02248nas a2200253   4500008004100000022001400041245009900055210006900154260010300223300002500326490000600351520128400357653002701641653002601668653001801694653002401712653002301736653002501759653002701784653001701811100002001828700002101848856012501869       2015                        eng d  a1664-302X00aCell scale host-pathogen modeling: another branch in the evolution of constraint-based methods0 aCell scale hostpathogen modeling another branch in the evolution  aPO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLANDbFRONTIERS MEDIA SAcOCT  aArticle Number: 10320 v63 a<p>Constraint-based models have become popular methods for systems biology as they enable the integration of complex, disparate datasets in a biologically cohesive framework that also supports the description of biological processes in terms of basic physicochemical constraints and relationships. The scope, scale, and application of genome scale models have grown from single cell bacteria to multi cellular interaction modeling; host-pathogen modeling represents one of these examples at the current horizon of constraint-based methods. There are now a small number of examples of host-pathogen constraint-based models in the literature, however there has not yet been a definitive description of the methodology required for the functional integration of genome scale models in order to generate simulation capable host-pathogen models. Herein we outline a systematic procedure to produce functional host-pathogen models, highlighting steps which require debugging and iterative revisions in order to successfully build a functional model. The construction of such models will enable the exploration of host-pathogen interactions by leveraging the growing wealth of omic data in order to better understand mechanism of infection and identify novel therapeutic strategies.</p>10aconstraint-based model10aflux balance analysis10ahost-pathogen10amathematical models10aomics-technologies10aoptimization methods10asalmonella typhimurium10atuberculosis1 aJamshidi, Neema1 aRaghunathan, Anu  uhttps://library.ncl.res.in/content/cell-scale-host-pathogen-modeling-another-branch-evolution-constraint-based-methods-102546nas a2200157   4500008004100000022001400041245014100055210006900196260000900265300002900274490000700303520190900310100002502219700002102244856012302265       2019                        eng d  a1932-620300aConstraints-based analysis identifies NAD(+) recycling through metabolic reprogramming in antibiotic resistant Chromobacterium violaceum0 aConstraintsbased analysis identifies NAD recycling through metab  cJAN   aArticle Number: e02100080 v143 a<p>In the post genomic era, high throughput data augment stoichiometric flux balance models to compute accurate metabolic flux states, growth and energy phenotypes. Investigating altered metabolism in the context of evolved resistant genotypes potentially provide simple strategies to overcome drug resistance and induce susceptibility to existing antibiotics. A genome-scale metabolic model (GSMM) for Chromobacterium violaceum, an opportunistic human pathogen, was reconstructed using legacy data. Experimental constraints were used to represent antibiotic susceptible and resistant populations. Model predictions were validated using growth and respiration data successfully. Differential flux distribution and metabolic reprogramming were identified as a response to antibiotics, chloramphenicol and streptomycin. Streptomycin resistant populations (StrpR) redirected tricarboxylic acid (TCA) cycle flux through the glyoxylate shunt. Chloramphenicol resistant populations (ChlR) resorted to overflow metabolism producing acetate and formate. This switch to fermentative metabolism is potentially through excess reducing equivalents and increased NADH/NAD ratios. Reduced proton gradients and changed Proton Motive Force (PMF) induced by antibiotics were also predicted and verified experimentally using flow cytometry based membrane potential measurements. Pareto analysis of NADH and ATP maintenance showed the decoupling of electron transfer and ATP synthesis in StrpR. Redox homeostasis and NAD(+) cycling through rewiring metabolic flux was implicated in re-sensitizing antibiotic resistant C. violaceum. These approaches can be used to probe metabolic vulnerabilities of resistant pathogens. On the verge of a post-antibiotic era, we foresee a critical need for systems level understanding of pathogens and host interaction to extend shelf life of antibiotics and strategize novel therapies.</p>1 aBanerjee, Deepanwita1 aRaghunathan, Anu  uhttps://library.ncl.res.in/content/constraints-based-analysis-identifies-nad-recycling-through-metabolic-reprogramming