Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks

The gene regulatory network (GRN) is the central decision‐making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large‐scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. DOI: http://dx.doi.org/10.7554/eLife.02863.00

3 tera-basepairs as a fundamental limit for robust DNA replication

10 p.-2 tab.In order to maintain functional robustness and species integrity, organisms must ensure high fidelity of the genome duplication process. This is particularly true during early development, where cell division is often occurring both rapidly and coherently. By studying the extreme limits of suppressing DNA replication failure due to double fork stall errors, we uncover a fundamental constant that describes a trade-off between genome size and architectural complexity of the developing organism. This constant has the approximate value N_U ≈ 3×10^12 basepairs, and depends only on two highly conserved molecular properties of DNA biology. We show that our theory is successful in interpreting a diverse range of data across the Eukaryota.MAM, LA and TJN acknowledge prior support from the Scottish Universities Life Sciences Alliance. JJB acknowledges support from Cancer Research UK (grant C303/A14301) and the Wellcome Trust (grant WT096598MA). TJN acknowledges prior support from the National Institutes of Health (Physical Sciences in Oncology Centers, U54 CA143682).Peer reviewe

Interaction Between Fast Ions and Microturbulence in Thermonuclear Devices:Theory and Modelling

The work carried out in this thesis focuses on the interaction between fast ions and turbulence. The aim of the project is to explore this phenomenon and develop the numerical framework required for investigations on present day machines and predictions for burning plasmas. The analysis of the background plasma turbulence and the resulting fast ion diffusivities is carried out with the gyrokinetic code GENE. A set of kinetic transport quantities are defined in order to discriminate the transport of ions with different energies. Gyroaveraging effects are studied. It is observed that only at large values of the E/Te ratio is the particle transport efficiently suppressed (E is the energy of a fast particle and Te the electron temperature). For smaller values, E/Te < 15, larger fast ion transport is observed due to resonant interactions between the particle motion and the phase velocity of the underlying turbulent waves. The transport of fusion generated alpha particles induced by electrostatic fluctuations is lower than collisional expectations, due to their large energies. Magnetic turbulence has an even smaller effect. To verify whether similar conclusions can be drawn for neutral beam ions, substantial upgrades to the VENUS code have been implemented. The results of numerical simulations of the beam ion transport in ITER, DEMO and TCV, with the inclusion of collisional and turbulent effects, are discussed. It is demonstrated that the transport of the 1 MeV ions generated by the neutral beam injector of ITER is only marginally affected by microturbulence and it is concluded that fast ion confinement is not compromised. Given the large plasma temperatures foreseen for DEMO, anomalous transport of beam ions is significant, and in particular collisional models fail to estimate the correct heat deposited on the ions and the electrons. Given the low energy of the planned TCV NBI injector, even stronger anomalies are expected. The effect, however, can be regulated with auxiliary ECRH heating, which would allow for new studies of the fast ion turbulent transport

A PETRI NET MODEL OF LIVER RESPONSE TO VISCERAL LEISHMANIASIS: SELF-REGULATION AND COMPLEX INTERPLAY IN THE VERTEBRATE IMMUNE SYSTEM

Visceral leishmaniasis (also called "Kala-azar") is a widespread disease, which is usually fatal in the absence of treatment. Characteristic of the liver immune response to leishmaniasis is a type of inflammation (granulomatous inflammation) that leads to the formation of "granulomas". A granuloma provides a very interesting micro-environment, which is maintained by the coordination of many cells of the immune system. Due to the complexity of the immune response, only a limited amount of modeling work exists in the context of granulomatous infection, and most of the current models focus only on the formation stage of granulomas. The primary goal of this thesis is to gain insights into the process of formation and development of a granuloma. To this end, we built a model of the granuloma formation and resolution in the liver using stochastic Petri nets, and performed several in silico experiments to study the nature of the immune response to leishmaniasis, possible therapeutic options, and the role of the cells involved. Additionally, the building of the model is extensively documented, and the most important qualitative and quantitative assumptions are referenced and discussed, with the aim of presenting a \u201cconceptual framework\u201d to be used when facing similar problems. The model is validated against available biological data, and its robustness is assessed using sensitivity analysis

Universal attenuators and their interactions with feedback loops in gene regulatory networks

Using a combination of mathematical modelling, statistical simulation and large-scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analyzing the preponderance of LRCs in the GRNs of Escherichia coli K12 and several other organisms, we find that very long LRCs are essentially absent. In both E. coli and M. tuberculosis we find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as 'universal attenuators'. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs.</p

Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers

The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred. Those genes and proteins that have survived from the 2R-WGD—termed 2R-ohnologues—belong to families of two to four members, and are enriched in signalling components relevant to cancer. Here, we find that while only approximately 30% of human transcript-coding genes are 2R-ohnologues, they carry 42–60% of the gene mutations in 30 different cancer types. Across a subset of cancer datasets, including melanoma, breast, lung adenocarcinoma, liver and medulloblastoma, we identified 673 2R-ohnologue families in which one gene carries mutations at multiple positions, while sister genes in the same family are relatively mutation free. Strikingly, in 315 of the 322 2R-ohnologue families displaying such a skew in multiple cancers, the same gene carries the heaviest mutation load in each cancer, and usually the second-ranked gene is also the same in each cancer. Our findings inspire the hypothesis that in certain cancers, heterogeneous combinations of genetic changes impair parts of the 2R-WGD signalling networks and force information flow through a limited set of oncogenic pathways in which specific non-mutated 2R-ohnologues serve as effectors. The non-mutated 2R-ohnologues are therefore potential therapeutic targets. These include proteins linked to growth factor signalling, neurotransmission and ion channels

Evidence for a new path to the self-sustainment of the thermonuclear fusion in magnetically confined burning plasma experiments

In this work we provide the first explanation for observations made in 1997 on the Joint European Torus of unexpected ion heating with fusion-born alpha particles occurring over time scales much shorter than those theoretically foreseen. We demonstrate that non-thermal alpha particles above a critical concentration stabilize ion-drift-wave turbulence, therefore significantly reducing one of the main energy loss channels for thermal ions. As such ion heating occurs over times scales much shorter than those classically predicted, this mechanism opens new prospects on additional paths for the self-sustainment of thermonuclear fusion reactions in magnetically confined plasmas

A phenomenological explanation for the anomalous ion heating observed in the JET alpha-heating experiment of 1997

In the so-called alpha-heating experiment performed on the JET tokamak during the deuterium-tritium campaign of 1997, the ion temperature was found to be far exceeding (both in absolute value and in its rise time) the level that could have been expected from direct collisional heating by the fusion-born alpha particles themselves and energy equi-partition with the electrons. To date, no explanation has been put forward for this long standing puzzle, despite much work having been performed on this subject in the early 2000s. Two analysis methods that have recently become available have been employed to re-analyse these observations of an anomalous ion heating. First, an algorithm based on the Sparse Representation of Signals has been used to analyse magnetic, reflectometry and electron cyclotron emission measurements of the turbulence spectra in the drift-wave range of frequencies. This analysis has then been complemented with turbulence simulations performed with the GENE code. We find, both experimentally and in the simulations, that the presence of a minority, but sufficiently large, population of fusion-born alpha particles that have not yet fully thermalized stabilizes the turbulence in the ion-drift direction, but practically does not affect the turbulence in the electron-drift direction. We link such stabilization of the ion-drift-wave turbulence to the increase in the ion temperature above the level achieved in similar discharges that did not have (at all or enough) alpha particles. When the fusion-born alpha particles have fully thermalized, the turbulence spectrum in the ion-drift direction re-appears at somewhat larger amplitudes, which we link to the ensuing reduction in the ion temperature. This phenomenological dynamics fully corresponds to the actual experimental observations. By taking into account an effect of the alpha particles that had not been previously considered, our new analysis finally presents a phenomenological explanation for the so-far-unexplained anomalous ion heating observed in the JET alpha-heating experiment of 1997. Through the formulation of an empirical criterion for ion-drift-wave turbulence stabilization by fusion-born alpha particles, we also show why similar observations were not made in the other deuterium-tritium experiments run so far in JET and TFTR. This allows assessing the operational domain for this stabilization mechanism for ion-drift-wave turbulence in future burning plasma experiments such as ITER, which may open a new path towards the sustainment of a high energy gain in such forthcoming devices