COnstraint-Based Reconstruction and Analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive software suite of interoperable COBRA methods. It has found widespread applications in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. Version 3.0 includes new methods for quality controlled reconstruction, modelling, topological analysis, strain and experimental design, network visualisation as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimisation solvers for multi-scale, multi-cellular and reaction kinetic modelling, respectively. This protocol can be adapted for the generation and analysis of a constraint-based model in a wide variety of molecular systems biology scenarios. This protocol is an update to the COBRA Toolbox 1.0 and 2.0. The COBRA Toolbox 3.0 provides an unparalleled depth of constraint-based reconstruction and analysis methods. ]); 61 | The MUST sets are the sets of reactions that must increase or decrease their flux in order to achieve the desired phenotype in the mutant strain. As shown in Figure 6, the first order MUST sets are MustU and MustL while second order MUST sets are denoted as MustUU, MustLL, and MustUL. After parameters and constraints are defined, the functions findMustL and findMustU are run to determine the mustU and mustL sets, respectively. Define an ID of the run with:Each time the MUST sets are determined, folders are generated to read inputs and store outputs, i.e., reports. These folders are located in the directory defined by the uniquely defined runID.62 | In order to find the first order MUST sets, constraints should be defined: >> constrOpt = struct('rxnList', {{'EX_gluc', 'R75', 'EX_suc'}}, 'values', [-100; 0; 155.5]); 63 | The first order MUST set MustL is determined by running: >> [mustLSet, pos_mustL] = findMustL(model, minFluxesW, maxFluxesW, ... 'constrOpt', constrOpt, 'runID', runID);If runID is set to 'TestoptForceL', a folder TestoptForceL is created, in which two additional folders InputsMustL and OutputsMustL are created. The InputsMustL folder contains all the inputs required to run the function findMustL, while the OutputsMustL folder contains the mustL set found and a report that summarises all the inputs and outputs. In order to maintain a chronological order of computational experiments, the report is timestamped.64 | Display the reactions that belong to the mustL set using: >> disp(mustLSet) 65 | The first order MUST set MustU is determined by running: >> [mustUSet, pos_mustU] = findMustU(model, minFluxesW, maxFluxesW, ... 'constrOpt', constrOpt, 'runID', runID);...

Monotonicity and nonmonotonicity play a key role in studying the global convergence and the efficiency of iterative schemes employed in the field of nonlinear optimization, where globally convergent and computationally efficient schemes are explored. This paper addresses some features of descent schemes and the motivation behind nonmonotone strategies and investigates the efficiency of an Armijotype line search equipped with some popular nonmonotone terms. More specifically, we propose two novel nonmonotone terms, combine them into Armijo's rule and establish the global convergence of sequences generated by these schemes. Furthermore, we report extensive numerical results and comparisons indicating the performance of the nonmonotone Armijo-type line searches using the most popular search directions for solving unconstrained optimization problems. Finally, we exploit the considered nonmonotone schemes to solve an important inverse problem arising in signal and image processing.

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This paper addresses some trust-region methods equipped with nonmonotone strategies for solving nonlinear unconstrained optimization problems. More specifically, the importance of using nonmonotone techniques in nonlinear optimization is motivated, then two new nonmonotone terms are proposed, and their combinations into the traditional trust-region framework are studied. The global convergence to first-and second-order stationary points and local superlinear and quadratic convergence rates for both algorithms are established. Numerical experiments on the CUTEst test collection of unconstrained problems and some highly nonlinear test functions are reported, where a comparison among state-of-theart nonmonotone trust-region methods show the efficiency of the proposed nonmonotne schemes.

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