Optimization-based models have been used to predict cellular behavior for over 25 years. The constraints in these models are derived from genome annotations, measured macro-molecular composition of cells, and by measuring the cell's growth rate and metabolism in different conditions. The cellular goal (the optimization problem that the cell is trying to solve) can be challenging to derive experimentally for many organisms, including human or mammalian cells, which have complex metabolic capabilities and are not well understood. Existing approaches to learning goals from data include (a) estimating a linear objective function, or (b) estimating linear constraints that model complex biochemical reactions and constrain the cell's operation. The latter approach is important because often the known observed biochemical reactions are not enough to explain observations, and hence there is a need to extend automatically the model complexity by learning new chemical reactions. However, this leads to nonconvex optimization problems, and existing tools cannot scale to realistically large metabolic models. Hence, constraint estimation is still used sparingly despite its benefits for modeling cell metabolism, which is important for developing novel antimicrobials against pathogens, discovering cancer drug targets, and producing value-added chemicals. Here, we develop the first approach to estimating constraint reactions from data that can scale to realistically large metabolic models. Previous tools have been used on problems having less than 75 biochemical reactions and 60 metabolites, which limits real-life-size applications. We perform extensive experiments using 75 large-scale metabolic network models for different organisms (including bacteria, yeasts, and mammals) and show that our algorithm can recover cellular constraint reactions, even when some measurements are missing.
As of mid-2013, over 640 published studies used COBRA for experimental investigation in various domains of engineering and health sciences @cite_30 . Successful applications of COBRA include engineering microbes to produce commodity or valuable chemicals @cite_7 , developing novel antimicrobials against infectious disease @cite_29 , and discovering new drug targets against cancer @cite_39 .
@cite_30 @cite_29 @cite_7 @cite_39
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Genome-scale models of metabolism and macromolecular expression (ME-models) explicitly compute the optimal proteome composition of a growing cell. ME-models expand upon the well-established genome-scale models of metabolism (M-models), and they enable a new fundamental understanding of cellular growth. ME-models have increased predictive capabilities and accuracy due to their inclusion of the biosynthetic costs for the machinery of life, but they come with a significant increase in model size and complexity. This challenge results in models which are both difficult to compute and challenging to understand conceptually. As a result, ME-models exist for only two organisms (Escherichia coli and Thermotoga maritima) and are still used by relatively few researchers. To address these challenges, we have developed a new software framework called COBRAme for building and simulating ME-models. It is coded in Python and built on COBRApy, a popular platform for using M-models. COBRAme streamlines computation and analysis of ME-models. It provides tools to simplify constructing and editing ME-models to enable ME-model reconstructions for new organisms. We used COBRAme to reconstruct a condensed E. coli ME-model called iJL1678b-ME. This reformulated model gives functionally identical solutions to previous E. coli ME-models while using 1 5 the number of free variables and solving in less than 10 minutes, a marked improvement over the 6 hour solve time of previous ME-model formulations. Errors in previous ME-models were also corrected leading to 52 additional genes that must be expressed in iJL1678b-ME to grow aerobically in glucose minimal in silico media. This manuscript outlines the architecture of COBRAme and demonstrates how ME-models can be created, modified, and shared most efficiently using the new software framework. Received 28 May 2002; revised 18 September 2002; accepted 24 September 2002; published 14 February 2003. [1] When an inverse problem is solved to estimate an unknown function such as the hydraulic conductivity in an aquifer or the contamination history at a site, one constraint is that the unknown function is known to be everywhere nonnegative. In this work, we develop a statistically rigorous method for enforcing function nonnegativity in Bayesian inverse problems. The proposed method behaves similarly to a Gaussian process with a linear variogram (i.e., unrestricted Brownian motion) for parameter values significantly greater than zero. The method uses the method of images to define a prior probability density function based on reflected Brownian motion that implicitly enforces nonnegativity. This work focuses on problems where the unknown is a function of a single variable (e.g., time). A Markov chain Monte Carlo (MCMC) method, specifically, a highly efficient Gibbs sampler, is implemented to generate conditional realizations of the unknown function. The new method is applied to the estimation of the trichloroethylene (TCE) and perchloroethylene (PCE) contamination history in an aquifer at Dover Air Force Base, Delaware, based on concentration profiles obtained from an underlying aquitard. INDEX TERMS: 1831 Hydrology: Groundwater quality; 1869 Hydrology: Stochastic processes; 3260 Mathematical Geophysics: Inverse theory; KEYWORDS: stochastic inverse modeling, contaminant source identification, inference under constraints, Markov chain Monte Carlo (MCMC), Gibbs sampling, Bayesian inference In de novo drug design, computational strategies are used to generate novel molecules with good affinity to the desired biological target. In this work, we show that recurrent neural networks can be trained as generative models for molecular structures, similar to statistical language models in natural language processing. We demonstrate that the properties of the generated molecules correlate very well with the properties of the molecules used to train the model. In order to enrich libraries with molecules active towards a given biological target, we propose to fine-tune the model with small sets of molecules, which are known to be active against that target. Against Staphylococcus aureus, the model reproduced 14 of 6051 hold-out test molecules that medicinal chemists designed, whereas against Plasmodium falciparum (Malaria) it reproduced 28 of 1240 test molecules. When coupled with a scoring function, our model can perform the complete de novo drug design cycle to generate large sets of novel molecules for drug discovery. Abstract Chemo-resistive transduction presents practical advantages for capturing the spatio-temporal and structural organization of chemical compounds dispersed in different human habitats. In an open sampling system, however, where the chemo-sensory elements are directly exposed to the environment being monitored, the identification and monitoring of chemical substances present a more difficult challenge due to the dispersion mechanisms of gaseous chemical analytes, namely diffusion, turbulence, and advection. The success of such actively changeable practice is influenced by the adequate implementation of algorithmically driven formalisms combined with the appropriate design of experimental protocols. On the basis of this functional joint-formulation, in this study we examine an innovative methodology based on the inhibitory processing mechanisms encountered in the structural assembly of the insect's brain, namely Inhibitory Support Vector Machine (ISVM) applied to training a sensor array platform and evaluate its capabilities relevant to odor detection and identification under complex environmental conditions. We generated — and made publicly available — an extensive and unique dataset with a chemical detection platform consisting of 72 conductometric met al-oxide based chemical sensors in a custom-designed wind tunnel test-bed facility to test our methodology. Our findings suggest that the aforementioned methodology can be a valuable tool to guide the decision of choosing the training conditions for a cost-efficient system calibration as well as an important step toward the understanding of the degradation level of the sensory system when the environmental conditions change.