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Variable cellular decision-making behavior in a constant synthetic network topology.

ABSTRACT: BACKGROUND:Modules of interacting components arranged in specific network topologies have evolved to perform a diverse array of cellular functions. For a network with a constant topological structure, its function within a cell may still be tuned by changing the number of instances of a particular component (e.g., gene copy number) or by modulating the intrinsic biochemical properties of a component (e.g., binding strength or catalytic efficiency). How such perturbations affect cellular response dynamics remains poorly understood. Here, we explored these effects in a common decision-making motif, cross-antagonism with autoregulation, by synthetically constructing this network in yeast. RESULTS:We employed the engineering design strategy of reuse to build this topology with a single protein building block, TetR, creating necessary components through TetR mutations and fusion partners. We then studied the impact of several topology-preserving perturbations - strength of cross-antagonism, number of operator sites in a promoter, and gene dosage - on decision-making behavior. We found that reducing TetR repression strength, which hinders cross-antagonism, resulted in a loss of mutually exclusive cell responses. Unexpectedly, increasing the number of operator sites also impeded decision-making exclusivity, which may be a consequence of the averaging effect that arises when multiple transcriptional activators and repressors are accommodated at a given locus. Stochastic simulations of this topology revealed that, even for networks with high TetR repression strength and a low number of operator sites, increasing gene dosage can reduce exclusivity in response dynamics. We further demonstrated this result experimentally by quantifying gene copy numbers in selected yeast clones with differing phenotypic responses. CONCLUSIONS:Our study illustrates how parameters that do not change the topological structure of a decision-making network can nonetheless exert significant influence on its response dynamics. These findings should further inform the study of native motifs, including the effects of topology-preserving mutations, and the robust engineering of synthetic networks.

SUBMITTER: Shah NA

PROVIDER: S-EPMC6515661 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Variable cellular decision-making behavior in a constant synthetic network topology.

Shah Najaf A NA Sarkar Casim A CA

BMC bioinformatics 20190514 1

<h4>Background</h4>Modules of interacting components arranged in specific network topologies have evolved to perform a diverse array of cellular functions. For a network with a constant topological structure, its function within a cell may still be tuned by changing the number of instances of a particular component (e.g., gene copy number) or by modulating the intrinsic biochemical properties of a component (e.g., binding strength or catalytic efficiency). How such perturbations affect cellular ...[more]

PMID: 31088350

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Project description:BackgroundMinistries of health in low- and middle-income countries often lack timely quality data for data-driven decision making in healthcare networks. We describe the design and implementation of decision-support electronic tools by the Ministry of Health of the State of Chiapas, in Mexico, as part of Salud Mesoamerica Initiative.MethodsThree electronic decision-support tools were designed through an iterative process focused on streamlined implementation: 1) to collect and report health facility data at health facilities; 2) to compile and analyze data at health district and central level; and, 3) to support stratified sampling of health facilities. Data was collected for five composite indicators measuring availability of equipment, medicines, and supplies for maternal and child health. Quality Assurance Teams collected data, evaluated results and supported quality improvement. Data was also analyzed at the central level and health districts for decision-making.ResultsData from 300 health facilities in four health districts was collected and analyzed (November 2014-June 2015). The first wave revealed gaps on availability of equipment and supplies in more than half of health facilities. Electronic tools provided the ministry of health officers new ways to visualize data, identify patterns and make hypothesis on root-causes. Between the first and second measurement, the number of missing items decreased, and actions performed by quality improvement teams became more proactive. In the final measurement, 89.7-100% of all health facilities achieved all the required items for each indicator.ConclusionsOur experience could help guide others seeking to implement electronic decision-support tools in low- and middle-income countries. Electronic decision-support tools supported data-driven decision-making by identifying gaps on heatmaps and graphs at the health facility, subdistrict, district or state level. Through a rapid improvement process, the Ministry of Health met targets of externally verified indicators. Using available information technology resources facilitated prompt implementation and adoption of technology.

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Variable cellular decision-making behavior in a constant synthetic network topology.

Publications

Variable cellular decision-making behavior in a constant synthetic network topology.

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