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);...

Levodopa has been the gold standard for Parkinson’s disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response particularly in late-stage (stage 3 and 4 on Hoehn and Yahr scale) patients. The routine dietary intervention consists of low-protein (<0.8 g/kg) diets or the redistribution of daily protein allowance to the last meal. Computational modeling was used to examine the fluctuation of gastrointestinal levodopa absorption under consideration of the diet by (i) identifying the group of patients that could benefit from dietary interventions, (ii) comparing existing diet recommendations for their impact on levodopa bioavailability, and (iii) suggesting a mechanism-based dietary intervention. We developed a multiscale computational model consisting of an ordinary differential equations-based advanced compartmentalized absorption and transit (ACAT) gut model and metabolic genome-scale small intestine epithelial cell model. We used this model to investigate complex spatiotemporal relationship between dietary amino acids and levodopa absorption. Our model predicted an improvement in bioavailability, as reflected by blood concentrations of levodopa with protein redistribution diet by 34% compared with a low-protein diet and by 11% compared with the ante cibum (a.c.) administration. These results are consistent with the reported better outcome in late-stage patients. A systematic analysis of the effect of different amino acids in the diet suggested that a serine-rich diet could improve the bioavailability by 22% compared with the a.c. administration. In addition, the slower gastric emptying rate in PD patients exacerbates the loss of levodopa due to competition. Optimizing dietary recommendations in quantity, composition, and intake time holds the promise to improve levodopa efficiency and patient’s quality of life based on highly detailed, mechanistic models of gut physiology endowed with improved extrapolative properties, thus paving the way for precision medical treatment.

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound–kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome.

Disturbances fundamentally alter ecosystem functions, yet predicting their impacts remains a key scientific challenge. While the study of disturbances is ubiquitous across many ecological disciplines, there is no agreed-upon, cross-disciplinary foundation for discussing or quantifying the complexity of disturbances, and no consistent terminology or methodologies exist. This inconsistency presents an increasingly urgent challenge due to accelerating global change and the threat of interacting disturbances that can destabilize ecosystem responses. By harvesting the expertise of an interdisciplinary cohort of contributors spanning 42 institutions across 15 countries, we identified an essential limitation in disturbance ecology: the word ‘disturbance’ is used interchangeably to refer to both the events that cause, and the consequences of, ecological change, despite fundamental distinctions between the two meanings. In response, we developed a generalizable framework of ecosystem disturbances, providing a well-defined lexicon for understanding disturbances across perspectives and scales. The framework results from ideas that resonate across multiple scientific disciplines and provides a baseline standard to compare disturbances across fields. This framework can be supplemented by discipline-specific variables to provide maximum benefit to both inter- and intra-disciplinary research. To support future syntheses and meta-analyses of disturbance research, we also encourage researchers to be explicit in how they define disturbance drivers and impacts, and we recommend minimum reporting standards that are applicable regardless of scale. Finally, we discuss the primary factors we considered when developing a baseline framework and propose four future directions to advance our interdisciplinary understanding of disturbances and their social-ecological impacts: integrating across ecological scales, understanding disturbance interactions, establishing baselines and trajectories, and developing process-based models and ecological forecasting initiatives. Our experience through this process motivates us to encourage the wider scientific community to continue to explore new approaches for leveraging Open Science principles in generating creative and multidisciplinary ideas.

Gene regulation plays a fundamental role in shaping tissue identity, function, and response to perturbation. Regulatory processes are controlled by complex networks of interacting elements, including transcription factors, miRNAs and their target genes. The structure of these networks helps to determine phenotypes and can ultimately influence the development of disease or response to therapy. We developed GRAND (https://grand.networkmedicine.org) as a database for computationally-inferred, context-specific gene regulatory network models that can be compared between biological states, or used to predict which drugs produce changes in regulatory network structure. The database includes 12 468 genome-scale networks covering 36 human tissues, 28 cancers, 1378 unperturbed cell lines, as well as 173 013 TF and gene targeting scores for 2858 small molecule-induced cell line perturbation paired with phenotypic information. GRAND allows the networks to be queried using phenotypic information and visualized using a variety of interactive tools. In addition, it includes a web application that matches disease states to potentially therapeutic small molecule drugs using regulatory network properties.

COVID-19 involves a number of organ systems and can present with a wide range of symptoms. From how the virus infects cells to how it spreads between people, the available research suggests that these patterns are very similar to those seen in the closely related viruses SARS-CoV-1 and possibly Middle East respiratory syndrome-related CoV (MERS-CoV).

The COVID-19 pandemic is a rapidly evolving crisis. With the worldwide scientific community shifting focus onto the SARS-CoV-2 virus and COVID-19, a large number of possible pharmaceutical approaches for treatment and prevention have been proposed.

Glioblastoma is an aggressive cancer of the brain and spine. While analysis of glioblastoma 'omics data has somewhat improved our understanding of the disease, it has not led to direct improvement in patient survival. Cancer survival is often characterized by differences in gene expression, but the mechanisms that drive these differences are generally unknown. We therefore set out to model the regulatory mechanisms associated with glioblastoma survival. We inferred individual patient gene regulatory networks using data from two different expression platforms from The Cancer Genome Atlas. We performed comparative network analysis between patients with long-and short-term survival. Seven pathways were identified as associated with survival, all of them involved in immune signaling; differential regulation of PD1 signaling was validated to correspond with outcome in an independent dataset from the German Glioma Network. In this pathway, transcriptional repression of genes for which treatment options are available was lost in short-term survivors; this was independent of mutational burden and only weakly associated with T-cell infiltration. Collectively, these results provide a new way to stratify glioblastoma patients that uses network features as biomarkers to predict survival. They also identify new potential therapeutic interventions, underscoring the value of analyzing gene regulatory networks in individual cancer patients. Statement of SignificanceGenome-wide network modeling of individual glioblastomas identifies dysregulation of PD1 signaling in patients with poor prognosis, indicating this approach can be used to understand how gene regulation influences cancer progression.'omics landscape for many different cancer types. Although this has somewhat improved our understanding of the biology underlying the development and progression of cancer(1), it has only led to direct improvement of patient survival for a limited subset of cancer types. For most cancers, Research.