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The approach we used allows in-depth exploration of each instance of pathway dysregulation to characterize its evolution across the transformation process.
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A significant finding of this study was several instances of pathways activated by the same receptor that were differentially regulated at the single-cell level.
For instance, downregulation of pathways related to protein synthesis and upregulation of genes related to extracellular matrix and to maturation of some organs such as blood vessels were observed in SAMR1.
Other instances of similar pathway knowledge bases are Arabidopsis reactome and Pathway studio [ 21, 22].
If a pathway was significantly enriched for a particular comparison, other instances of this pathway were retained for closer examination.
Although the origins of these clusters have been identified, no instances of intermediate pathway assembly have been observed.
Although multiple drug resistance is not an instance of a metabolic pathway it falls into the scope of this study: multiple genes are required to generate a fitness advantage in special environments in which many drugs are found.
However, the iterations could also be interpreted as isolated instances of signaling pathways in one cell, in which case multiple parallel pathways compensate for high noise levels.
This is accompanied by increased microgliosis, astrogliosis, motor neuron loss and activation, for instance, of the MAPK pathways in the lumbar spinal cord of end-stage SOD1-G93A mice lacking P2X7 (Apolloni et al., 2013b).
To the left of the dashed curve, where exposure is low compared to cost, are instances of empty pathways (white shapes) or polymorphic equilibria (grey shapes).
The few exceptions that violate the otherwise good congruency between TCGs and 16S rRNA subtree regions point strongly to instances of whole-pathway trp-operon displacement.
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