposomes or cells mediated by pore formation with the idea of using it in practice to obtain basic information about the underlying rates and mechanism. The approach encompasses permeation of molecules through any kind of pore-like defects in a cell membrane as they are induced by the action of some external agent. The approach broadens an earlier treatment to the more realistic general case in which a distribution of pore lifetimes must be taken into account. We derive a theoretical retention function describing the amount of marker remaining in the cells, formulated in terms of the pore activation and inactivation kinetics. The phenomenological efflux function evaluated directly from experimental data, is directly comparable with this retention function so long as the experimental signal is linearly related to the marker concentration. With the use of self-quenching dyes the relationship between signal and concentration is not, in general, linear, so that a more complicated treatment may be required. Even for these dyes, however, linearity holds under the frequently encountered condition of "all-or-none" release of dye from vesicles, a condition that can itself be verified experimentally.     

A possible mechanism of the influence of neuromodulators and modifiable inhibition on long-term potentiation and long-term depression of excitatory inputs to main hippocampal neurons

A hypothetic mechanism explaining the influence of various neuromodulators and modifiable disynaptic inhibition on the long-term potentiation and depression (LTP and LTD) of excitatory inputs to granule and pyramidal hippocampal cells is proposed. According to this mechanism, facilitation of the LTD/LTP of excitatory inputs to an inhibitory interneuron caused by the action of a neuromodulator on a receptor bound with Gi/0/(Gs or Gq/11) protein can reduce/augment the GABA release, weaken/intensify the target cell inhibition, and promote the induction of the LTP/LTD of excitatory inputs to this cell. In the absence of the inhibition, the same neuromodulator would promote the LTD/LTP induction in the target cell by activating the same receptor types. The resulting effect of a neuromodulator on a target cell depends on the ratio between the "strengths" of its excitatory and inhibitory inputs, on the presence of receptors of the same or different types at the interneuron and the target cell, and on the neuromodulator concentration due to its different affinity for receptors, interaction with which provide its influence on postsynaptic processes in opposite directions. The consequences of suggested mechanism are in agreement with the known experimental data.     

Model systems for aging research: syncretic concepts and diversity of mechanisms

A variety of very different phenomena have been subsumed under the heading of "aging" research. A review of recent experimental data, in several of the best-studied model systems for the investigation of aging, indicates that molecular changes which are putative or demonstrated proximal causes of senescent deterioration are generally not shared by other systems examined. It is thus argued that different aberrant biochemical processes have evolved as the "weakest link" limiting longevity or intermeiotic interval in different systems, although in each case the germ line must be exempted.