Robust set stabilization of Boolean control networks with impulsive effects

This paper addresses the robust set stabilization problem of Boolean control networks (BCNs) with impulsive effects via the semi-tensor product method. Firstly, the closed-loop system consisting of a BCN with impulsive effects and a given state feedback control is converted into an algebraic form. Secondly, based on the algebraic form, some necessary and sufficient conditions are presented for the robust set stabilization of BCNs with impulsive effects under a given state feedback control and a free-form control sequence, respectively. Thirdly, as applications, some necessary and sufficient conditions are presented for robust partial stabilization and robust output tracking of BCNs with impulsive effects, respectively. The study of two illustrative examples shows that the obtained new results are effective

Transient and stochastic dynamics in cellular processes

This Thesis studies different cellular and cell population processes driven by non-linear and stochastic dynamics. The problems addressed here gravitate around the concepts of transient dynamics and relaxation from a perturbed to a steady state. In this regard, in all processes studied, stochastic fluctuations, either intrinsically present in or externally applied to these systems play an important and constructive role, by either driving the systems out of equilibrium, interfering with the underlying deterministic laws, or establishing suitable levels of heterogeneity. The first part of the Thesis is committed the analysis of genetically regulated transient cellular processes. Here, we analyse, from a theoretical standpoint, three genetic circuits with pulsed excitable dynamics. We show that all circuits can work in two different excitable regimes, in contrast to what was previously speculated. We also study how, in the presence of molecular noise, these excitable circuits can generate periodic polymodal pulses due to the combination of two noise induced phenomena: stabilisation of an unstable spiral point and coherence resonance. We also studied an excitable genetic mechanism for the regulation of the transcriptional fluctuations observed in some pluripotency factors in Embryonic Stem cells. In the embryo, pluripotency is a transient cellular state and the exit of cells from it seems to be associated with transcriptional fluctuations. In regard to pluripotency control, we also propose a novel mechanism based on the post-translational regulation of a small set of four pluripotency factors. We have validated the theoretical model, based on the formation of binary complexes among these factors, with quantitative experimental data at the single-cell level. The model suggests that the pluripotency state does not depend on the cellular levels of a single factor, but rather on the equilibrium of correlations between the different proteins. In addition, the model is able to anticipate the phenotype of several mutant cell types and suggests that the regulatory function of the protein interactions is to buffer the transcriptional activity of Oc4, a key pluripotency factor. In the second part of the Thesis we studied the behaviour of a computational cell signalling network of the human fibroblast in the presence of external fluctuations and signals. The results obtained here indicate that the network responds in a nontrivial manner to background chatter, both intrinsically and in the presence of external periodic signals. We show that these responses are consequence of the rerouting of the signal to different network information-transmission paths that emerge as noise is modulated. Finally, we also study the cell population dynamics during the formation of microbial biofilms, wrinkled pellicles of bacteria glued by an extracellular matrix that are one of the simplest cases of self-organised multicellular structures. In this Thesis we develop a spatiotemporal model of cellular growth and death that accounts for the experimentally observed patterns of massive bacterial death that precede wrinkle formation in biofilms. These localised patterns focus mechanical forces during biofilm expansion and trigger the formation of the characteristic ridges. In this sense, the proposed model suggests that the death patterns emerge from the mobility changes in bacteria due to the production of extracellular matrix and the spatially inhomogeneous cellular growth. An important prediction of the model is that matrix productions is crucial for the appearance of the patterns and, therefore for winkle formation. We have also experimentally validated validated this prediction with matrix deficient bacterial strains, which show neither death patterns nor wrinkles.En aquesta Tesi s’estudien diferents processos intracel·lulars i de poblacions cel·lulars regits per dinàmica estocàstica i no lineal. El problemes biològics tractats graviten al voltant el concepte de dinàmica transitòria i de relaxació d’un estat dinàmic pertorbat a l’estat estacionari. En aquest sentit, en tots els processos estudiats, les fluctuacions estocàstiques, presents intrínsecament o aplicades de forma externa, hi tenen un paper constructiu, ja sigui empenyent els sistemes fora de l’equilibri, interferint amb les lleis deterministes subjacents, o establint els nivells d’heterogeneïtat necessaris. La primera part de la Tesi es dedica a l’estudi de processos cel·lulars transitoris regulats genèticament. En ella analitzem des d’un punt de vista teòric tres circuits genètics de control de polsos excitables i, contràriament al que s’havia especulat anteriorment, establim que tots ells poden treballar en dos tipus de règim excitable. Analitzem també com, en presència de soroll molecular, aquests circuits excitables poden generar polsos periòdics i multimodals degut a la combinació de dos fenòmens induïts per soroll: l’estabilització estocàstica d’estats inestables i la ressonància de coherència. D’altra banda, estudiem com un mecanisme genètic excitable pot ser el responsable de regular a nivell transcripcional les fluctuacions que s’observen experimentalment en alguns factors de pluripotència en cèl·lules mare embrionàries. En l’embrió, la pluripotència és un estat cel·lular transitori i la sortida de les cèl·lules d’aquest sembla que està associada a fluctuacions transcripcionals. En relació al control de la pluripotència, presentem també un nou mecanisme basat en la regulació post-traduccional d’un petit conjunt de 4 factors de pluripotència. El model teòric proposat, basat en la formació de complexos entre els diferents factors de pluripotència, l’hem validat mitjançant experiments quantitatius en cèl·lules individuals. El model postula que l’estat de pluripotència no depèn dels nivells cel·lulars d’un únic factor, sinó d’un equilibri de correlacions entre diverses proteïnes. A més, prediu el fenotip de cèl·lules mutants i suggereix que la funció reguladora de les interaccions entre les quatre proteïnes és la d’esmorteir l’activitat transcripcional d’Oct4, un dels principals factors de pluripotència. En el segon apartat de la Tesi estudiem el comportament d’una xarxa computacional de senyalització cel·lular de fibroblast humà en presència de senyals externs fluctuants i cíclics. Els resultats obtinguts mostren que la xarxa respon de forma no trivial a les fluctuacions ambientals, fins i tot en presència d’una senyal externa. Diferents nivells de soroll permeten modular la resposta de la xarxa, mitjançant la selecció de rutes alternatives de transmissió de la informació. Finalment, estudiem la dinàmica de poblacions cel·lulars durant la formació de biofilms, pel·lícules arrugades d’aglomerats de bacteris que conformen un dels exemples més simples d’estructures multicel·lulars autoorganitzades. En aquesta Tesi presentem un model espai-temporal de creixement i mort cel·lular motivat per l’evidència experimental sobre l’aparició de patrons de mort massiva de bacteris previs a la formació de les arrugues dels biofilms. Aquests patrons localitzats concentren les forces mecàniques durant l’expansió del biofilm i inicien la formació de les arrugues característiques. En aquest sentit, el model proposat explica com es formen els patrons de mort a partir dels canvis de mobilitat dels bacteris deguts a la producció de matriu extracel·lular combinats amb un creixement espacialment heterogeni. Una important predicció del model és que la producció de matriu és un procés clau per a l’aparició dels patrons i, per tant de les arrugues. En aquest aspecte, els nostres resultats experimentals en bacteris mutants que no produeixen components essencials de la matriu, confirmen les prediccions

A sequentially constructive circuit semantics for Esterel

Static Single Assignment (SSA) is an established concept that facilitates various program optimizations. However, it is typically restricted to sequential programming. We present an approach that extends SSA for concurrent, reactive programming, specifically for the synchronous language Esterel. This extended SSA transformation expands the class of programs that can be compiled by existing Esterel compilers without causality problems. It also offers a new, efficient solution for the well-studied signal reincarnation problem. Finally, our approach rules out speculation/backtracking, unlike the recently proposed sequentially constructive model of computation

Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate in silico (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways

A probabilistic chemical programmable computer

The exponential growth of the power of modern digital computers is based upon the miniaturisation of vast nanoscale arrays of electronic switches, but this will be eventually constrained by fabrication limits and power dissipation. Chemical processes have the potential to scale beyond these limits performing computations through chemical reactions, yet the lack of well-defined programmability limits their scalability and performance. We present a hybrid digitally programmable chemical array as a probabilistic computational machine that uses chemical oscillators partitioned in interconnected cells as a computational substrate. This hybrid architecture performs efficient computation by distributing between chemical and digital domains together with error correction. The efficiency is gained by combining digital with probabilistic chemical logic based on nearest neighbour interactions and hysteresis effects. We demonstrated the implementation of one- and two- dimensional Chemical Cellular Automata and solutions to combinatorial optimization problems.Comment: 20 page manuscript, 6 figures, 112 page supplementary volum