Survey of interactive evolutionary decomposition-based multiobjective optimization methods.

Interactive methods support decision-makers in finding the most preferred solution for multiobjective optimization problems, where multiple conflicting objective functions must be optimized simultaneously. These methods let a decision-maker provide preference information iteratively during the solution process to find solutions of interest, allowing them to learn about the trade-offs in the problem and the feasibility of the preferences. Several interactive evolutionary multiobjective optimization methods have been proposed in the literature.

Structure-Agnostic Bioactivity-Driven Combinatorial Biosynthesis Reveals New Antidiabetic and Anticancer Triterpenoids.

Although combinatorial biosynthesis can dramatically expand the chemical structures of bioactive natural products to identify molecules with improved characteristics, progress in this direction has been hampered by the difficulty in isolating and characterizing the numerous produced compounds. This challenge could be overcome with improved designs that enable the analysis of the bioactivity of the produced metabolites ahead of the time-consuming isolation procedures. Herein, we showcase a structure-agnostic bioactivity-driven combinatorial biosynthesis workflow that introduces bioactivity assessment as a selection-driving force to guide iterative combinatorial biosynthesis rounds towards enzyme combinations with increasing bioactivity.

Celastrol: A century-long journey from the isolation to the biotechnological production and the development of an antiobesity drug.

Celastrol, a triterpenoid found in the root of the traditional medicinal plant Tripterygium wilfordii, is a potent anti-inflammatory and antiobesity agent. However, pharmacological exploitation of celastrol has been hindered by the limited accessibility of plant material, the co-existence of other toxic compounds in the same plant tissue, and the lack of an efficient chemical synthesis method. In this review, we highlight recent progress in elucidating celastrol biosynthesis and discuss how this knowledge can facilitate its scalable bioproduction using cell factories and its further development as an antiobesity and anti-inflammatory drug.

Machine learning models for assessing risk factors affecting health care costs: 12-month exercise-based cardiac rehabilitation.

Introduction: Exercise-based cardiac rehabilitation (ECR) has proven to be effective and cost-effective dominant treatment option in health care. However, the contribution of well-known risk factors for prognosis of coronary artery disease (CAD) to predict health care costs is not well recognized. Since machine learning (ML) applications are rapidly giving new opportunities to assist health care professionals' work, we used selected ML tools to assess the predictive value of defined risk factors for health care costs during 12-month ECR in patients with CAD.

Machine learning models in predicting health care costs in patients with a recent acute coronary syndrome: A prospective pilot study.

Background: Health care budgets are limited, requiring the optimal use of resources. Machine learning (ML) methods may have an enormous potential for effective use of health care resources.

Objective: We assessed the applicability of selected ML tools to evaluate the contribution of known risk markers for prognosis of coronary artery disease to predict health care costs for all reasons in patients with a recent acute coronary syndrome (n = 65, aged 65 ± 9 years) for 1-year follow-up.

Biosynthesis and biotechnological production of the anti-obesity agent celastrol.

Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility.

Treed Gaussian Process Regression for Solving Offline Data-Driven Continuous Multiobjective Optimization Problems.

For offline data-driven multiobjective optimization problems (MOPs), no new data is available during the optimization process. Approximation models (or surrogates) are first built using the provided offline data, and an optimizer, for example, a multiobjective evolutionary algorithm, can then be utilized to find Pareto optimal solutions to the problem with surrogates as objective functions. In contrast to online data-driven MOPs, these surrogates cannot be updated with new data and, hence, the approximation accuracy cannot be improved by considering new data during the optimization process.

Expanding the terpene biosynthetic code with non-canonical 16 carbon atom building blocks.

Humankind relies on specialized metabolites for medicines, flavors, fragrances, and numerous other valuable biomaterials. However, the chemical space occupied by specialized metabolites, and, thus, their application potential, is limited because their biosynthesis is based on only a handful of building blocks. Engineering organisms to synthesize alternative building blocks will bypass this limitation and enable the sustainable production of molecules with non-canonical chemical structures, expanding the possible applications.

A GPCR-based yeast biosensor for biomedical, biotechnological, and point-of-use cannabinoid determination.

Eukaryotic cells use G-protein coupled receptors to sense diverse signals, ranging from chemical compounds to light. Here, we exploit the remarkable sensing capacity of G-protein coupled receptors to construct yeast-based biosensors for real-life applications. To establish proof-of-concept, we focus on cannabinoids because of their neuromodulatory and immunomodulatory activities.

Interactive multiobjective optimization for finding the most preferred exercise therapy modality in knee osteoarthritis.

Background: There are no explicit guidelines or tools available to support clinicians in selecting exercise therapy modalities according to the characteristics of individual patients despite the apparent need.

Objective: This study develops a methodology based on a novel multiobjective optimization model and examines its feasibility as a decision support tool to support healthcare professionals in comparing different modalities and identifying the most preferred one based on a patient's needs.

Methods: Thirty-one exercise therapy modalities were considered from 21 randomized controlled trials.

An Independent Evolutionary Origin for Insect Deterrent Cucurbitacins in Iberis amara.

Pieris rapae and Phyllotreta nemorum are Brassicaceae specialists, but do not feed on Iberis amara spp. that contain cucurbitacins. The cucurbitacins are highly oxygenated triterpenoid, occurring widespread in cucurbitaceous species and in a few other plant families.

Potential of interactive multiobjective optimization in supporting the design of a groundwater biodenitrification process.

The design of water treatment plants requires simultaneous analysis of technical, economic and environmental aspects, identified by multiple conflicting objectives. We demonstrated the advantages of an interactive multiobjective optimization (MOO) method over a posteriori methods in an unexplored field, namely the design of a biological treatment plant for drinking water production, that tackles the process drawbacks, contrarily to what happens in a traditional volumetric-load-driven design procedure. Specifically, we consider a groundwater denitrification biofilter, simulated by the Activated Sludge Model modified with two-stage denitrification kinetics.

Integrated metabolomics identifies CYP72A67 and CYP72A68 oxidases in the biosynthesis of Medicago truncatula oleanate sapogenins.

Introduction: Triterpene saponins are important bioactive plant natural products found in many plant families including the Leguminosae.

Objectives: We characterize two Medicago truncatula cytochrome P450 enzymes, MtCYP72A67 and MtCYP72A68, involved in saponin biosynthesis including both in vitro and in planta evidence.

Methods: UHPLC-(-)ESI-QToF-MS was used to profile saponin accumulation across a collection of 106 M.

Metabolic alteration of cell suspension cultures overexpressing in the plastids or cytosol.

Previous studies showed that geraniol could be an upstream limiting factor in the monoterpenoid pathway towards the production of terpenoid indole alkaloid (TIA) in cells and hairy root cultures. This shortage in precursor availability could be due to (1) limited expression of the plastidial resulted in a low activity of the enzyme to catalyze the conversion of geranyl diphosphate to geraniol; or (2) the limitation of geraniol transport from plastids to cytosol. Therefore, in this study, 's () gene was overexpressed in either plastids or cytosol of a non-TIA producing cell line.

The TriForC database: a comprehensive up-to-date resource of plant triterpene biosynthesis.

Triterpenes constitute a large and important class of plant natural products with diverse structures and functions. Their biological roles range from membrane structural components over plant hormones to specialized plant defence compounds. Furthermore, triterpenes have great potential for a variety of commercial applications such as vaccine adjuvants, anti-cancer drugs, food supplements and agronomic agents.

A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules.

Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck.

An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids.

Saponins are a structurally diverse family of triterpenes that are widely found as main constituents in many traditional plant-based medicines and often have bioactivities of industrial interest. The heterologous production of triterpene saponins in microbes remains challenging and only limited successful pathway engineering endeavors have been reported. To improve the production capacities of a Saccharomyces cerevisiae saponin production platform, we assessed the effects of several hitherto unexplored gene knockout targets on the heterologous production of triterpenoids.

The ancient CYP716 family is a major contributor to the diversification of eudicot triterpenoid biosynthesis.

Triterpenoids are widespread bioactive plant defence compounds with potential use as pharmaceuticals, pesticides and other high-value products. Enzymes belonging to the cytochrome P450 family have an essential role in creating the immense structural diversity of triterpenoids across the plant kingdom. However, for many triterpenoid oxidation reactions, the corresponding enzyme remains unknown.

The basic helix-loop-helix transcription factor BIS2 is essential for monoterpenoid indole alkaloid production in the medicinal plant Catharanthus roseus.

Monoterpenoid indole alkaloids (MIAs) are produced as plant defence compounds. In the medicinal plant Catharanthus roseus, they comprise the anticancer compounds vinblastine and vincristine. The iridoid (monoterpenoid) pathway forms one of the two branches that feed MIA biosynthesis and its activation is regulated by the transcription factor (TF) basic helix-loop-helix (bHLH) iridoid synthesis 1 (BIS1).

Projections onto the Pareto surface in multicriteria radiation therapy optimization.

Purpose: To eliminate or reduce the error to Pareto optimality that arises in Pareto surface navigation when the Pareto surface is approximated by a small number of plans.

Methods: The authors propose to project the navigated plan onto the Pareto surface as a postprocessing step to the navigation. The projection attempts to find a Pareto optimal plan that is at least as good as or better than the initial navigated plan with respect to all objective functions.

The bHLH transcription factor BIS1 controls the iridoid branch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus.

Plants make specialized bioactive metabolites to defend themselves against attackers. The conserved control mechanisms are based on transcriptional activation of the respective plant species-specific biosynthetic pathways by the phytohormone jasmonate. Knowledge of the transcription factors involved, particularly in terpenoid biosynthesis, remains fragmentary.

Iridoid synthase activity is common among the plant progesterone 5β-reductase family.

Catharanthus roseus, the Madagascar periwinkle, synthesizes bioactive monoterpenoid indole alkaloids, including the anti-cancer drugs vinblastine and vincristine. The monoterpenoid branch of the alkaloid pathway leads to the secoiridoid secologanin and involves the enzyme iridoid synthase (IS), a member of the progesterone 5β-reductase (P5βR) family. IS reduces 8-oxogeranial to iridodial.

Iridoid Synthase Activity Is Common among the Plant Progesterone 5β-Reductase Family.

Catharanthus roseus, the Madagascar periwinkle, synthesizes bioactive monoterpenoid indole alkaloids, among which the anti-cancer drugs vinblastine and vincristine. The monoterpenoid branch of the alkaloid pathway leads to the secoiridoid secologanin and involves the enzyme iridoid synthase (IS), a member of the progesterone 5β-reductase (P5βR) family. IS reduces 8-oxogeranial to iridodial.

Screening sleep disordered breathing in stroke unit.

In acute stroke, OSA has been found to impair rehabilitation and increase mortality but the effect of central apnea is more unclear. The aim of the present study was to evaluate the feasibility of using limited ambulatory recording system (sleep mattress to evaluate nocturnal breathing and EOG-electrodes for sleep staging) in sleep disordered breathing (SDB) diagnostics in mild acute cerebral ischemia patients and to discover the prevalence of various SDB-patterns among these patients. 42 patients with mild ischemic stroke or transient ischemic attack were studied.