Numerical simulation of blood flow is a challenging topic due to the multiphase nature of this biological fluid. The choice of a specific method among the ones available in literature is often motivated by the physical scale of interest. Single-phase approximation allows for lower computational time, but does not consider this multiphase nature. Cell-level simulation, on the other hand, requires high computational resources and is limited to small scales. This work proposes a scale-up approach for cell-level simulation of blood flow, in the framework of unresolved CFD-DEM technique. This method offers the possibility to simulate hundreds of thousands of particles with limited computational effort, but requires specific models for fluid-particle interactions. Regarding blood flow, drag and lift force acting on the red blood cells (RBCs) are responsible for several macroscopic blood characteristics. Despite several correlations available for drag and lift force acting on rigid particles, specific force models for the simulation of deformable particles compatible with RBCs physics are missing. This study employs data obtained from cell-level simulations to derive equations then used in unresolved simulation of RBCs. The strategy followed during the modeling phase is presented, together with the model verification and validation. This approach returns satisfying results when used to simulate blood flow in large-scale channels. Up to half a million RBCs are considered, and computational effort is reported to allow a comparison with other existing methods. Future perspectives include further improvement of the model, such as a deeper understanding of particle-particle interactions.

2\'-deoxy-ATP (dATP) improves cardiac function by increasing the rate of crossbridge cycling and Ca[Formula: see text] transient decay. However, the mechanisms of these effects and how therapeutic responses to dATP are achieved when dATP is only a small fraction of the total ATP pool remain poorly understood. Here, we used a multiscale computational modeling approach to analyze the mechanisms by which dATP improves ventricular function. We integrated atomistic simulations of prepowerstroke myosin and actomyosin association, filament-scale Markov state modeling of sarcomere mechanics, cell-scale analysis of myocyte Ca[Formula: see text] dynamics and contraction, organ-scale modeling of biventricular mechanoenergetics, and systems level modeling of circulatory dynamics. Molecular and Brownian dynamics simulations showed that dATP increases the actomyosin association rate by 1.9 fold. Markov state models predicted that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady-state force development at low dATP fractions by 1.3 fold due to mechanosensing and nearest-neighbor cooperativity. This was found to be the dominant mechanism by which small amounts of dATP can improve contractile function at myofilament to organ scales. Together with faster myocyte Ca[Formula: see text] handling, this led to improved ventricular contractility, especially in a failing heart model in which dATP increased ejection fraction by 16% and the energy efficiency of cardiac contraction by 1%. This work represents a complete multiscale model analysis of a small molecule myosin modulator from single molecule to organ system biophysics and elucidates how the molecular mechanisms of dATP may improve cardiovascular function in heart failure with reduced ejection fraction.

The digestion of starch-based foods in the intestinal tract is important for human health. Modeling the details enhances fundamental understanding and glycemic prediction accuracy. It is, however, a challenge to take granular properties into account. A multiscale digestion model has been proposed to characterize mass transfer and hydrolysis reaction at both the intestine and particle scales, seamlessly integrating inter-scale mass exchange. A specific grid scheme was formulated for the shrinkage and transport of the particle computational domain. By incorporating additional glycemic-related processes, e.g., intestinal absorption, a dietary property-based glycemic prediction system has been developed. Its effectiveness was validated based on a human tolerance experiment of cooked rice particles. The model-based investigation comprehensively reveals the impact of initial size on digestion behavior, specifically in terms of enzyme distribution and particle evolution. This work also demonstrates the significance of modeling both particle-scale diffusion and intestine-scale transport, a combination not previously explored. The results indicate that ignoring the former mechanism leads to an overestimation of the glycemic peak by at least 50.8%, while ignoring the latter results in an underestimation of 16.3%.

In a deep-learning-based algorithm, generative adversarial networks can generate images similar to an input. Using this algorithm, an artificial three-dimensional (3D) microstructure can be reproduced from two-dimensional images. Although the generated 3D microstructure has a similar appearance, its reproducibility should be examined for practical applications. This study used an automated serial sectioning technique to compare the 3D microstructures of two dual-phase steels generated from three orthogonal surface images with their corresponding observed 3D microstructures. The mechanical behaviors were examined using the finite element analysis method for the representative volume element, in which finite element models of microstructures were directly constructed from the 3D voxel data using a voxel coarsening approach. The macroscopic material responses of the generated microstructures captured the anisotropy caused by the microscopic morphology. However, these responses did not quantitatively align with those of the observed microstructures owing to inaccuracies in reproducing the volume fraction of the ferrite/martensite phase. Additionally, the generation algorithm struggled to replicate the microscopic morphology, particularly in cases with a low volume fraction of the martensite phase where the martensite connectivity was not discernible from the input images. The results demonstrate the limitations of the generation algorithm and the necessity for 3D observations.
This study provided the comparison between experimentally observed and computationally generated 3D microstructures of dual-phase steels in the macro- and microscopic material behaviors with finite element analysis method for periodic microstructure.

A fundamental understanding of how HIV-1 envelope (Env) protein facilitates fusion is still lacking. The HIV-1 fusion peptide, consisting of 15 to 22 residues, is the N-terminus of the gp41 subunit of the Env protein. Further, this peptide, a promising vaccine candidate, initiates viral entry into target cells by inserting and anchoring into human immune cells. The influence of membrane lipid reorganization and the conformational changes of the fusion peptide during the membrane insertion and anchoring processes, which can significantly affect HIV-1 cell entry, remains largely unexplored due to the limitations of experimental measurements. In this work, we investigate the insertion of the fusion peptide into an immune cell membrane mimic through multiscale molecular dynamics simulations. We mimic the native T-cell by constructing a 9-lipid asymmetric membrane, along with geometrical restraints accounting for insertion in the context of gp41. To account for the slow timescale of lipid mixing while enabling conformational changes, we implement a protocol to go back and forth between atomistic and coarse-grained simulations. Our study provides a molecular understanding of the interactions between the HIV-1 fusion peptide and the T-cell membrane, highlighting the importance of conformational flexibility of fusion peptides and local lipid reorganization in stabilizing the anchoring of gp41 into the targeted host membrane during the early events of HIV-1 cell entry. Importantly, we identify a motif within the fusion peptide critical for fusion that can be further manipulated in future immunological studies.

Composition is a powerful principle for systems biology, focused on the interfaces, interconnections, and orchestration of distributed processes. Whereas most systems biology models focus on the structure or dynamics of specific subsystems in controlled conditions, compositional systems biology aims to connect such models into integrative multiscale simulations. This emphasizes the space between models-a compositional perspective asks what variables should be exposed through a submodel\'s interface? How do coupled models connect and translate across scales? How can we connect domain-specific models across biological and physical research areas to drive the synthesis of new knowledge? What is required of software that integrates diverse datasets and submodels into unified multiscale simulations? How can the resulting integrative models be accessed, flexibly recombined into new forms, and iteratively refined by a community of researchers? This essay offers a high-level overview of the key components for compositional systems biology, including: 1) a conceptual framework and corresponding graphical framework to represent interfaces, composition patterns, and orchestration patterns; 2) standardized composition schemas that offer consistent formats for composable data types and models, fostering robust infrastructure for a registry of simulation modules that can be flexibly assembled; 3) a foundational set of biological templates-schemas for cellular and molecular interfaces, which can be filled with detailed submodels and datasets, and are designed to integrate knowledge that sheds light on the molecular emergence of cells; and 4) scientific collaboration facilitated by user-friendly interfaces for connecting researchers with datasets and models, and which allows a community of researchers to effectively build integrative multiscale models of cellular systems.

Soft condensed matter is challenging to study due to the vast time and length scales that are necessary to accurately represent complex systems and capture their underlying physics. Multiscale simulations are necessary to study processes that have disparate time and/or length scales, which abound throughout biology and other complex systems. Herein we present ezAlign, an open-source software for converting coarse-grained molecular dynamics structures to atomistic representation, allowing multiscale modeling of biomolecular systems. The ezAlign v1.1 software package is publicly available for download at github.com/LLNL/ezAlign. Its underlying methodology is based on a simple alignment of an atomistic template molecule, followed by position-restraint energy minimization, which forces the atomistic molecule to adopt a conformation consistent with the coarse-grained molecule. The molecules are then combined, solvated, minimized, and equilibrated with position restraints. Validation of the process was conducted on a pure POPC membrane and compared with other popular methods to construct atomistic membranes. Additional examples, including surfactant self-assembly, membrane proteins, and more complex bacterial and human plasma membrane models, are also presented. By providing these examples, parameter files, code, and an easy-to-follow recipe to add new molecules, this work will aid future multiscale modeling efforts.

Meeting food safety requirements without jeopardizing quality attributes or sustainability involves adopting a holistic perspective of food products, their manufacturing processes and their storage and distribution practices. The virtualization of the food supply chain offers opportunities to evaluate, simulate, and predict challenges and mishaps potentially contributing to present and future food safety risks. Food systems virtualization poses several requirements: (1) a comprehensive framework composed of instrumental, digital, and computational methods to evaluate internal and external factors that impact food safety; (2) nondestructive and real-time sensing methods, such as spectroscopic-based techniques, to facilitate mapping and tracking food safety and quality indicators; (3) a dynamic platform supported by the Internet of Things (IoT) interconnectivity to integrate information, perform online data analysis and exchange information on product history, outbreaks, exposure to risky situations, etc.; and (4) comprehensive and complementary mathematical modeling techniques (including but not limited to chemical reactions and microbial inactivation and growth kinetics) based on extensive data sets to make realistic simulations and predictions possible. Despite current limitations in data integration and technical skills for virtualization to reach its full potential, its increasing adoption as an interactive and dynamic tool for food systems evaluation can improve resource utilization and rational design of products, processes and logistics for enhanced food safety. Virtualization offers affordable and reliable options to assist stakeholders in decision-making and personnel training. This chapter focuses on definitions and requirements for developing and applying virtual food systems, including digital twins, and their role and future trends in enhancing food safety.

Pulmonary hypertension (PH) is a debilitating disease that alters the structure and function of both the proximal and distal pulmonary vasculature. This alters pressure-flow relationships in the pulmonary arterial and venous trees, though there is a critical knowledge gap in the relationships between proximal and distal hemodynamics in disease. Multiscale computational models enable simulations in both the proximal and distal vasculature. However, model inputs and measured data are inherently uncertain, requiring a full analysis of the sensitivity and uncertainty of the model. Thus, this study quantifies model sensitivity and output uncertainty in a spatially multiscale, pulse-wave propagation model of pulmonary hemodynamics. The model includes fifteen proximal arteries and twelve proximal veins, connected by a two-sided, structured tree model of the distal vasculature. We use polynomial chaos expansions to expedite sensitivity and uncertainty quantification analyses and provide results for both the proximal and distal vasculature. We quantify uncertainty in blood pressure, blood flow rate, wave intensity, wall shear stress, and cyclic stretch. The latter two are important stimuli for endothelial cell mechanotransduction. We conclude that, while nearly all the parameters in our system have some influence on model predictions, the parameters describing the density of the microvascular beds have the largest effects on all simulated quantities in both the proximal and distal arterial and venous circulations.

CFRP hybrid bonded-bolted (HBB) joints combine the advantages of traditional joining methods, namely adhesive bonding, and bolting, to achieve optimal connection performance, making them the most favored connection method. The structural parameters of CFRP HBB joints, including overlap length, bolt-hole spacing, and fit clearance relationships, have a complex impact on connection performance. To enhance the connectivity performance of joint structures, this paper develops a multiscale finite element analysis model to investigate the impact of structural parameters on the strength of CFRP HBB joint structures. Coupled with experimental validation, the study reveals how changes in structural parameters affect the unidirectional tensile failure force of the joints. Building on this, an analytical approach and inverse design methodology for the mechanical properties of CFRP HBB joints based on deep supervised learning algorithms are developed. Neural networks accurately and efficiently predict the performance of joints with unprecedented combinations of parameters, thus expediting the inverse design process. This research combines experimentation and multiscale finite element analysis to explore the unknown relationships between the mechanical properties of CFRP HBB joints and their structural parameters. Furthermore, leveraging DNN neural networks, a rapid calculation method for the mechanical properties of hybrid joints is proposed. The findings lay the groundwork for the broader application and more intricate design of composite materials and their connection structures.