Oriol Güell

Magnetically driven Janus micro-ellipsoids realized via asymmetric gathering of the magnetic charge.

Spherical microspheres are widely employed for the most disparate purposes, such us to assemble three-dimensional structures, [ 1 ] to realize photonic band-gap materials, [ 2 ] porous membranes, [ 3 ] or to transport and release chemicals. [ 4 ] During standard growth processes, colloidal particles acquire a spherical shape since the latter minimizes the interfacial energy. However, this shape limits the number of new structures which can be assembled by using these particles as building blocks. Thus colloids with tailored anisotropic shape or susceptibility, either electric [ 5 ] or magnetic, [ 6 ] will signifi cantly extend the possibilities to build up new microstructures, [ 7 ] to manipulate the particles via exertion of forces or torques, or to use them as active component in microfl uidics and lab-on-a-chip applications. [ 8 ]

Essential plasticity and redundancy of metabolism unveiled by synthetic lethality analysis.

We unravel how functional plasticity and redundancy are essential mechanisms underlying the ability to survive of metabolic networks. We perform an exhaustive computational screening of synthetic lethal reaction pairs in Escherichia coli in a minimal medium and we find that synthetic lethal pairs divide in two different groups depending on whether the synthetic lethal interaction works as a backup or as a parallel use mechanism, the first corresponding to essential plasticity and the second to essential redundancy. In E. coli, the analysis of pathways entanglement through essential redundancy supports the view that synthetic lethality affects preferentially a single function or pathway. In contrast, essential plasticity, the dominant class, tends to be inter-pathway but strongly localized and unveils Cell Envelope Biosynthesis as an essential backup for Membrane Lipid Metabolism. When comparing E. coli and Mycoplasma pneumoniae, we find that the metabolic networks of the two organisms exhibit a large difference in the relative importance of plasticity and redundancy which is consistent with the conjecture that plasticity is a sophisticated mechanism that requires a complex organization. Finally, coessential reaction pairs are explored in different environmental conditions to uncover the interplay between the two mechanisms. We find that synthetic lethal interactions and their classification in plasticity and redundancy are basically insensitive to medium composition, and are highly conserved even when the environment is enriched with nonessential compounds or overconstrained to decrease maximum biomass formation.

Predicting effects of structural stress in a genome-reduced model bacterial metabolism

Mycoplasma pneumoniae is a human pathogen recently proposed as a genome-reduced model for bacterial systems biology. Here, we study the response of its metabolic network to different forms of structural stress, including removal of individual and pairs of reactions and knockout of genes and clusters of co-expressed genes. Our results reveal a network architecture as robust as that of other model bacteria regarding multiple failures, although less robust against individual reaction inactivation. Interestingly, metabolite motifs associated to reactions can predict the propagation of inactivation cascades and damage amplification effects arising in double knockouts. We also detect a significant correlation between gene essentiality and damages produced by single gene knockouts, and find that genes controlling high-damage reactions tend to be expressed independently of each other, a functional switch mechanism that, simultaneously, acts as a genetic firewall to protect metabolism. Prediction of failure propagation is crucial for metabolic engineering or disease treatment.

Detecting the Significant Flux Backbone of Escherichia coli metabolism

The heterogeneity of computationally predicted reaction fluxes in metabolic networks within a single flux state can be exploited to detect their significant flux backbone. Here, we disclose the backbone of Escherichia coli, and compare it with the backbones of other bacteria. We find that, in general, the core of the backbones is mainly composed of reactions in energy metabolism corresponding to ancient pathways. In E. coli, the synthesis of nucleotides and the metabolism of lipids form smaller cores which rely critically on energy metabolism. Moreover, the consideration of different media leads to the identification of pathways sensitive to environmental changes. The metabolic backbone of an organism is thus useful to trace simultaneously both its evolution and adaptation fingerprints.

Mapping high-growth phenotypes in the flux space of microbial metabolism.

Experimental and empirical observations on cell metabolism cannot be understood as a whole without their integration into a consistent systematic framework. However, the characterization of metabolic flux phenotypes is typically reduced to the study of a single optimal state, such as maximum biomass yield that is by far the most common assumption. Here, we confront optimal growth solutions to the whole set of feasible flux phenotypes (FFPs), which provides a benchmark to assess the likelihood of optimal and high-growth states and their agreement with experimental results. In addition, FFP maps are able to uncover metabolic behaviours, such as aerobic fermentation accompanying exponential growth on sugars at nutrient excess conditions, that are unreachable using standard models based on optimality principles. The information content of the full FFP space provides us with a map to explore and evaluate metabolic behaviour and capabilities, and so it opens new avenues for biotechnological and biomedical applications.

Assessing the Significance and Predicting the Effects of Knockout Cascades in Metabolic Networks

We explore the effects of different forms of structural stress on the robustness of metabolic networks and we use two different kinds of randomization methods [4, 5]. We also explore the effects of single and multiple gene knockouts in the metabolic network of a genome-reduced bacterium.

Cellular Metabolism at the Systems Level

This chapter reviews basic concepts of cellular metabolism. First, an overall view of the architecture of cellular metabolism is given, from the large-scale of Catabolism and Anabolism to biochemical pathways, reactions, and metabolites. Fundamental concepts of chemical kinetics and thermodynamics are mentioned, followed by a brief consideration of key ideas about regulation, control, and evolution of metabolism. Finally, the need for a systems-level approach is discussed. Aims and objectives, together with an outline of this thesis, are included at the end of the chapter.

Structural Knockout Cascades in Metabolic Networks

This chapter presents the analysis of the response of metabolic networks of model organisms to different forms of structural stress, including removals of individual and pairs of reactions and knockouts of single or co-expressed genes.

Methods and Data

This chapter describes the basics of the fundamental techniques used in this thesis. It is divided in three parts: (1) complex network tools applied to metabolism, (2) description of Flux Balance Analysis (FBA)—used to compute metabolic fluxes at steady state—and of Flux Variability Analysis—a variant of FBA to bound minimum and maximum fluxes for each reaction—and (3) a description of all the genome-scale metabolic reconstructions analysed in this thesis.

Effects of Reaction Knockouts on Steady States of Metabolism

The activity and essentiality of metabolic reactions of two model organisms, Escherichia coli and Mycoplasma pneumoniae, are studied using flux balance analysis in different environments. In particular, synthetic lethal pairs correspond to combinations of active and active or inactive non-essential reactions whose simultaneous deletion causes cell death. Lethal knockouts of pairs of reactions separate in two different groups depending on whether the pair of reactions works as a backup or as a parallel use mechanism, the first corresponding to essential plasticity and the second to essential redundancy. Within this perspective, functional plasticity and redundancy are essential mechanisms underlying the ability to survive of metabolic networks.