Constraint-based Approach Research Articles

Harnessing the optimization of enzyme catalytic rates in engineering of metabolic phenotypes.

The increasing availability of enzyme turnover number measurements from experiments and of turnover number predictions from deep learning models prompts the use of these enzyme parameters in precise metabolic engineering. Yet, there is no computational approach that allows the prediction of metabolic engineering strategies that rely on the modification of turnover numbers. It is also unclear if modifications of turnover numbers without alterations in the host's transcriptional regulatory machinery suffice to increase the production of chemicals of interest. Here, we present a constraint-based modeling approach, termed Overcoming Kinetic rate Obstacles (OKO), that uses enzyme-constrained metabolic models to predict in silico strategies to increase the production of a given chemical, while ensuring specified cell growth. We demonstrate that the application of OKO to enzyme-constrained metabolic models of Escherichia coli and Saccharomyces cerevisiae results in strategies that can at least double the production of over 40 compounds with little penalty to growth. Interestingly, we show that the overproduction of compounds of interest does not entail only an increase in the values of turnover numbers. Lastly, we demonstrate that a refinement of OKO, allowing also for manipulation of enzyme abundance, facilitates the usage of the available compendia and deep learning models of turnover numbers in the design of precise metabolic engineering strategies. Our results expand the usage of genome-scale metabolic models toward the identification of targets for protein engineering, allowing their direct usage in the generation of innovative metabolic engineering designs for various biotechnological applications.

Type Inference Logics

Type inference is essential for statically-typed languages such as OCaml and Haskell. It can be decomposed into two (possibly interleaved) phases: a generator converts programs to constraints; a solver decides whether a constraint is satisfiable. Elaboration, the task of decorating a program with explicit type annotations, can also be structured in this way. Unfortunately, most machine-checked implementations of type inference do not follow this phase-separated, constraint-based approach. Those that do are rarely executable, lack effectful abstractions, and do not include elaboration. To close the gap between common practice in real-world implementations and mechanizations inside proof assistants, we propose an approach that enables modular reasoning about monadic constraint generation in the presence of elaboration. Our approach includes a domain-specific base logic for reasoning about metavariables and a program logic that allows us to reason abstractly about the meaning of constraints. To evaluate it, we report on a machine-checked implementation of our techniques inside the Coq proof assistant. As a case study, we verify both soundness and completeness for three elaborating type inferencers for the simply typed lambda calculus with Booleans. Our results are the first demonstration that type inference algorithms can be verified in the same form as they are implemented in practice: in an imperative style, modularly decomposed into constraint generation and solving, and delivering elaborated terms to the remainder of the compiler chain.

Understanding flux switching in metabolic networks through an analysis of synthetic lethals

Biological systems are robust and redundant. The redundancy can manifest as alternative metabolic pathways. Synthetic double lethals are pairs of reactions that, when deleted simultaneously, abrogate cell growth. However, removing one reaction allows the rerouting of metabolites through alternative pathways. Little is known about these hidden linkages between pathways. Understanding them in the context of pathogens is useful for therapeutic innovations. We propose a constraint-based optimisation approach to identify inter-dependencies between metabolic pathways. It minimises rerouting between two reaction deletions, corresponding to a synthetic lethal pair, and outputs the set of reactions vital for metabolic rewiring, known as the synthetic lethal cluster. We depict the results for different pathogens and show that the reactions span across metabolic modules, illustrating the complexity of metabolism. Finally, we demonstrate how the two classes of synthetic lethals play a role in metabolic networks and influence the different properties of a synthetic lethal cluster.

ANS-SCMC: A matrix completion method based on adaptive neighbourhood similarity and sparse constraints for predicting microbe-disease associations.

The use of matrix completion methods to predict the association between microbes and diseases can effectively improve treatment efficiency. However, the similarity measures used in the existing methods are often influenced by various factors such as neighbourhood size, choice of similarity metric, or multiple parameters for similarity fusion, making it challenging. Additionally, matrix completion is currently limited by the sparsity of the initial association matrix, which restricts its predictive performance. To address these problems, we propose a matrix completion method based on adaptive neighbourhood similarity and sparse constraints (ANS-SCMC) for predict microbe-disease potential associations. Adaptive neighbourhood similarity learning dynamically uses the decomposition results as effective information for the next learning iteration by simultaneously performing local manifold structure learning and decomposition. This approach effectively preserves fine local structure information and avoids the influence of weight parameters directly involved in similarity measurement. Additionally, the sparse constraint-based matrix completion approach can better handle the sparsity challenge in the association matrix. Finally, the algorithm we proposed has achieved significantly higher predictive performance in the validation compared to several commonly used prediction methods proposed to date. Furthermore, in the case study, the prediction algorithm achieved an accuracy of up to 80% for the top 10 microbes associated with type 1 diabetes and 100% for Crohn's disease respectively.

Regional Grid Power Supply Radius Planning—A Sensitivity Constraint-Based Approach

Regional Grid Power Supply Radius Planning—A Sensitivity Constraint-Based Approach

Processing causal structure sentences in Mandarin Chinese: an eye movements study.

It remains uncertain whether causal structure prediction can improve comprehension in Chinese sentences and whether the position of the headword mediates the prediction effect. We conducted an experiment to explore the effect of causal prediction and headword position in Chinese sentence reading. Participants were asked to read sentences containing causal connectives with their eye movements recorded. In the experiment, we manipulated the causal structure of the sentence and the position of the headword. We found a promoting effect of causal structure on first-pass reading time and a hindering impact on total reading time. However, the effect was not mediated by the headword position. The results show that causal syntactic prediction facilitated early-stage processing and increased the integration cost in the late stage of Chinese sentence processing. These findings also support the constraint-based approach, which suggests an isolation between semantic and syntactic processing.

Tumato 2.0 - a constraint-based planning approach for safe and robust robot behavior

Tumato 2.0 - a constraint-based planning approach for safe and robust robot behavior

Energy Efficiency and Load Optimization in Heterogeneous Networks through Dynamic Sleep Strategies: A Constraint-Based Optimization Approach

Energy Efficiency and Load Optimization in Heterogeneous Networks through Dynamic Sleep Strategies: A Constraint-Based Optimization Approach

Position-Based Nonlinear Gauss-Seidel for Quasistatic Hyperelasticity

Position based dynamics [Müller et al. 2007] is a powerful technique for simulating a variety of materials. Its primary strength is its robustness when run with limited computational budget. Even though PBD is based on the projection of static constraints, it does not work well for quasistatic problems. This is particularly relevant since the efficient creation of large data sets of plausible, but not necessarily accurate elastic equilibria is of increasing importance with the emergence of quasistatic neural networks [Bailey et al. 2018; Chentanez et al. 2020; Jin et al. 2022; Luo et al. 2020]. Recent work [Macklin et al. 2016] has shown that PBD can be related to the Gauss-Seidel approximation of a Lagrange multiplier formulation of backward Euler time stepping, where each constraint is solved/projected independently of the others in an iterative fashion. We show that a position-based, rather than constraint-based nonlinear Gauss-Seidel approach resolves a number of issues with PBD, particularly in the quasistatic setting. Our approach retains the essential PBD feature of stable behavior with constrained computational budgets, but also allows for convergent behavior with expanded budgets. We demonstrate the efficacy of our method on a variety of representative hyperelastic problems and show that both successive over relaxation (SOR), Chebyshev and multiresolution-based acceleration can be easily applied.

Assessing the nexus between currency exchange rate returns, currency risk hedging and international investments: Intelligent network-based analysis

Through the exogenous growth model, the inflow of international investments promotes economic growth by the inclusion of foreign technologies in production functions and capital accumulation. But the proportional increasing outflow of international investments from emerging countries rapidly squeezes their economies. The main reasons of the massive gap between the inflow and outflow of international investments are devaluation of their home currency and inaccessibility of the foreign exchange derivatives instruments for potential currency risk hedging. The previous studies have strongly ignored the role of two-way multicurrency cross-risk hedging (MCCRH) in bilateral flows of international investments by conditioning effect of the currency returns. By considering the significance of the subject matter, it is needed to assess the interaction between two-way MCCRH, currency returns of multicurrency exchange rate returns (MCERRs) and bilateral flows of international investments, and conditional dependency of random variables of the intelligent network structure. The regression-based MLP and probabilistic Bayes intelligent neural networks represented that the two-way MCCRH and currency returns of MCERRs have a strong impact on bilateral flows of international investments in an emerging country. The constraint-based approach of the probabilistic Bayes intelligent neural network showed that the two-way MCCRH conditionally affects the bilateral flows of international investments given the percentage of currency returns of MCERRs. This study may assist policymakers and regulators to enhance currency returns and availability of foreign exchange derivatives instruments at the least cost to grab more intention of international investors for investments that will expand the economic growth of Pakistan.

GEM-based computational modeling for exploring metabolic interactions in a microbial community.

Microbial communities play fundamental roles in every complex ecosystem, such as soil, sea and the human body. The stability and diversity of the microbial community depend precisely on the composition of the microbiota. Any change in the composition of these communities affects microbial functions. An important goal of studying the interactions between species is to understand the behavior of microbes and their responses to perturbations. These interactions among species are mediated by the exchange of metabolites within microbial communities. We developed a computational model for the microbial community that has a separate compartment for exchanging metabolites. This model can predict possible metabolites that cause competition, commensalism, and mutual interactions between species within a microbial community. Our constraint-based community metabolic modeling approach provides insights to elucidate the pattern of metabolic interactions for each common metabolite between two microbes. To validate our approach, we used a toy model and a syntrophic co-culture of Desulfovibrio vulgaris and Methanococcus maripaludis, as well as another in co-culture between Geobacter sulfurreducens and Rhodoferax ferrireducens. For a more general evaluation, we applied our algorithm to the honeybee gut microbiome, composed of seven species, and the epiphyte strain Pantoea eucalypti 299R. The epiphyte strain Pe299R has been previously studied and cultured with six different phyllosphere bacteria. Our algorithm successfully predicts metabolites, which imply mutualistic, competitive, or commensal interactions. In contrast to OptCom, MRO, and MICOM algorithms, our COMMA algorithm shows that the potential for competitive interactions between an epiphytic species and Pe299R is not significant. These results are consistent with the experimental measurements of population density and reproductive success of the Pe299R strain.

Feature-weight and cluster-weight learning in fuzzy c-means method for semi-supervised clustering

Semi-supervised clustering aims to guide the clustering by utilizing auxiliary information about the class labels. Among the semi-supervised clustering categories, the constraint-based approach uses the available pairwise constraints in some steps of the clustering procedure, usually by adding new terms to the objective function. Considering this category, Semi-supervised FCM (SSFCM) is a semi-supervised version of the fuzzy c-means algorithm, which takes advantage of fuzzy logic and auxiliary class distribution knowledge. Despite the performance enhancement caused by incorporating this extra knowledge in the clustering process, semi-supervised fuzzy approaches still suffer from some problems. All the data attributes in the feature space are assumed to have equal importance in the cluster formation, while some features may be more informative than others. Thus the feature importance issue is not addressed in the semi-supervised category. This paper proposes a novel Semi-Supervised Fuzzy c-means approach, which is designed based on Feature-Weight, and Cluster-Weight learning, named SSFCM-FWCW. Inspired by the SSFCM, a fuzzy objective function is presented, which is composed of (1) a semi-supervised term representing the external class knowledge; (2) a feature weighting; and (3) a cluster weighting. Both feature weights and cluster weights are determined adaptively during the clustering. Considering these two techniques leads to insensitivity to the initial center selection, insensitivity to noise, and consequently helps to form an optimal clustering structure. Experimental comparisons are carried out on several benchmark datasets to evaluate the proposed approach's performance, and promising results are achieved. The Matlab implementation source code of the proposed method is publicly accessible at https://github.com/Amin-Golzari-Oskouei/SSFCM-FWCW.

Designing function-specific minimal microbiomes from large microbial communities

Microorganisms exist in large communities of diverse species, exhibiting various functionalities. The mammalian gut microbiome, for instance, has the functionality of digesting dietary fibre and producing different short-chain fatty acids. Not all microbes present in a community contribute to a given functionality; it is possible to find a minimal microbiome, which is a subset of the large microbiome, that is capable of performing the functionality while maintaining other community properties such as growth rate and metabolite production. Such a minimal microbiome will also contain keystone species for SCFA production in that community. In this work, we present a systematic constraint-based approach to identify a minimal microbiome from a large community for a user-proposed function. We employ a top-down approach with sequential deletion followed by solving a mixed-integer linear programming problem with the objective of minimising the L1-norm of the membership vector. Notably, we consider quantitative measures of community growth rate and metabolite production rates. We demonstrate the utility of our algorithm by identifying the minimal microbiomes corresponding to three model communities of the gut, and discuss their validity based on the presence of the keystone species in the community. Our approach is generic, flexible and finds application in studying a variety of microbial communities. The algorithm is available from https://github.com/RamanLab/minMicrobiome.

A bounded constraint-based approach to aid in fault localization from a counterexample

A bounded constraint-based approach to aid in fault localization from a counterexample

Constraint-based analysis of heat transport and irreversibility in magnetic nanofluidic thermal systems

Purpose This paper aims to investigate the thermal performance of equivalent square and circular thermal systems and compare the heat transport and irreversibility of magnetohydrodynamic (MHD) nanofluid flow within these systems. Design/methodology/approach The research uses a constraint-based approach to analyze the impact of geometric shapes on heat transfer and irreversibility. Two equivalent systems, a square cavity and a circular cavity, are examined, considering identical heating/cooling lengths and fluid flow volume. The analysis includes parameters such as magnetic field strength, nanoparticle concentration and accompanying irreversibility. Findings This study reveals that circular geometry outperforms square geometry in terms of heat flow, fluid flow and heat transfer. The equivalent circular thermal system is more efficient, with heat transfer enhancements of approximately 17.7%. The corresponding irreversibility production rate is also higher, which is up to 17.6%. The total irreversibility production increases with Ra and decreases with a rise in Ha. However, the effect of magnetic field orientation (γ) on total EG is minor. Research limitations/implications Further research can explore additional geometric shapes, orientations and boundary conditions to expand the understanding of thermal performance in different configurations. Experimental validation can also complement the numerical analysis presented in this study. Originality/value This research introduces a constraint-based approach for evaluating heat transport and irreversibility in MHD nanofluid flow within square and circular thermal systems. The comparison of equivalent geometries and the consideration of constraint-based analysis contribute to the originality and value of this work. The findings provide insights for designing optimal thermal systems and advancing MHD nanofluid flow control mechanisms, offering potential for improved efficiency in various applications. Graphical Abstract

A fast and robust constraint-based online re-optimization approach for automated online adaptive intensity modulated proton therapy in head and neck cancer

Objective. In head-and-neck cancer intensity modulated proton therapy, adaptive radiotherapy is currently restricted to offline re-planning, mitigating the effect of slow changes in patient anatomies. Daily online adaptations can potentially improve dosimetry. Here, a new, fully automated online re-optimization strategy is presented. In a retrospective study, this online re-optimization approach was compared to our trigger-based offline re-planning (offlineTB re-planning) schedule, including extensive robustness analyses. Approach. The online re-optimization method employs automated multi-criterial re-optimization, using robust optimization with 1 mm setup-robustness settings (in contrast to 3 mm for offlineTB re-planning). Hard planning constraints and spot addition are used to enforce adequate target coverage, avoid prohibitively large maximum doses and minimize organ-at-risk doses. For 67 repeat-CTs from 15 patients, fraction doses of the two strategies were compared for the CTVs and organs-at-risk. Per repeat-CT, 10.000 fractions with different setup and range robustness settings were simulated using polynomial chaos expansion for fast and accurate dose calculations. Main results. For 14/67 repeat-CTs, offlineTB re-planning resulted in <50% probability of D 98% ≥ 95% of the prescribed dose (D pres) in one or both CTVs, which never happened with online re-optimization. With offlineTB re-planning, eight repeat-CTs had zero probability of obtaining D 98% ≥ 95%D pres for CTV7000, while the minimum probability with online re-optimization was 81%. Risks of xerostomia and dysphagia grade ≥ II were reduced by 3.5 ± 1.7 and 3.9 ± 2.8 percentage point [mean ± SD] (p < 10−5 for both). In online re-optimization, adjustment of spot configuration followed by spot-intensity re-optimization took 3.4 min on average. Significance. The fast online re-optimization strategy always prevented substantial losses of target coverage caused by day-to-day anatomical variations, as opposed to the clinical trigger-based offline re-planning schedule. On top of this, online re-optimization could be performed with smaller setup robustness settings, contributing to improved organs-at-risk sparing.

Factors and pathways of non-suicidal self-injury in children: insights from computational causal analysis.

Non-suicidal self-injury (NSSI) has become a significant public health issue, especially prevalent among adolescents. The complexity and multifactorial nature of NSSI necessitate a comprehensive understanding of its underlying causal factors. This research leverages the causal discovery methodology to explore these causal associations in children. An observational dataset was scrutinized using the causal discovery method, particularly employing the constraint-based approach. By integrating machine learning and causal inference techniques, the study aimed to determine direct causal relationships associated with NSSI. The robustness of the causal relationships was evaluated using three methods to construct and validate it: the PC (Peter and Clark) method, Fast Causal Inference (FCI) method, and the GAE (Graphical Autoencoder) method. Analysis identified nine nodes with direct causal relationships to NSSI, including life satisfaction, depression, family dysfunction, sugary beverage consumption, PYD (positive youth development), internet addiction, COVID-19 related PTSD, academic anxiety, and sleep duration. Four principal causal pathways were identified, highlighting the roles of lockdown-induced lifestyle changes, screen time, positive adolescent development, and family dynamics in influencing NSSI risk. An in-depth analysis of the factors leading to Non-Suicidal Self-Injury (NSSI), highlighting the intricate connections among individual, family, and pandemic-related influences. The results, derived from computational causal analysis, underscore the critical need for targeted interventions that tackle these diverse causative factors.

Genome scale metabolic network modelling for metabolic profile predictions.

Metabolic profiling (metabolomics) aims at measuring small molecules (metabolites) in complex samples like blood or urine for human health studies. While biomarker-based assessment often relies on a single molecule, metabolic profiling combines several metabolites to create a more complex and more specific fingerprint of the disease. However, in contrast to genomics, there is no unique metabolomics setup able to measure the entire metabolome. This challenge leads to tedious and resource consuming preliminary studies to be able to design the right metabolomics experiment. In that context, computer assisted metabolic profiling can be of strong added value to design metabolomics studies more quickly and efficiently. We propose a constraint-based modelling approach which predicts in silico profiles of metabolites that are more likely to be differentially abundant under a given metabolic perturbation (e.g. due to a genetic disease), using flux simulation. In genome-scale metabolic networks, the fluxes of exchange reactions, also known as the flow of metabolites through their external transport reactions, can be simulated and compared between control and disease conditions in order to calculate changes in metabolite import and export. These import/export flux differences would be expected to induce changes in circulating biofluid levels of those metabolites, which can then be interpreted as potential biomarkers or metabolites of interest. In this study, we present SAMBA (SAMpling Biomarker Analysis), an approach which simulates fluxes in exchange reactions following a metabolic perturbation using random sampling, compares the simulated flux distributions between the baseline and modulated conditions, and ranks predicted differentially exchanged metabolites as potential biomarkers for the perturbation. We show that there is a good fit between simulated metabolic exchange profiles and experimental differential metabolites detected in plasma, such as patient data from the disease database OMIM, and metabolic trait-SNP associations found in mGWAS studies. These biomarker recommendations can provide insight into the underlying mechanism or metabolic pathway perturbation lying behind observed metabolite differential abundances, and suggest new metabolites as potential avenues for further experimental analyses.

Schwa Absorption in English: A Constraint-based Approach

Schwa Absorption in English: A Constraint-based Approach

An [formula omitted]-constrained multiobjective differential evolution with adaptive gradient-based repair method for real-world constrained optimization problems

Over the past decade, incorporating information from the objective function into the constraint-handling process has garnered considerable attention in evolutionary algorithm research. Stemming from this, multiobjective optimization has emerged as a promising approach that simultaneously optimizes the objective function and constraints. However, the challenges associated with optimizing objective functions and satisfying constraints exhibit significant variability. Some constraints and/or objective functions can be exceptionally challenging, necessitating specific methods to identify the optimal solution within a limited feasible region. This study proposes an adaptive gradient descent-based repair method to enhance the search capability for both objective function optimization and constraint satisfaction. This method leverages objective function information to rectify infeasible solutions using gradient descent, thereby reducing the limitations of a purely constraint-based approach and automating the application of the repair method. Furthermore, an enhanced variant of the ɛ-constrained multiobjective differential evolution algorithm is developed for solving constrained optimization problems. The efficacy of the proposed approach is assessed using 57 benchmark test functions derived from real-world applications. Empirical results demonstrate that our approach is capable of locating high-quality solutions, outperforming several selected state-of-the-art algorithms.