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Bifidobacterium longum subsp. infantis is a representative and dominant species in the infant gut and is considered a beneficial microbe. This organism displays multiple adaptations to thrive in the infant gut, regarded as a model for human milk oligosaccharides (HMOs) utilization. These carbohydrates are abundant in breast milk and include different molecules based on lactose. They contain fucose, sialic acid, and N-acetylglucosamine. Bifidobacterium metabolism is complex, and a systems view of relevant metabolic pathways and exchange metabolites during HMO consumption is missing. To address this limitation, a refined genome-scale network reconstruction of this bacterium is presented using a previous reconstruction of B. infantis ATCC 15967 as a template. The latter was expanded based on an extensive revision of genome annotations, current literature, and transcriptomic data integration. The metabolic reconstruction (iLR578) accounted for 578 genes, 1,047 reactions, and 924 metabolites. Starting from this reconstruction, we built context-specific genome-scale metabolic models using RNA-seq data from cultures growing in lactose and three HMOs. The models revealed notable differences in HMO metabolism depending on the functional characteristics of the substrates. Particularly, fucosyl-lactose showed a divergent metabolism due to a fucose moiety. High yields of lactate and acetate were predicted under growth rate maximization in all conditions, whereas formate, ethanol, and 1,2-propanediol were substantially lower. Similar results were also obtained under near-optimal growth on each substrate when varying the empirically observed acetate-to-lactate production ratio. Model predictions displayed reasonable agreement between central carbon metabolism fluxes and expression data across all conditions. Flux coupling analysis revealed additional connections between succinate exchange and arginine and sulfate metabolism and a strong coupling between central carbon reactions and adenine metabolism. More importantly, specific networks of coupled reactions under each carbon source were derived and analyzed. Overall, the presented network reconstruction constitutes a valuable platform for probing the metabolism of this prominent infant gut bifidobacteria.

Use of generative models and deep learning for physics-based systems is currently dominated by the task of emulation. However, the remarkable flexibility offered by data-driven architectures would suggest to extend this representation to other aspects of system analysis including model inversion and identifiability. We introduce InVAErt (pronounced invert) networks, a comprehensive framework for data-driven analysis and synthesis of parametric physical systems which uses a deterministic encoder and decoder to represent the forward and inverse solution maps, a normalizing flow to capture the probabilistic distribution of system outputs, and a variational encoder designed to learn a compact latent representation for the lack of bijectivity between inputs and outputs. We formally analyze how changes in the penalty coefficients affect the stationarity condition of the loss function, the phenomenon of posterior collapse, and propose strategies for latent space sampling, since we find that all these aspects significantly affect both training and testing performance. We verify our framework through extensive numerical examples, including simple linear, nonlinear, and periodic maps, dynamical systems, and spatio-temporal PDEs.