Augmented Sparse Reconstruction of Protein Signaling Networks

The problem of reconstructing and identifying intracellular protein signaling and biochemical networks is of critical importance in biology today. We sought to develop a mathematical approach to this problem using, as a test case, one of the most well-studied and clinically important signaling networks in biology today, the epidermal growth factor receptor (EGFR) driven signaling cascade. More specifically, we suggest a method, augmented sparse reconstruction, for the identification of links among nodes of ordinary differential equation (ODE) networks from a small set of trajectories with different initial conditions. Our method builds a system of representation by using a collection of integrals of all given trajectories and by attenuating block of terms in the representation itself. The system of representation is then augmented with random vectors, and minimization of the 1-norm is used to find sparse representations for the dynamical interactions of each node. Augmentation by random vectors is crucial, since sparsity alone is not able to handle the large error-in-variables in the representation. Augmented sparse reconstruction allows to consider potentially very large spaces of models and it is able to detect with high accuracy the few relevant links among nodes, even when moderate noise is added to the measured trajectories. After showing the performance of our method on a model of the EGFR protein network, we sketch briefly the potential future therapeutic applications of this approach.Comment: 24 pages, 6 figure

Sustainable metabolic engineering for sustainability optimisation of industrial biotechnology

Funding Information: This research has been supported by the European Regional Development Fund within the project No. 1.1.1.2/VIAA/3/19/528 “Decision Support Tool for an Integrated Food Waste Valorisation System (DeSTInation)” and project No. 1.1.1.1/19/A/047 “Sustainable Microbial Valorisation of Waste Lipids into Biosurfactants”. Funding Information: This research has been supported by the European Regional Development Fund within the project No. 1.1.1.2/VIAA/3/19/528 ?Decision Support Tool for an Integrated Food Waste Valorisation System (DeSTInation)? and project No.?1.1.1.1/19/A/047 ?Sustainable Microbial Valorisation of Waste Lipids into Biosurfactants?. Publisher Copyright: © 2021 The AuthorsIndustrial biotechnology represents one of the most innovating and labour-productive industries with an estimated stable economic growth, thus giving space for improvement of the existing and setting up new value chains. In addition, biotechnology has clear environmental advantages over the chemical industry. Still, biotechnology's environmental contribution is sometimes valued with controversy and societal aspects are frequently ignored. Environmental, economic and societal sustainability of various bioprocesses becomes increasingly important due to the growing understanding about complex and interlinked consequences of different human activities. Neglecting the sustainability issues in the development process of novel solutions may lead to sub-optimal biotechnological production, causing adverse environmental and societal problems proportional to the production volumes. In the paper, sustainable metabolic engineering (SME) concept is proposed to assess and optimize the sustainability of biotechnological production that can be derived from the features of metabolism of the exploited organism. The SME concept is optimization of metabolism where economic, environmental and societal sustainability parameters of all incoming and outgoing fluxes and produced biomass of the applied organisms are considered. The extension of characterising features of strains designed by metabolic engineering methods with sustainability estimation enables ab initio improvement of the biotechnological production design.publishersversionPeer reviewe

Environmental boundary conditions for the origin of life converge to an organo-sulfur metabolism

Published in final edited form as: Nat Ecol Evol. 2019 December ; 3(12): 1715–1724. doi:10.1038/s41559-019-1018-8.It has been suggested that a deep memory of early life is hidden in the architecture of metabolic networks, whose reactions could have been catalyzed by small molecules or minerals before genetically encoded enzymes. A major challenge in unravelling these early steps is assessing the plausibility of a connected, thermodynamically consistent proto-metabolism under different geochemical conditions, which are still surrounded by high uncertainty. Here we combine network-based algorithms with physico-chemical constraints on chemical reaction networks to systematically show how different combinations of parameters (temperature, pH, redox potential and availability of molecular precursors) could have affected the evolution of a proto-metabolism. Our analysis of possible trajectories indicates that a subset of boundary conditions converges to an organo-sulfur-based proto-metabolic network fuelled by a thioester- and redox-driven variant of the reductive tricarboxylic acid cycle that is capable of producing lipids and keto acids. Surprisingly, environmental sources of fixed nitrogen and low-potential electron donors are not necessary for the earliest phases of biochemical evolution. We use one of these networks to build a steady-state dynamical metabolic model of a protocell, and find that different combinations of carbon sources and electron donors can support the continuous production of a minimal ancient 'biomass' composed of putative early biopolymers and fatty acids.80NSSC17K0295 - Intramural NASA; 80NSSC17K0296 - Intramural NASA; T32 GM100842 - NIGMS NIH HHSAccepted manuscrip

Demand response within the energy-for-water-nexus - A review. ESRI WP637, October 2019

A promising tool to achieve more flexibility within power systems is demand re-sponse (DR). End-users in many strands of industry have been subject to research up to now regarding the opportunities for implementing DR programmes. One sector that has received little attention from the literature so far, is wastewater treatment. However, case studies indicate that the potential for wastewater treatment plants to provide DR services might be significant. This review presents and categorises recent modelling approaches for industrial demand response as well as for the wastewater treatment plant operation. Furthermore, the main sources of flexibility from wastewater treatment plants are presented: a potential for variable electricity use in aeration, the time-shifting operation of pumps, the exploitation of built-in redundan-cy in the system and flexibility in the sludge processing. Although case studies con-note the potential for DR from individual WWTPs, no study acknowledges the en-dogeneity of energy prices which arises from a large-scale utilisation of DR. There-fore, an integrated energy systems approach is required to quantify system and market effects effectively

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field

The protein cost of metabolic fluxes: prediction from enzymatic rate laws and cost minimization

Bacterial growth depends crucially on metabolic fluxes, which are limited by the cell's capacity to maintain metabolic enzymes. The necessary enzyme amount per unit flux is a major determinant of metabolic strategies both in evolution and bioengineering. It depends on enzyme parameters (such as kcat and KM constants), but also on metabolite concentrations. Moreover, similar amounts of different enzymes might incur different costs for the cell, depending on enzyme-specific properties such as protein size and half-life. Here, we developed enzyme cost minimization (ECM), a scalable method for computing enzyme amounts that support a given metabolic flux at a minimal protein cost. The complex interplay of enzyme and metabolite concentrations, e.g. through thermodynamic driving forces and enzyme saturation, would make it hard to solve this optimization problem directly. By treating enzyme cost as a function of metabolite levels, we formulated ECM as a numerically tractable, convex optimization problem. Its tiered approach allows for building models at different levels of detail, depending on the amount of available data. Validating our method with measured metabolite and protein levels in E. coli central metabolism, we found typical prediction fold errors of 3.8 and 2.7, respectively, for the two kinds of data. ECM can be used to predict enzyme levels and protein cost in natural and engineered pathways, establishes a direct connection between protein cost and thermodynamics, and provides a physically plausible and computationally tractable way to include enzyme kinetics into constraint-based metabolic models, where kinetics have usually been ignored or oversimplified

Optimization techniques in respiratory control system models

One of the most complex physiological systems whose modeling is still an open study is the respiratory control system where different models have been proposed based on the criterion of minimizing the work of breathing (WOB). The aim of this study is twofold: to compare two known models of the respiratory control system which set the breathing pattern based on quantifying the respiratory work; and to assess the influence of using direct-search or evolutionary optimization algorithms on adjustment of model parameters. This study was carried out using experimental data from a group of healthy volunteers under CO2 incremental inhalation, which were used to adjust the model parameters and to evaluate how much the equations of WOB follow a real breathing pattern. This breathing pattern was characterized by the following variables: tidal volume, inspiratory and expiratory time duration and total minute ventilation. Different optimization algorithms were considered to determine the most appropriate model from physiological viewpoint. Algorithms were used for a double optimization: firstly, to minimize the WOB and secondly to adjust model parameters. The performance of optimization algorithms was also evaluated in terms of convergence rate, solution accuracy and precision. Results showed strong differences in the performance of optimization algorithms according to constraints and topological features of the function to be optimized. In breathing pattern optimization, the sequential quadratic programming technique (SQP) showed the best performance and convergence speed when respiratory work was low. In addition, SQP allowed to implement multiple non-linear constraints through mathematical expressions in the easiest way. Regarding parameter adjustment of the model to experimental data, the evolutionary strategy with covariance matrix and adaptation (CMA-ES) provided the best quality solutions with fast convergence and the best accuracy and precision in both models. CMAES reached the best adjustment because of its good performance on noise and multi-peaked fitness functions. Although one of the studied models has been much more commonly used to simulate respiratory response to CO2 inhalation, results showed that an alternative model has a more appropriate cost function to minimize WOB from a physiological viewpoint according to experimental data.Postprint (author's final draft