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Nanocarrier-mediated delivery and release of short non-coding RNA (e.g., miRNA or siRNA) into the cells with subsequent suppression of the populations of some of the mRNAs and proteins is of interest in the context of the development of a new generation of drugs. Bearing in mind such applications, the author shows the specifics of the corresponding transient kinetics by using three generic models without and with feedback resulting in bistability in the gene expression. In the absence of feedback, the suppression of the mRNA and protein population is transient. In the case of bistable kinetics, non-coding RNA can induce transition from the initial steady state to another steady state. The duration of this transition can be much longer than the time scale characterizing the drop of the non-coding RNA population. Quantitatively, the effect of the delivered non-coding RNA on gene expression can be appreciable if the maximum non-coding RNA population in the cytoplasm is comparable to or above 1000. All these conclusions have been drawn on the basis of calculations performed with the kinetic parameters typical for human cells. [ABSTRACT FROM AUTHOR]

The author presents theoretical mean-field analysis of the initial phase of the kinetics of intracellular replication of plus-stranded RNA viruses, which are abundant and include, e.g., the hepatitis C virus (HCV). The treatment is based on the conventional concept that the replication process of such viruses takes place at the membrane complexes formed with participation of viral proteins, e.g., NS5A in the HCV case. The key novel prediction supported by Monte Carlo calculations is that this scheme may be insufficient in order to describe the very initial phase of the process, because the initial intracellular viral RNA and protein populations may in this case go extinct rather than overcome the kinetic barrier for transition to the full-scale infection of a host cell. Practically, this means that in such situations, the conventional replication scenario should be complemented by another pathway, e.g., by replication outside the membrane without viral proteins, which operates in the very beginning. [ABSTRACT FROM AUTHOR]

Nanocarrier-mediated mRNA delivery and release into the cells with subsequent translation to protein is of interest in the context of the development of a new generation of drugs. In particular, this protein can play a role of a transcription factor and be used as a tool to regulate temporarily the genetic networks. The corresponding transient kinetics of gene expression are expected to depend on the mechanism and duration of mRNA release. Assuming the release to be rapid on the time scale of other steps, the author shows theoretically the mRNA-related transient features of gene expression occurring in stable, bistable, and oscillatory regimes in a single cell. Qualitatively, the results obtained are found to be fairly similar to those reported earlier for the situation when the release is slow. Thus, the features of the transient kinetics under consideration appear to be less sensitive to the duration of mRNA release compared to what one might expect. [ABSTRACT FROM AUTHOR]

Recent direct observations of localization of mRNAs and proteins both in prokaryotic and eukaryotic cells can be related to slowdown of diffusion of these species due to macromolecular crowding and their ability to aggregate and form immobile or slowly mobile complexes. Here, a generic kinetic model describing both these factors is presented and comprehensively analyzed. Although the model is non-linear, an accurate self-consistent analytical solution of the corresponding reaction-diffusion equation has been constructed, the types of localized protein distributions have been explicitly shown, and the predicted kinetic regimes of gene expression have been classified. [ABSTRACT FROM AUTHOR]

Abstract: The long-term changes of the neuron function are often related to the interplay of the membrane voltage pulses and gene expression. In the present work, this phenomenon is modeled by combining the standard stochastic integrate-and-fire neuron model with generic kinetic models describing gene expression. The three scenarios under consideration include, respectively, the voltage-related regulation of (i) gene transcription into mRNA, (ii) gene transcription into miRNA, and (iii) proteasome formation. Typical transient and steady-state kinetics are shown. The latter kinetics exhibit a unique steady state, bistability, or oscillations. The conditions of realization of these regimes are investigated numerically. The transient and oscillatory kinetics are predicted on the time scale of about one hour or longer. The implications of these results for interpretation of synaptic plasticity and learning and long-term memory are briefly discussed. [Copyright &y& Elsevier]

In eukaryotic cells, many genes are transcribed into non-coding RNAs. Small RNAs or, more specifically, microRNAs (miRNAs) form an abundant sub-class of such RNAs. miRNAs are transcribed as long noncoding RNA and then generated via a processing pathway down to the 20-24-nucleotide length. The key ability of miRNAs is to associate with target mRNAs and to suppress their translation and/or facilitate degradation. Using the mean-field kinetic equations and Monte Carlo simulations, we analyze two aspects of this interplay. First, we describe the situation when the formation of mRNA or miRNA is periodically modulated by a transcription factor which itself is not perturbed by these species. Depending on the ratio between the mRNA and miRNA formation rates, the corresponding induced periodic kinetics are shown to be either nearly harmonic or shaped as anti-phase pulses. The second part of the work is related to recent experimental studies indicating that differentiation of stem cells often involves changes in gene transcription into miRNAs and/or the interference between miRNAs, mRNAs and proteins. In particular, the regulatory protein obtained via mRNA translation may suppress the miRNA formation, and the latter may suppress in turn the miRNA-mRNA association and degradation. The corresponding bistable kinetics are described in detail. [ABSTRACT FROM AUTHOR]

Recent experiments show that mRNAs and proteins can be localized both in prokaryotic and eukaryotic cells. To describe such situations, I present a 3D mean-field kinetic model aimed primarily at gene expression in prokaryotic cells, including the formation of mRNA, its translation into protein, and slow diffusion of these species. Under steady-state conditions, the mRNA and protein spatial distribution is described by simple exponential functions. The protein concentration near the gene transcribed into mRNA is shown to depend on the protein and mRNA diffusion coefficients and degradation rate constants. [ABSTRACT FROM AUTHOR]

Recent experiments indicate that several viruses may encode microRNAs (miRNAs) in cells. Such RNAs may interfere with the host mRNAs and proteins. We present a kinetic analysis of this interplay. In our treatment, the viral miRNA is considered to be able to associate with the host mRNA with subsequent degradation. This process may result in a decline of the mRNA population and also in a decline of the population of the protein encoded by this mRNA. With these ingredients, we first show the types of the corresponding steady-state kinetics in the cases of positive and negative regulation of the miRNA synthesis by the protein. In addition, we scrutinize the situation when the protein regulates the virion replication or, in other words, provides a feedback for the replication. For the negative feedback, the replication rate is found to increase with increasing the intracellular virion population. For the positive feedback, the replication rate first increases and then drops. These features may determine the stability of steady states. [ABSTRACT FROM AUTHOR]

We present a kinetic model describing the growth of eukaryotic cells or, more specifically, the dependence of the cell volume on time in terms of the global interplay of the mRNA and protein synthesis and degradation and lipid synthesis. Addressing two long-standing questions in this interdisciplinary field, we explain why the average protein concentration in growing cells is nearly constant and the growth can accurately be fitted by using a bilinear or exponential function. [ABSTRACT FROM AUTHOR]

Abstract: Kinetics of gene expression may be bistable or oscillatory due to the feedbacks between the RNA and protein synthesis. In complex genetic networks, kinetic oscillations may influence bistability. Following this line, we have performed a mean-field analysis and Monte Carlo simulations of periodic perturbation of the bistable kinetics of expression of two genes with mutual suppression of the mRNA production due to negative regulation of the gene transcription by protein. The perturbation is realized via modulation of the rate of the mRNA formation. In the mean-field kinetics, the mRNA and protein concentrations repeat themselves during each period. In the stochastic kinetics, this is also the case, provided that the modulation amplitude is small. If the modulation is appreciable, the latter kinetics exhibit new features. Specifically, the model predicts stochastic intermittence of the states of the genes. If the modulation amplitude is close to maximum, the change of the gene states during subsequent perturbation periods occurs fully at random. Taking into account that the model we use is generic, the results obtained are expected to be of interest far beyond the biophysics and biochemistry of gene expression. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, protein-coding sequences constitute a relatively small part of the genome. The rest of the genome is transcribed to non-coding RNAs (ncRNAs). Such RNAs form the cornerstone of a regulatory network that operates in parallel with the protein network. Their biological functions are based primarily on the ability to pair with and deactivate target messenger RNAs (mRNAs). To clarify the likely role of ncRNAs in complex genetic networks, we present and comprehensively analyze a kinetic model of one of the key counterparts of the network architectures. Specifically, the genes transcribed to ncRNAs are considered to interplay with a hierarchical two-layer set of genes transcribed to mRNAs. The genes forming the bottom layer are regulated from the top and negatively self-regulated. If the former regulation is positive, the dependence of the RNA populations on the governing parameters is found to be often non-monotonous. Specifically, the model predicts bistability. If the regulation is negative, the dependence of the RNA populations on the governing parameters is monotonous. In particular, the population of the mRNAs, corresponding to the genes forming the bottom layer, is nearly constant. [ABSTRACT FROM AUTHOR]

The feedbacks between the mRNA and protein synthesis may result in kinetic bistability and oscillations. Two generic models predicting bistability include, respectively, a gene with positive regulation of the mRNA production by protein and two genes with mutual suppression of the mRNA production due to negative regulation of the gene transcription by protein. The simplest model predicting oscillations describes a gene with negative regulation of the mRNA production by protein formed via mRNA translation and a few steps of conversion. We complement these models by the steps of non-coding RNA (ncRNA) formation and ncRNA-mRNA association and degradation. With this extension, the bistability can often be observed as well. Without and with ncRNA, the biochemistry behind the steady states may be different. In the latter case, for example, ncRNA may control the mRNA population in the situations when this population is relatively small, and one can observe a switch in the mRNA, protein and ncRNA populations. Our analysis of oscillatory kinetics of the mRNA-protein interplay shows that with ncRNA the oscillations may be observed in a wider range of parameters and the amplitude of oscillations may be larger. [ABSTRACT FROM AUTHOR]

Abstract: The kinetics of gene expression can be bistable due to the feedback between the mRNA and protein formation. In eukaryotic cells, the interplay between mRNAs and proteins can be influenced by non-coding RNAs. Some of these RNAs, e.g., microRNAs, may target hundreds of distinct mRNAs. The model presented here shows how a non-coding RNA can be used as a mediator in order to involve numerous mRNAs and proteins into a bistable network. [Copyright &y& Elsevier]

In eukaryotic cells, the gene transcription often results in the formation of non-coding RNAs (ncRNAs). The key function of such RNAs is to bind to and modulate the activity of mRNAs and/or proteins. To scrutinize this ncRNA function in a cell, the author (i) proposes a spatio-temporal kinetic model, including ncRNA–protein association and degradation, (ii) derives a criterion of feasibility of the ncRNA gradients, and (iii) shows that this criterion can be satisfied with physically reasonable values of the model parameters. Thus, the ncRNA gradients are feasible. For the ncRNA–mRNA association and degradation, the situation is similar. The likely biological role of such gradients is open for debate. [ABSTRACT FROM AUTHOR]

Abstract: The author proposes a kinetic model describing the interplay of messenger ribonucleic acid (mRNA), protein, produced via translation of this RNA, and nonprotein coding RNA (ncRNA). The model includes association of mRNA and ncRNA and regulation of the ncRNA production by protein. In the case of positive feedback between the production of protein and ncRNA, the steady state of the system is found to be unique. For negative feedback, the model predicts in the mean-field case either unique steady state or bistable kinetics. With incorporation of fluctuations, the bistability is manifested in the form of kinetic bursts provided that the number of reactants is low. Basically, the model describes the simplest biological switch operating with participation of ncRNA. Although the results obtained are applicable to ncRNSs in general, the presentation is focused primarily on microRNAs (miRNAs) which form a large important subclass of ncRNAs and are thought to regulate up to one third of all human genes. [Copyright &y& Elsevier]