Mapping the landscape of metabolic goals of a cell

Genome-scale flux balance models of metabolism provide testable predictions of all metabolic rates in an organism, by assuming that the cell is optimizing a metabolic goal known as the objective function. We introduce an efficient inverse flux balance analysis (invFBA) approach, based on linear programming duality, to characterize the space of possible objective functions compatible with measured fluxes. After testing our algorithm on simulated E. coli data and time-dependent S. oneidensis fluxes inferred from gene expression, we apply our inverse approach to flux measurements in long-term evolved E. coli strains, revealing objective functions that provide insight into metabolic adaptation trajectories.MURI W911NF-12-1-0390 - Army Research Office (US); MURI W911NF-12-1-0390 - Army Research Office (US); 5R01GM089978-02 - National Institutes of Health (US); IIS-1237022 - National Science Foundation (US); DE-SC0012627 - U.S. Department of Energy; HR0011-15-C-0091 - Defense Sciences Office, DARPA; National Institutes of Health; R01GM103502; 5R01DE024468; 1457695 - National Science Foundatio

Optimal static pricing for a tree network

We study the static pricing problem for a network service provider in a loss system with a tree structure. In the network, multiple classes share a common inbound link and then have dedicated outbound links. The motivation is from a company that sells phone cards and needs to price calls to different destinations. We characterize the optimal static prices in order to maximize the steady-state revenue. We report new structural findings as well as alternative proofs for some known results. We compare the optimal static prices versus prices that are asymptotically optimal, and through a set of illustrative numerical examples we show that in certain cases the loss in revenue can be significant. Finally, we show that static prices obtained using the reduced load approximation of the blocking probabilities can be easily obtained and have near-optimal performance, which makes them more attractive for applications.Massachusetts Institute of Technology. Center for Digital BusinessUnited States. Office of Naval Research (Contract N00014-95-1-0232)United States. Office of Naval Research (Contract N00014-01-1-0146)National Science Foundation (U.S.) (Contract DMI-9732795)National Science Foundation (U.S.) (Contract DMI-0085683)National Science Foundation (U.S.) (Contract DMI-0245352

On the large deviations behaviour of acyclic networks of G/G/1 queues

'Research supported by a Presidential Young Investigator award DDM-9158118 with matching funds from Draper Laboratory, and by the ARO under grant DAAL-03-92-G-0115. We consider a single class, acyclic network of G/G/1 queues. We impose some mild assump-tions on the service and external arrival processes and we characterize the large deviations behaviour of all the processes resulting from various operations in the network. For the net-work model that we are considering, these operations are passing-through-a-single-server-queue (the process resulting from this operation being the departure process), superposition of independent processes, and Bernoulli splitting of a process to a number of processes. We also characterize the large deviations behaviour of the waiting time and the queue length observed by a typical customer in a single server queue. We prove that the assumptions imposed on the external arrival processes are preserved by these operations, and we show how to inductively apply these results to obtain the large deviations behaviour of the wait-ing time and the queue length in all the queues of the network. Our results indicate how these large deviations occur, by concretely characterizing the most likely path that leads to them

Heparin requirements for full anticoagulation are higher for patients on dabigatran than for those on warfarin – a model-based study

Thomas Edrich,1,2 Gyorgy Frendl,2 Gregory Michaud,3 Ioannis Ch Paschalidis4 1Department of Anesthesiology, Perioperative Medicine and General Intensive Care Medicine, Salzburg General Hospital and Paracelsus Private Medical University, Salzburg, Austria, 2Department of Anesthesiology, Perioperative and Pain Medicine, 3Department of Medicine, Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, 4Department of Electrical and Computer Engineering, Division of Systems Engineering, Boston University, Boston, MA, USA Purpose: Dabigatran (D) is increasingly used for chronic anticoagulation in place of warfarin (W). These patients may present for catheter-based procedures requiring full anticoagulation with heparin. This study compares the heparin sensitivity of patients previously on dabigatran, on warfarin, or on no chronic anticoagulant during ablation of atrial fibrillation. Patients and methods: In a retrospective study of patients treated with D, W, or neither drug (N) undergoing atrial ablation, the timing of heparin doses and resulting activated clotting times were collected. First, the initial activated clotting time response to the first heparin bolus was compared. Then, a non-linear mixed effects modelling (NONMEM) analysis was performed, fitting a pharmacokinetic and -dynamic model to the entire anticoagulation course of each patient. Resulting model coefficients were used to compare the different patient groups. Results: Data for 66 patients on dabigatran, 95 patients on warfarin, and 27 patients on no anticoagulation were retrieved. The last dose of dabigatran or warfarin had occurred 27 hours and 15 hours before the procedure. Groups D and N both responded significantly less (P<0.05) to the initial heparin bolus than Group W (approximately 50%). Likewise, the model coefficients resulting from the fit to each group reflected a significantly lower heparin sensitivity in groups D and N compared to W. Clearances of the heparin effect in the model did not differ significantly among groups. Conclusion: Patients on warfarin with an average INR of 1.5 or higher are more sensitive to heparin than patients not previously anticoagulated or patients who discontinued dabigatran 27 hours earlier (approximately two half-lives) warfarin. Keywords: atrial fibrillation, electrophysiology, NONMEM, PKPD mode