SummaryThe plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here, we present a protein-DNA network between Arabidopsis transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.
Given the vast behavioral repertoire and biological complexity of even the simplest organisms, accurately predicting phenotypes in novel environments and unveiling their biological organization is a challenging endeavor. Here, we present an integrative modeling methodology that unifies under a common framework the various biological processes and their interactions across multiple layers. We trained this methodology on an extensive normalized compendium for the gram-negative bacterium Escherichia coli, which incorporates gene expression data for genetic and environmental perturbations, transcriptional regulation, signal transduction, and metabolic pathways, as well as growth measurements. Comparison with measured growth and high-throughput data demonstrates the enhanced ability of the integrative model to predict phenotypic outcomes in various environmental and genetic conditions, even in cases where their underlying functions are under-represented in the training set. This work paves the way toward integrative techniques that extract knowledge from a variety of biological data to achieve more than the sum of their parts in the context of prediction, analysis, and redesign of biological systems.
The development of a scalable framework for biodesign automation is a formidable challenge given the expected increase in part availability and the ever-growing complexity of synthetic circuits. To allow for (a) the use of previously constructed and characterized circuits or modules and (b) the implementation of designs that can scale up to hundreds of nodes, we here propose a divide-and-conquer Synthetic Biology Reusable Optimization Methodology (SBROME). An abstract user-defined circuit is first transformed and matched against a module database that incorporates circuits that have previously been experimentally characterized. Then the resulting circuit is decomposed to subcircuits that are populated with the set of parts that best approximate the desired function. Finally, all subcircuits are subsequently characterized and deposited back to the module database for future reuse. We successfully applied SBROME toward two alternative designs of a modular 3-input multiplexer that utilize pre-existing logic gates and characterized biological parts.
A tantalizing question in evolutionary biology is whether evolution can be predicted from past experiences. To address this question, we created a coherent compendium of more than 15,000 mutation events for the bacterium Escherichia coli under 178 distinct environmental settings. Compendium analysis provides a comprehensive view of the explored environments, mutation hotspots and mutation co-occurrence. While the mutations shared across all replicates decrease with the number of replicates, our results argue that the pairwise overlapping ratio remains the same, regardless of the number of replicates. An ensemble of predictors trained on the mutation compendium and tested in forward validation over 35 evolution replicates achieves a 49.2 ± 5.8% (mean ± std) precision and 34.5 ± 5.7% recall in predicting mutation targets. This work demonstrates how integrated datasets can be harnessed to create predictive models of evolution at a gene level and elucidate the effect of evolutionary processes in well-defined environments.
BackgroundA tantalizing question in medical informatics is how to construct knowledge from heterogeneous datasets, and as an extension, inform clinical decisions. The emergence of large-scale data integration in electronic health records (EHR) presents tremendous opportunities. However, our ability to efficiently extract informed decision support is limited due to the complexity of the clinical states and decision process, missing data and lack of analytical tools to advice based on statistical relationships.ObjectiveDevelopment and assessment of a data-driven method that infers the probability distribution of the current state of patients with sepsis, likely trajectories, optimal actions related to antibiotic administration, prediction of mortality and length-of-stay.MethodsWe present a data-driven, probabilistic framework for clinical decision support in sepsis-related cases. We first define states, actions, observations and rewards based on clinical practice, expert knowledge and data representations in an EHR dataset of 1492 patients. We then use Partially Observable Markov Decision Process (POMDP) model to derive the optimal policy based on individual patient trajectories and we evaluate the performance of the model-derived policies in a separate test set. Policy decisions were focused on the type of antibiotic combinations to administer. Multi-class and discriminative classifiers were used to predict mortality and length of stay.ResultsData-derived antibiotic administration policies led to a favorable patient outcome in 49% of the cases, versus 37% when the alternative policies were followed (P=1.3e-13). Sensitivity analysis on the model parameters and missing data argue for a highly robust decision support tool that withstands parameter variation and data uncertainty. When the optimal policy was followed, 387 patients (25.9%) have 90% of their transitions to better states and 503 patients (33.7%) patients had 90% of their transitions to worse states (P=4.0e-06), while in the non-policy cases, these numbers are 192 (12.9%) and 764 (51.2%) patients (P=4.6e-117), respectively. Furthermore, the percentage of transitions within a trajectory that lead to a better or better/same state are significantly higher by following the policy than for non-policy cases (605 vs 344 patients, P=8.6e-25). Mortality was predicted with an AUC of 0.7 and 0.82 accuracy in the general case and similar performance was obtained for the inference of the length-of-stay (AUC of 0.69 to 0.73 with accuracies from 0.69 to 0.82).ConclusionsA data-driven model was able to suggest favorable actions, predict mortality and length of stay with high accuracy. This work provides a solid basis for a scalable probabilistic clinical decision support framework for sepsis treatment that can be expanded to other clinically relevant states and actions, as well as a data-driven model that can be adopted in other clinical areas with sufficient training data.
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