Interplay of viral miRNAs and host mRNAs and proteins

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.     

Non-coding RNAs and complex distributed genetic networks

In eukaryotic cells, the mRNA-protein interplay can be dramatically influenced by non-coding RNAs (ncRNAs). Although this new paradigm is now widely accepted, an understanding of the effect of ncRNAs on complex genetic networks is lacking. To clarify what may happen in this case, we propose a mean-field kinetic model describing the influence of ncRNA on a complex genetic network with a distributed architecture including mutual protein-mediated regulation of many genes transcribed into mRNAs. ncRNA is considered to associate with mRNAs and inhibit their translation and/or facilitate degradation. Our results are indicative of the richness of the kinetics under consideration. The main complex features are found to be bistability and oscillations. One could expect to find kinetic chaos as well. The latter feature has however not been observed in our calculations. In addition, we illustrate the difference in the regulation of distributed networks by mRNA and ncRNA.     

Hierarchical genetic networks and noncoding RNAs

In eukaryotic cells, many genes are transcribed into noncoding RNAs. Such RNAs may associate with mRNAs and inhibit their translation and facilitate degradation. To clarify what may happen in this case, we propose a kinetic model describing the effect of noncoding RNAs on a mRNA-protein network with the hierarchical three-layer architecture. For positive regulation of the layers, our model predicts either bistability with a fairly narrow hysteresis loop or a unique steady state. For negative or mixed regulation, the steady state is found to be unique.     

A generic 3D kinetic model of gene expression

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.     

ncRNA-mediated bistability in the synthesis of hundreds of distinct mRNAs and proteins

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.     

Switches in gene expression including microRNA and a large number of distinct mRNAs

In eukaryotic cells, the kinetics of gene expression depends on the interplay of messenger RNAs (mRNAs), proteins, and nonprotein coding RNAs, or, more specifically, microRNAs. Some microRNAs may target hundreds of mRNAs. To describe this case, the author proposes a kinetic model implying that the microRNA synthesis is suppressed by the protein produced via the translation of one of the target mRNAs. With physically reasonable model parameters, the model predicts bistability or, in other words, switches in the expression of hundreds of genes. The text was submitted by the author in English.     

Interplay of noncoding RNAs,mRNAs, and proteins during the growth of eukaryotic cells

Numerous biological functions of noncoding RNAs (ncRNAs) in eukaryotic cells are based primarily on their ability to pair with target mRNAs and then either to prevent translation or to result in rapid degradation of the mRNA-ncRNA complex. Using a general model describing this scenario, we show that ncRNAs may help to maintain constant mRNA and protein concentrations during the growth of cells. The possibility of observation of this effect on the global scale is briefly discussed.     

Non-coding RNAs and a layered architecture of genetic networks

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.     

Oscillatory dynamics in a simple gene regulatory network mediated by small RNAs

More and more experiments show that small RNAs regulate gene expression by repressing translation of messenger RNAs (mRNAs) or degrading mRNAs. In this paper, we incorporate the small RNAs into a simple gene regulatory network and investigate its dynamical behaviors. In addition, we also derive the theoretical results of globally asymptotic stability and provide the sufficient conditions for the oscillation of the simple gene regulatory network, and further demonstrate that the amplitudes against the change of delay in the gene regulatory network are robust.     

Sonochemical degradation of chlorophenols in water

Sonochemical degradation of dilute aqueous solutions of 2-, 3- and 4-chlorophenol and pentachlorophenol has been investigated under air or argon atmosphere. The degradation follows first-order kinetics in the initial state with rates in the range 4.5-6.6 microM min-1 under air and 6.0-7.2 microM min-1 under argon at a concentration of 100 microM of chlorophenols. The rate of OH radical formation from water is 19.8 microM min-1 under argon and 14.7 microM min-1 under air in the same sonolysis conditions. The sonolysis of chlorophenols is effectively inhibited, but not completely, by the addition of t-BuOH, which is known to be an efficient OH radical scavenger in aqueous sonolysis. This suggests that the main degradation of chlorophenols proceeds via reaction with OH radicals; a thermal reaction also occurs, although its contribution is small. The addition of appropriate amounts of Fe(II) ions accelerates the degradation. This is probably due to the regeneration of OH radicals from hydrogen peroxide, which would be formed from recombination of OH radicals and which may contribute a little to the degradation. The ability to inhibit bacterial multiplication of pentachlorophenol decreases with ultrasonic irradiation.     

Translation by Ribosomes with mRNA Degradation: Exclusion Processes on Aging Tracks

We investigate the role of degradation of mRNA on protein synthesis using the totally asymmetric simple exclusion process (TASEP) as the underlying model for ribosome dynamics. mRNA degradation has a strong effect on the lifetime distribution of the mRNA, which in turn affects polysome statistics such as the number of ribosomes present on an mRNA strand of a given size. An average over mRNA of all ages is equivalent to an average over possible configurations of the corresponding TASEP—both before steady state and in steady state. To evaluate the relevant quantities for the translation problem, we first study the approach towards steady state of the TASEP, starting with an empty lattice representing an unloaded mRNA. When approaching the high density phase, the system shows two distinct phases with the entry and exit boundaries taking control of the density at their respective ends in the second phase. The approach towards the maximal current phase exhibits the surprising property that the ribosome entry flux can exceed the maximum possible steady state value. In all phases, the averaging over the mRNA age distribution shows a decrease in the average ribosome density profile as a function of distance from the entry boundary. For entry/exit parameters corresponding to the high density phase of TASEP, the average ribosome density profile also has a maximum near the exit end.     

Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra

ABSTRACT: BACKGROUND: Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this question in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17beta-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5alpha-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5alpha-reductase mRNA levels. RESULTS: We find ERalpha and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERalpha mRNA down-regulation and ERbeta mRNA up-regulation by testosterone was found. 5alpha reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. CONCLUSIONS: We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and increasing AR mRNA. Further, testosterone may increase local dopamine synthesis and metabolism, thereby changing dopamine regulation within the substantia nigra. We show that testosterone action through both AR and ERs modulates synthesis of sex steroid receptor by altering AR and ER mRNA levels in normal adolescent male substantia nigra. Increased sex steroids in the brain at adolescence may alter substantia nigra dopamine pathways, increasing vulnerability for the development of psychopathology.