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At least 37 records · Page 2

Generating synthetic signaling networks for in silico modeling studies

Predictive models of signaling pathways have proven to be difficult to develop. Reasons include the uncertainty in the number of species, the complexity in species’ interactions, and the sparseness and uncertainty in experimental data. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. For example, uncertainty and sparseness of the data often result in overfitted models that have little predictive value beyond recapitulating the experimental data itself. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. However, to determine the effectiveness of any new algorithm, a baseline model is needed to test its performance. To meet this need, we developed a method for generating artificial synthetic networks that are reasonably realistic and thus can be treated as ground truth models. These synthetic models can then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. Here, we describe a simple approach for generating synthetic signaling networks that can be used for this purpose.

42 ENGINEERING↗

DyG-DPCD: A Distributed Parallel Community Detection Algorithm for Large-Scale Dynamic Graphs

Dynamic (Temporal) graphs capture the valuable evolution of real-world systems, from the continuously evolving patterns of social interactions and genetic pathways to the dynamic fluctuations of economic forces. Detecting communities for such evolving networks poses unique challenges. Detecting and analyzing the evolution of communities within dynamic graphs unlocks valuable insights into the underlying structural and temporal patterns of real-world systems. However, the sheer volume of modern graph data and the inherent complexity of the temporal dimension pose significant challenges to scalable community detection algorithms. Addressing this gap, our work explores the limited landscape of scalable distributed-memory parallel methods specifically designed for dynamic network community detection. We propose a novel parallel algorithm, DyG-DPCD (Dynamic Graph Distributed Parallel Community Detection), to detect communities in dynamic networks using the Message Passing Interface (MPI) framework. We present a vertex-centric approach, allowing us to detect communities through local optimization. Furthermore, we enhance our baseline algorithm by incorporating three heuristics, which improve the algorithm’s performance significantly while maintaining the quality of the solutions. We demonstrate the efficiency of our algorithm by experimenting on several real-world large-scale networks with hundreds of millions of edges spanning diverse domains. Notably, DyG-DPCD achieves speedups between 25× and 30× for large networks that we experimented on using NERSC compute nodes. In conclusion, our algorithm outperforms the STINGER parallel re-agglomeration algorithm by 30×.

97 MATHEMATICS AND COMPUTING↗

Tensor network representation of non-abelian gauge theory coupled to reduced staggered fermions

We show how to construct a tensor network representation of the path integral for reduced staggered fermions coupled to a non-abelian gauge field in two dimensions. The resulting formulation is both memory and computation efficient because reduced staggered fermions can be represented in terms of a minimal number of tensor indices while the gauge sector can be approximated using Gaussian quadrature with a truncation. Numerical results obtained using the Grassmann TRG algorithm are shown for the case of SU(2) lattice gauge theory and compared to Monte Carlo results.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Linking metabolic phenotypes to pathogenic traits among “ Candidatus Liberibacter asiaticus” and its hosts

Candidatus Liberibacter asiaticus (CLas) has been associated with Huanglongbing, a lethal vector-borne disease affecting citrus crops worldwide. While comparative genomics has provided preliminary insights into the metabolic capabilities of this uncultured microorganism, a comprehensive functional characterization is currently lacking. Here, we reconstructed and manually curated genome-scale metabolic models for the six CLas strains A4, FL17, gxpsy, Ishi-1, psy62, and YCPsy, in addition to a model of the closest related culturable microorganism, L. crescens BT-1. Predictions about nutrient requirements and changes in growth phenotypes of CLas were confirmed using in vitro hairy root-based assays, while the L. crescens BT-1 model was validated using cultivation assays. Host-dependent metabolic phenotypes were revealed using expression data obtained from CLas-infected citrus trees and from the CLas-harboring psyllid Diaphorina citri Kuwayama. These results identified conserved and unique metabolic traits, as well as strain-specific interactions between CLas and its hosts, laying the foundation for the development of model-driven Huanglongbing management strategies.

59 BASIC BIOLOGICAL SCIENCES↗

Predicting stress response and improved protein overproduction in Bacillus subtilis

Abstract Bacillus subtilis is a well-characterized microorganism and a model for the study of Gram-positive bacteria. The bacterium can produce proteins at high densities and yields, which has made it valuable for industrial bioproduction. Like other cell factories, metabolic modeling of B. subtilis has discovered ways to optimize its metabolism toward various applications. The first genome-scale metabolic model (M-model) of B. subtilis was published more than a decade ago and has been applied extensively to understand metabolism, to predict growth phenotypes, and served as a template to reconstruct models for other Gram-positive bacteria. However, M-models are ill-suited to simulate the production and secretion of proteins as well as their proteomic response to stress. Thus, a new generation of metabolic models, known as metabolism and gene expression models (ME-models), has been initiated. Here, we describe the reconstruction and validation of a ME model of B. subtilis , i JT964-ME. This model achieved higher performance scores on the prediction of gene essentiality as compared to the M-model. We successfully validated the model by integrating physiological and omics data associated with gene expression responses to ethanol and salt stress. The model further identified the mechanism by which tryptophan synthesis is upregulated under ethanol stress. Further, we employed i JT964-ME to predict amylase production rates under two different growth conditions. We analyzed these flux distributions and identified key metabolic pathways that permitted the increase in amylase production. Models like i JT964-ME enable the study of proteomic response to stress and the illustrate the potential for optimizing protein production in bacteria.

59 BASIC BIOLOGICAL SCIENCES↗

Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine

The human microbiome influences the efficacy and safety of a wide variety of commonly prescribed drugs. Designing precision medicine approaches that incorporate microbial metabolism would require strain- and molecule-resolved, scalable computational modeling. Here, we extend our previous resource of genome-scale metabolic reconstructions of human gut microorganisms with a greatly expanded version. AGORA2 (assembly of gut organisms through reconstruction and analysis, version 2) accounts for 7,302 strains, includes strain-resolved drug degradation and biotransformation capabilities for 98 drugs, and was extensively curated based on comparative genomics and literature searches. The microbial reconstructions performed very well against three independently assembled experimental datasets with an accuracy of 0.72 to 0.84, surpassing other reconstruction resources and predicted known microbial drug transformations with an accuracy of 0.81. We demonstrate that AGORA2 enables personalized, strain-resolved modeling by predicting the drug conversion potential of the gut microbiomes from 616 patients with colorectal cancer and controls, which greatly varied between individuals and correlated with age, sex, body mass index and disease stages. AGORA2 serves as a knowledge base for the human microbiome and paves the way to personalized, predictive analysis of host–microbiome metabolic interactions.

59 BASIC BIOLOGICAL SCIENCES↗

A metabolic modeling platform for the computation of microbial ecosystems in time and space (COMETS)

Genome-scale stoichiometric modeling of metabolism has become a standard systems biology tool for modeling cellular physiology and growth. Extensions of this approach are emerging as a valuable avenue for predicting, understanding and designing microbial communities. Computation of microbial ecosystems in time and space (COMETS) extends dynamic flux balance analysis to generate simulations of multiple microbial species in molecularly complex and spatially structured environments. Here we describe how to best use and apply the most recent version of COMETS, which incorporates a more accurate biophysical model of microbial biomass expansion upon growth, evolutionary dynamics and extracellular enzyme activity modules. In addition to a command-line option, COMETS includes user-friendly Python and MATLAB interfaces compatible with the well-established COBRA models and methods, as well as comprehensive documentation and tutorials. Overall, this protocol provides a detailed guideline for installing, testing and applying COMETS to different scenarios, generating simulations that take from a few minutes to several days to run, with broad applicability to microbial communities across biomes and scales.

59 BASIC BIOLOGICAL SCIENCES↗

Multi-Attribute Subset Selection enables prediction of representative phenotypes across microbial populations

The interpretation of complex biological datasets requires the identification of representative variables that describe the data without critical information loss. This is particularly important in the analysis of large phenotypic datasets (phenomics). Here we introduce Multi-Attribute Subset Selection (MASS), an algorithm which separates a matrix of phenotypes (e.g., yield across microbial species and environmental conditions) into predictor and response sets of conditions. Using mixed integer linear programming, MASS expresses the response conditions as a linear combination of the predictor conditions, while simultaneously searching for the optimally descriptive set of predictors. We apply the algorithm to three microbial datasets and identify environmental conditions that predict phenotypes under other conditions, providing biologically interpretable axes for strain discrimination. MASS could be used to reduce the number of experiments needed to identify species or to map their metabolic capabilities. The generality of the algorithm allows addressing subset selection problems in areas beyond biology.

59 BASIC BIOLOGICAL SCIENCES↗

bngsim

An embeddable simulation library for biochemical reaction networks

Hlavacek, Bill [Los Alamos National Laboratory]↗

The hierarchical organization of autocatalytic reaction networks and its relevance to origin of life

Abiogenesis has long been suspected to require that chemical reaction networks contain multiple autocatalytic cores, but little is known about what features of these networks allow for the gradual accretion of complexity. To identify realistic scenarios for the emergence of life-like properties, we develop the concept of a seed-dependent autocatalytic system (SDAS), which is a subnetwork that can autocatalytically self-maintain given a flux of food, but cannot be initiated by food alone. Rather, initiation of SDASs requires the transient introduction of chemical “seeds”. We show that, depending on the topological relationship of SDASs in a chemical reaction network, a food-driven system can accrete complexity in a historically contingent manner, governed by rare seeding events. We develop new algorithms for detecting and analyzing SDASs in chemical reaction databases and describe parallels between multi-SDAS networks and biological ecosystems. Applying our algorithms to both an abiotic reaction network and a biochemical one, each driven by a set of simple food chemicals, we detect SDASs that are organized as trophic tiers, of which the higher tier can be seeded by relatively simple chemicals if the lower tier is already activated. This indicates that sequential activation of trophically organized SDASs by seed chemicals that are not much more complex than what already exist could be a mechanism of gradual complexification from relatively simple abiotic reactions to more complex life-like systems. Interestingly, in both reaction networks, higher-tier SDASs include chemicals that might alter emergent features of chemical systems and could serve as early targets of selection. Our analysis provides computational tools for analyzing very large chemical/biochemical reaction networks and suggests new approaches to studying abiogenesis in the lab.

Zhen Peng↗

Modeling the Normal and Neoplastic Cell Cycle with 'Realistic Boolean Genetic Networks': Their Application for Understanding Carcinogenesis and Assessing Therapeutic Strategies

In this paper we show how Boolean genetic networks could be used to address complex problems in cancer biology. First, we describe a general strategy to generate Boolean genetic networks that incorporate all relevant biochemical and physiological parameters and cover all of their regulatory interactions in a deterministic manner. Second, we introduce 'realistic Boolean genetic networks' that produce time series measurements very similar to those detected in actual biological systems. Third, we outline a series of essential questions related to cancer biology and cancer therapy that could be addressed by the use of 'realistic Boolean genetic network' modeling.

Szallasi, Zoltan↗

Integrative teaching of metabolic modeling and flux analysis with interactive python modules

Abstract The modeling of rates of biochemical reactions—fluxes—in metabolic networks is widely used for both basic biological research and biotechnological applications. A number of different modeling methods have been developed to estimate and predict fluxes, including kinetic and constraint‐based (Metabolic Flux Analysis and flux balance analysis) approaches. Although different resources exist for teaching these methods individually, to‐date no resources have been developed to teach these approaches in an integrative way that equips learners with an understanding of each modeling paradigm, how they relate to one another, and the information that can be gleaned from each. We have developed a series of modeling simulations in Python to teach kinetic modeling, metabolic control analysis, 13C‐metabolic flux analysis, and flux balance analysis. These simulations are presented in a series of interactive notebooks with guided lesson plans and associated lecture notes. Learners assimilate key principles using models of simple metabolic networks by running simulations, generating and using data, and making and validating predictions about the effects of modifying model parameters. We used these simulations as the hands‐on computer laboratory component of a four‐day metabolic modeling workshop and participant survey results showed improvements in learners' self‐assessed competence and confidence in understanding and applying metabolic modeling techniques after having attended the workshop. The resources provided can be incorporated in their entirety or individually into courses and workshops on bioengineering and metabolic modeling at the undergraduate, graduate, or postgraduate level.

Kaste, Joshua A. M.↗

Decoding the protein–ligand interactions using parallel graph neural networks

Abstract Protein–ligand interactions (PLIs) are essential for biochemical functionality and their identification is crucial for estimating biophysical properties for rational therapeutic design. Currently, experimental characterization of these properties is the most accurate method, however, this is very time-consuming and labor-intensive. A number of computational methods have been developed in this context but most of the existing PLI prediction heavily depends on 2D protein sequence data. Here, we present a novel parallel graph neural network (GNN) to integrate knowledge representation and reasoning for PLI prediction to perform deep learning guided by expert knowledge and informed by 3D structural data. We develop two distinct GNN architectures: $$\hbox {GNN}_{\mathrm{F}}$$ GNN F is the base implementation that employs distinct featurization to enhance domain-awareness, while $$\hbox {GNN}_{\mathrm{P}}$$ GNN P is a novel implementation that can predict with no prior knowledge of the intermolecular interactions. The comprehensive evaluation demonstrated that GNN can successfully capture the binary interactions between ligand and protein’s 3D structure with 0.979 test accuracy for $$\hbox {GNN}_{\mathrm{F}}$$ GNN F and 0.958 for $$\hbox {GNN}_{\mathrm{P}}$$ GNN P for predicting activity of a protein–ligand complex. These models are further adapted for regression tasks to predict experimental binding affinities and $$\hbox {pIC}_{\mathrm{50}}$$ pIC 50 crucial for compound’s potency and efficacy. We achieve a Pearson correlation coefficient of 0.66 and 0.65 on experimental affinity and 0.50 and 0.51 on $$\hbox {pIC}_{\mathrm{50}}$$ pIC 50 with $$\hbox {GNN}_{\mathrm{F}}$$ GNN F and $$\hbox {GNN}_{\mathrm{P}}$$ GNN P , respectively, outperforming similar 2D sequence based models. Our method can serve as an interpretable and explainable artificial intelligence (AI) tool for predicted activity, potency, and biophysical properties of lead candidates. To this end, we show the utility of $$\hbox {GNN}_{\mathrm{P}}$$ GNN P on SARS-Cov-2 protein targets by screening a large compound library and comparing the prediction with the experimentally measured data.

59 BASIC BIOLOGICAL SCIENCES↗

Co-catabolism of arginine and succinate drives symbiotic nitrogen fixation

Biological nitrogen fixation emerging from the symbiosis between bacteria and crop plants holds promise to increase the sustainability of agriculture. One of the biggest hurdles for the engineering of nitrogen-fixing organisms is an incomplete knowledge of metabolic interactions between microbe and plant. In contrast to the previously assumed supply of only succinate, we describe here the CATCH-N cycle as a novel metabolic pathway that co-catabolizes plant provided arginine and succinate to drive the energy-demanding process of symbiotic nitrogen fixation in endosymbiotic rhizobia. Using systems biology, isotope labeling studies and transposon sequencing in conjunction with biochemical characterization, we uncovered highly redundant network components of the CATCH-N cycle including transaminases that interlink the co-catabolism of arginine and succinate. The CATCH-N cycle uses N2 as an additional sink for reductant and therefore delivers up to 25% higher yields of nitrogen than classical arginine catabolism—two alanines and three ammonium ions are secreted for each input of arginine and succinate. We argue that the CATCH-N cycle has evolved as part of a synergistic interaction to sustain bacterial metabolism in the microoxic and highly acid environment of symbiosomes. Thus, the CATCHN cycle entangles the metabolism of both partners to promote symbiosis. Our results provide a theoretical framework and metabolic blueprint for the rational design of plants and plant-associated organisms with new properties to improve nitrogen fixation.

59 BASIC BIOLOGICAL SCIENCES↗

Metabolite discovery through global annotation of untargeted metabolomics data

Liquid chromatography–high-resolution mass spectrometry (LC-MS)-based metabolomics aims to identify and quantify all metabolites, but most LC-MS peaks remain unidentified. Here we present a global network optimization approach, NetID, to annotate untargeted LC-MS metabolomics data. The approach aims to generate, for all experimentally observed ion peaks, annotations that match the measured masses, retention times and (when available) tandem mass spectrometry fragmentation patterns. Peaks are connected based on mass differences reflecting adduction, fragmentation, isotopes, or feasible biochemical transformations. Global optimization generates a single network linking most observed ion peaks, enhances peak assignment accuracy, and produces chemically informative peak–peak relationships, including for peaks lacking tandem mass spectrometry spectra. Applying this approach to yeast and mouse data, we identified five previously unrecognized metabolites (thiamine derivatives and N-glucosyl-taurine). Isotope tracer studies indicate active flux through these metabolites. Furthermore, NetID applies existing metabolomic knowledge and global optimization to substantially improve annotation coverage and accuracy in untargeted metabolomics datasets, facilitating metabolite discovery.

59 BASIC BIOLOGICAL SCIENCES↗

Cellerator: extending a computer algebra system to include biochemical arrows for signal transduction simulations

Cellerator describes single and multi-cellular signal transduction networks (STN) with a compact, optionally palette-driven, arrow-based notation to represent biochemical reactions and transcriptional activation. Multi-compartment systems are represented as graphs with STNs embedded in each node. Interactions include mass-action, enzymatic, allosteric and connectionist models. Reactions are translated into differential equations and can be solved numerically to generate predictive time courses or output as systems of equations that can be read by other programs. Cellerator simulations are fully extensible and portable to any operating system that supports Mathematica, and can be indefinitely nested within larger data structures to produce highly scaleable models.

Non-NASA Center↗

Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator

Gene activator proteins comprise distinct DNA-binding and transcriptional activation domains (ADs). Because few ADs have been described, we tested domains tiling all yeast transcription factors for activation in vivo and identified 150 ADs. By mRNA display, we showed that 73% of ADs bound the Med15 subunit of Mediator, and that binding strength was correlated with activation. AD-Mediator interaction in vitro was unaffected by a large excess of free activator protein, pointing to a dynamic mechanism of interaction. Structural modeling showed that ADs interact with Med15 without shape complementarity (‘fuzzy’ binding). ADs shared no sequence motifs, but mutagenesis revealed biochemical and structural constraints. Finally, a neural network trained on AD sequences accurately predicted ADs in human proteins and in other yeast proteins, including chromosomal proteins and chromatin remodeling complexes. These findings solve the longstanding enigma of AD structure and function and provide a rationale for their role in biology.

60 APPLIED LIFE SCIENCES↗

Satellite Mapping of Rain-Induced Nitric Oxide Emissions from Soils

We use space-based observations of NO2 columns from the Global Ozone Monitoring Experiment (GOME) to map the spatial and seasonal variations of NOx emissions over Africa during 2000. The GOME observations show not only enhanced tropospheric NO2 columns from biomass burning during the dry season but also comparable enhancements from soil emissions during the rainy season over the Sahel. These soil emissions occur in strong pulses lasting 1-3 weeks following the onset of rain, and affect 3 million sq km of semiarid sub-Saharan savanna. Surface observations of NO2 from the International Global Atmospheric Chemistry (IGAC)/Deposition of Biochemically Important Trace Species (DEBITS)/Africa (IDAF) network over West Africa provide further evidence for a strong role for microbial soil sources. By combining inverse modeling of GOME NO2 columns with space-based observations of fires, we estimate that soils contribute 3.3+/-1.8 TgN/year, similar to the biomass burning source (3.8+/-2.1 TgN/year), and thus account for 40% of surface NO(x) emissions over Africa. Extrapolating to all the tropics, we estimate a 7.3 TgN/year biogenic soil source, which is a factor of 2 larger compared to model-based inventories but agrees with observation-based inventories. These large soil NO(x) emissions are likely to significantly contribute to the ozone enhancement originating from tropical Africa.

Jaegle, L.↗