With COVID-19 becoming endemic, there is a continuing need to find biomarkers characterizing the disease and aiding in patient stratification. We studied the relation between COVID-19 and cholesterol ...biosynthesis by comparing 10 intermediates of cholesterol biosynthesis during the hospitalization of 164 patients (admission, disease deterioration, discharge) admitted to the University Medical Center of Ljubljana. The concentrations of zymosterol, 24-dehydrolathosterol, desmosterol, and zymostenol were significantly altered in COVID-19 patients. We further developed a predictive model for disease severity based on clinical parameters alone and their combination with a subset of sterols. Our machine learning models applying 8 clinical parameters predicted disease severity with excellent accuracy (AUC = 0.96), showing substantial improvement over current clinical risk scores. After including sterols, model performance remained better than COVID-GRAM. This is the first study to examine cholesterol biosynthesis during COVID-19 and shows that a subset of cholesterol-related sterols is associated with the severity of COVID-19.
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•Intracellular synthesis of cholesterol is significantly modified during COVID-19•A handful of clinical variables outperform current patient stratification tools•A subset of cholesterol-related sterols was associated with COVID-19 severity
Assessment in health technology; Lipid; Bioinformatics
Boolean networks provide an effective mechanism for describing interactions and dynamics of gene regulatory networks (GRNs). Deriving accurate Boolean descriptions of GRNs is a challenging task. The ...number of experiments is usually much smaller than the number of genes. In addition, binarization leads to a loss of information and inconsistencies arise in binarized time-series data. The inference of Boolean networks from binarized time-series data alone often leads to complex and overfitted models. To obtain relevant Boolean models of gene regulatory networks, inference methods could incorporate data from multiple sources and prior knowledge in terms of general network structure and/or exact interactions. We propose the Boolean network inference method SAILoR (Structure-Aware Inference of Logic Rules). SAILoR incorporates time-series gene expression data in combination with provided reference networks to infer accurate Boolean models. SAILoR automatically extracts topological properties from reference networks. These can describe a more general structure of the GRN or can be more precise and describe specific interactions. SAILoR infers a Boolean network by learning from both continuous and binarized time-series data. It navigates between two main objectives, topological similarity to reference networks and correspondence with gene expression data. By incorporating the NSGA-II multi-objective genetic algorithm, SAILoR relies on the wisdom of crowds. Our results indicate that SAILoR can infer accurate and biologically relevant Boolean descriptions of GRNs from both a static and a dynamic perspective. We show that SAILoR improves the static accuracy of the inferred network compared to the network inference method dynGENIE3. Furthermore, we compared the performance of SAILoR with other Boolean network inference approaches including Best-Fit, REVEAL, MIBNI, GABNI, ATEN, and LogBTF. We have shown that by incorporating prior knowledge about the overall network structure, SAILoR can improve the structural correctness of the inferred Boolean networks while maintaining dynamic accuracy. To demonstrate the applicability of SAILoR, we inferred context-specific Boolean subnetworks of female Drosophila melanogaster before and after mating.
Travel time data and variability of travel times can be used to quantify the network performance as an important aspect of sustainable development in modern cities. We introduce a data collection and ...analysis framework to be employed as an integral part of a neighbourhood sustainability assessment (NSA). The proposed framework performs a targeted selection and evaluation of indicators based on publicly available traffic data, specifically addressing short-term observations of travel times and traffic counts. Entailing a hybrid and modular approach, we demonstrate the applicability of travel time reliability measures by combining different datasets, various variability estimators, and visualisation methods, to advance the interpretation strength of the assessment. Implemented are regression methods based on cosinor models, which allow us to analyse the rhythmic behaviour of travel time trends. These models can be applied to assess the differential rhythmicity among different factors, like route, weather conditions and type of day (i.e., weekend or workday). Further, the same datasets are used to evaluate two reliability metrics, i.e., a travel time index and a planning time index. We demonstrate the application of the suggested framework on several strategic routes associated with three testbed neighbourhoods in Ljubljana, Slovenia. The results show that average travel times and their variations are affected by route, day of the week, and weather conditions, and correlate with vehicles count data. Analyses of rhythmicity give straightforward insights into travel time trends, appropriate for comparative analysis and thus well-suited for use in NSA and monitoring practices. To the best of our knowledge, this work presents the first study quantifying reliability indicators intended for integration with NSA standards.
•Travel time distributions are analysed to formulate indicators for the neighbourhood sustainability assessment (NSA)•We enhance NSA methods based on short-term observations of travel times and traffic counts•Cosinor regression is applied for detection and characterization of rhythmicity of travel times•The interchangeable use and integration of two data sources, Google Direction API and roadway counters, is examined•The study provides recommendations for the straightforward analysis and presentation of travel times and their variability
Boolean descriptions of gene regulatory networks can provide an insight into interactions between genes. Boolean networks hold predictive power, are easy to understand, and can be used to simulate ...the observed networks in different scenarios.
We review fundamental and state-of-the-art methods for inference of Boolean networks. We introduce a methodology for a straightforward evaluation of Boolean inference approaches based on the generation of evaluation datasets, application of selected inference methods, and evaluation of performance measures to guide the selection of the best method for a given inference problem. We demonstrate this procedure on inference methods REVEAL (REVerse Engineering ALgorithm), Best-Fit Extension, MIBNI (Mutual Information-based Boolean Network Inference), GABNI (Genetic Algorithm-based Boolean Network Inference) and ATEN (AND/OR Tree ENsemble algorithm), which infers Boolean descriptions of gene regulatory networks from discretised time series data.
Boolean inference approaches tend to perform better in terms of dynamic accuracy, and slightly worse in terms of structural correctness. We believe that the proposed methodology and provided guidelines will help researchers to develop Boolean inference approaches with a good predictive capability while maintaining structural correctness and biological relevance.
Boolean network inference; Gene regulatory networks; Static validation; Dynamic validation; Systems biology
Synthetic biology applications often require engineered computing structures, which can be programmed to process the information in a given way. However, programming of these structures usually ...requires significant amount of trial-and-error genetic engineering. This process is to some degree analogous to the design of application-specific integrated circuits (ASIC) in the domain of digital electronic circuits, which often require complex and time-consuming workflows to obtain a desired response.
We describe a design of programmable biological circuits that can be configured without additional genetic engineering. Their configuration can be changed in vivo, i.e. during the execution of their biological program, simply with an introduction of programming inputs. These, e.g., increase the degradation rates of selected proteins that store the current configuration of the circuit. Programming can be thus performed in the field as in the case of field-programmable gate array (FPGA) circuits, which present an attractive alternative of ASICs in digital electronics.
We describe a basic programmable unit, which we denote configurable (bio)logical block (CBLB) inspired by the architecture of configurable logic blocks (CLBs), basic functional units within the FPGA circuits. The design of a CBLB is based on distributed cellular computing modules, which makes its biological implementation easier to achieve. We establish a computational model of a CBLB and analyse its response with a given set of biologically feasible parameter values. Furthermore, we show that the proposed CBLB design exhibits correct behaviour for a vast range of kinetic parameter values, different population ratios, and as well preserves this response in stochastic simulations.
•We introduce a concept of field-programmable biological circuits.•The concept is based on a design of configurable (bio)logic blocks (CBLBs).•CBLBs are based on a distributed implementation of a biological multiplexer and memory.•The design is verified using computational modelling and analysis approaches.•(Re)programmability is demonstrated on different logic functions.
Gene regulatory networks with different topological and/or dynamical properties might exhibit similar behavior. System that is less perceptive for the perturbations of its internal and external ...factors should be preferred. Methods for sensitivity and robustness assessment have already been developed and can be roughly divided into local and global approaches. Local methods focus only on the local area around nominal parameter values. This can be problematic when parameters exhibits the desired behavior over a large range of parameter perturbations or when parameter values are unknown. Global methods, on the other hand, investigate the whole space of parameter values and mostly rely on different sampling techniques. This can be computationally inefficient. To address these shortcomings 'glocal' approaches were developed that apply global and local approaches in an effective and rigorous manner.
Herein, we present a computational approach for 'glocal' analysis of viable parameter regions in biological models. The methodology is based on the exploration of high-dimensional viable parameter spaces with global and local sampling, clustering and dimensionality reduction techniques. The proposed methodology allows us to efficiently investigate the viable parameter space regions, evaluate the regions which exhibit the largest robustness, and to gather new insights regarding the size and connectivity of the viable parameter regions. We evaluate the proposed methodology on three different synthetic gene regulatory network models, i.e. the repressilator model, the model of the AC-DC circuit and the model of the edge-triggered master-slave D flip-flop.
The proposed methodology provides a rigorous assessment of the shape and size of viable parameter regions based on (1) the mathematical description of the biological system of interest, (2) constraints that define feasible parameter regions and (3) cost function that defines the desired or observed behavior of the system. These insights can be used to assess the robustness of biological systems, even in the case when parameter values are unknown and more importantly, even when there are multiple poorly connected viable parameter regions in the solution space. Moreover, the methodology can be efficiently applied to the analysis of biological systems that exhibit multiple modes of the targeted behavior.
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