The role of mRNA and protein stability in the function of coupled positive and negative feedback systems in eukaryotic cells

Oscillators and switches are important elements of regulation in biological systems. These are composed of coupling negative feedback loops, which cause oscillations when delayed, and positive feedback loops, which lead to memory formation. Here, we examine the behavior of a coupled feedback system, the Negative Autoregulated Frustrated bistability motif (NAF). This motif is a combination of two previously explored motifs, the frustrated bistability motif (FBM) and the negative auto regulation motif (NAR), which both can produce oscillations. The NAF motif was previously suggested to govern long term memory formation in animals, and was used as a synthetic oscillator in bacteria. We build a mathematical model to analyze the dynamics of the NAF motif. We show analytically that the NAF motif requires an asymmetry in the strengths of activation and repression links in order to produce oscillations. We show that the effect of time delays in eukaryotic cells, originating from mRNA export and protein import, are negligible in this system. Based on the reported protein and mRNA half-lives in eukaryotic cells, we find that even though the NAF motif possesses the ability for oscillations, it mostly promotes constant protein expression at the biologically relevant parameter regimes

Fragile DNA Repair Mechanism Reduces Ageing in Multicellular Model

DNA damages, as well as mutations, increase with age. It is believed that these result from increased genotoxic stress and decreased capacity for DNA repair. The two causes are not independent, DNA damage can, for example, through mutations, compromise the capacity for DNA repair, which in turn increases the amount of unrepaired DNA damage. Despite this vicious circle, we ask, can cells maintain a high DNA repair capacity for some time or is repair capacity bound to continuously decline with age? We here present a simple mathematical model for ageing in multicellular systems where cells subjected to DNA damage can undergo full repair, go apoptotic, or accumulate mutations thus reducing DNA repair capacity. Our model predicts that at the tissue level repair rate does not continuously decline with age, but instead has a characteristic extended period of high and non-declining DNA repair capacity, followed by a rapid decline. Furthermore, the time of high functionality increases, and consequently slows down the ageing process, if the DNA repair mechanism itself is vulnerable to DNA damages. Although counterintuitive at first glance, a fragile repair mechanism allows for a faster removal of compromised cells, thus freeing the space for healthy peers. This finding might be a first step toward understanding why a mutation in single DNA repair protein (e.g. Wrn or Blm) is not buffered by other repair proteins and therefore, leads to severe ageing disorders

Asymmetric segregation of damaged cellular components in spatially structured multicellular organisms.

The asymmetric distribution of damaged cellular components has been observed in species ranging from fission yeast to humans. To study the potential advantages of damage segregation, we have developed a mathematical model describing ageing mammalian tissue, that is, a multicellular system of somatic cells that do not rejuvenate at cell division. To illustrate the applicability of the model, we specifically consider damage incurred by mutations to mitochondrial DNA, which are thought to be implicated in the mammalian ageing process. We show analytically that the asymmetric distribution of damaged cellular components reduces the overall damage level and increases the longevity of the cell population. Motivated by the experimental reports of damage segregation in human embryonic stem cells, dividing symmetrically with respect to cell-fate, we extend the model to consider spatially structured systems of cells. Imposing spatial structure reduces, but does not eliminate, the advantage of asymmetric division over symmetric division. The results suggest that damage partitioning could be a common strategy for reducing the accumulation of damage in a wider range of cell types than previously thought

Moderate stem-cell telomere shortening rate postpones cancer onset in a stochastic model

Mammalian cells are restricted from proliferating indefinitely. Telomeres at the end of each chromosome are shortened at cell division and, when they reach a critical length, the cell will enter permanent cell cycle arrest - a state known as senescence. This mechanism is thought to be tumor suppressing, as it helps prevent precancerous cells from dividing uncontrollably. Stem cells express the enzyme telomerase, which elongates the telomeres, thereby postponing senescence. However, unlike germ cells and most types of cancer cells, stem cells only express telomerase at levels insufficient to fully maintain the length of their telomeres leading to a slow decline in proliferation potential. It is not yet fully understood how this decline influences the risk of cancer and the longevity of the organism. We here develop a stochastic model to explore the role of telomere dynamics in relation to both senescence and cancer. The model describes the accumulation of cancerous mutations in a multicellular organism and creates a coherent theoretical framework for interpreting the results of several recent experiments on telomerase regulation. We demonstrate that the longest average cancer free life span before cancer onset is obtained when stem cells start with relatively long telomeres that are shortened at a steady rate at cell division. Furthermore, the risk of cancer early in life can be reduced by having a short initial telomere length. Finally, our model suggests that evolution will favour a shorter than optimal average cancer free life span in order to postpone cancer onset until late in life

Expert Game experiment predicts emergence of trust in professional communication networks

Strong social capital is increasingly recognized as an organizational advantage. Better knowledge sharing and reduced transaction costs increase work efficiency. To mimic the formation of the associated communication network, we propose the Expert Game, where each individual must find a specific expert and receive her help. Participants act in an impersonal environment and under time constraints that provide short-term incentives for noncooperative behavior. Despite these constraints, we observe cooperation between individuals and the self-organization of a sustained trust network, which facilitates efficient communication channels with increased information flow. We build a behavioral model that explains the experimental dynamics. Analysis of the model reveals an exploitation protection mechanism and measurable social capital, which quantitatively describe the economic utility of trust

a) The time spent in steady state increases with the initial repair rate , rate of apoptosis <i>a</i>, and fragility of the repair mechanism Δ. (Parameters that are not varied are set to the values given in the caption of figure 2) b) For the well mixed system, the time spent at steady state, increases drastically with system size <i>N</i>. For spatially structured systems the increase is linear. (Parameters used: ),

<p>a) The time spent in steady state increases with the initial repair rate , rate of apoptosis <i>a</i>, and fragility of the repair mechanism Δ. (Parameters that are not varied are set to the values given in the caption of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036018#pone-0036018-g002" target="_blank">figure 2</a>) b) For the well mixed system, the time spent at steady state, increases drastically with system size <i>N</i>. For spatially structured systems the increase is linear. (Parameters used: ), </p

Time development of a spatially organized cell population that divides symmetrically (a) and asymmetrically (b).

<p>Initially, all cells have damage level , but soon clusters of damaged cells occur. The boundary between damaged and less damaged clusters performs a random walk with a drift towards the more damaged cells, since these are less likely to go apoptotic. Eventually the system will collapse to a state where all cells have damage level . This happens much sooner for a symmetrically dividing cell population than for one that divides asymmetrically. The parameters are: , , . Other choices of parameters yield similar results.</p